Assessment of the quality and content of clinical practice guidelines (CPGs) for vitamin D and for immigrants using the AGREE-II instrument: a protocol for systematic review.

INTRODUCTION: Worldwide, more immigrants experience vitamin D (vitD) deficiency than non-immigrants, which is attributed to ethnic variations, place or region of birth, skin pigmentation, clothing style, and resettlement-related changes in diet, physical activity, and sun exposure. Current recommendations in clinical practice guidelines (CPGs) concerning vitD are inadequate to address vitD deficiency among immigrants. CPGs may also lack guidance for physicians on vitD supplementation for immigrants. Moreover, there are concerns about the overall quality of these CPGs. OBJECTIVES: This systematic review will collate and critically appraise CPGs relevant to immigrants' health and vitD. Moreover, we will evaluate whether the CPGs of vitD including recommendations for immigrants and clarify whether the CPGs of immigrants include recommendations on vitD. METHODS: A systematic search of Ovid MEDLINE® ALL, EMBASE, and Turning Research Into Practice (TRIP) electronic databases, guideline repositories, and gray literature will be conducted to identify relevant CPGs. Two reviewers will independently evaluate the methodological quality of the retrieved guidelines using the Appraisal of Guidelines, Research, and Evaluation-II (AGREE-II) instrument. CPGs scoring ≥60% in at least four domains, including "rigor of development," will be considered high quality. CONCLUSION: Evaluating the quality and content of relevant CPGs may support researchers in developing national and global guidelines for immigrants. Furthermore, it may support vitD testing, nutritional counseling, and supplementation for vulnerable immigrant sub-populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021240562.

Catheter Ablation of Low-Voltage Areas for Persistent Atrial Fibrillation: Procedural Outcomes Using High-Density Voltage Mapping.

BACKGROUND: Several approaches have been proposed to address the challenge of catheter ablation of persistent atrial fibrillation (AF). However, the optimal ablation strategy is unknown. We sought to evaluate the efficacy of pulmonary vein isolation (PVI) plus low-voltage area (LVA) ablation using contemporary high-density mapping to identify LVA in patients with persistent AF. METHODS: Consecutive patients accepted for AF catheter ablation were studied. High-density bipolar voltage mapping data were acquired in sinus rhythm using multipolar catheters to detect LVA (defined as bipolar voltage < 0.5 mV). Semiautomated impedance-based software was used to ensure catheter contact during data collection. Patients underwent PVI + LVA ablation (if LVA present). RESULTS: A total of 145 patients were studied; 95 patients undergoing PVI + LVA ablation were compared with 50 controls treated with PVI only. Average age was 61 ± 10 years, and 80% were male. Baseline characteristics were comparable. Freedom from atrial tachycardia/AF at 18 months was 72% after PVI + LVA ablation vs 58% in controls (P = 0.022). Median procedure duration (273 [240, 342] vs 305 [262, 360] minutes; P = 0.019) and radiofrequency delivery (50 [43, 63] vs 55 [35, 68] minutes; P = 0.39) were longer in the PVI + LVA ablation group. Multivariable analysis showed that the ablation strategy (PVI + LVA) was the only independent predictor of freedom from atrial tachycardia/AF (hazard ratio, 0.53; 95% confidence interval, 0.29-0.96; P = 0.036). There were no adverse safety outcomes associated with LVA ablation. CONCLUSIONS: An individualized strategy of high-density mapping to assess the atrial substrate followed by PVI combined with LVA ablation is associated with improved outcomes. Adequately powered randomized clinical trials are needed to determine the role of PVI + LVA ablation for persistent AF.

Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews.

The Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: "physical function," "pain," "spinal mobility," "spinal stiffness," and "patient's global assessment" (PGA). The core set for clinical record keeping further includes the domains "peripheral joints/entheses" and "acute phase reactants," and the core set for DC-ART further includes the domains "fatigue" and "spine radiographs/hip radiographs." The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998.Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [OR], dependent variable) across all trials.Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and "missing data") should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.

Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Neurologists' perspectives on medical cannabis for pediatric drug-resistant epilepsy in Canada: A qualitative interview study.

PURPOSE: To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy. METHODS: In this qualitative study, we interviewed neurologists who provide care to children with drug-resistant epilepsy in Canada. Through semi-structured telephone interviews, we sought participants' views about and experiences with medical cannabis for the treatment of drug-resistant epilepsy in children. Here we present a thematic summary of the interviews. RESULTS: The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children's care, including medical cannabis, others referred interested families to non-neurology health care professionals. CONCLUSION: Our findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, in order to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.

Cannabis-based products for pediatric epilepsy: An updated systematic review.

PURPOSE: To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children. METHODS: We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits. RESULTS: Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events. CONCLUSION: Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy. PROSPERO: CRD42018084755.

Tai Chi for rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, autoimmune disease that results in joint deformity and immobility of the musculoskeletal system. The major goals of treatment are to relieve pain, reduce inflammation, slow down or stop joint damage, prevent disability, and preserve or improve the person's sense of well-being and ability to function. Tai Chi, interchangeably known as Tai Chi Chuan, is an ancient Chinese health-promoting martial art form that has been recognized in China as an effective arthritis therapy for centuries. This is an update of a review published in 2004. OBJECTIVES: To assess the benefits and harms of Tai Chi as a treatment for people with rheumatoid arthritis (RA). SEARCH METHODS: We updated the search of CENTRAL, MEDLINE, Embase, and clinical trial registries from 2002 to September 2018. SELECTION CRITERIA: We selected randomized controlled trials and controlled clinical trials examining the benefits (ACR improvement criteria or pain, disease progression, function, and radiographic progression), and harms (adverse events and withdrawals) of exercise programs with Tai Chi instruction or incorporating principles of Tai Chi philosophy. We included studies of any duration that included control groups who received either no therapy or alternate therapy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Adding three studies (156 additional participants) to the original review, this update contains a total of seven trials with 345 participants. Participants were mostly women with RA, ranging in age from 16 to 80 years, who were treated in outpatient settings in China, South Korea, and the USA. The majority of the trials were at high risk of bias for performance and detection bias, due to the lack of blinding of participants or assessors. Almost 75% of the studies did not report random sequence generation, and we judged the risk of bias as unclear for allocation concealment in the majority of studies. The duration of the Tai Chi programs ranged from 8 to 12 weeks.It is uncertain whether Tai Chi-based exercise programs provide a clinically important improvement in pain among Tai Chi participants compared to no therapy or alternate therapy. The change in mean pain in control groups, measured on visual analog scale (VAS 0 to 10 score, reduced score means less pain) ranged from a decrease of 0.51 to an increase of 1.6 at 12 weeks; in the Tai Chi groups, pain was reduced by a mean difference (MD) of -2.15 (95% confidence interval (CI) -3.19 to -1.11); 22% absolute improvement (95% CI, 11% to 32% improvement); 2 studies, 81 participants; very low-quality evidence, downgraded for imprecision, blinding and attrition bias.There was very low-quality evidence, downgraded for, blinding, and attrition, that was inconclusive for an important difference in disease activity, measured using Disease Activity Scale (DAS-28-ESR) scores (0 to 10 scale, lower score means less disease activity), with no change in the control group and 0.40 reduction (95% CI -1.10 to 0.30) with Tai Chi; 4% absolute improvement (95% CI 11% improvement to 3% worsening); 1 study, 43 participants.For the assessment of function, the change in mean Health Assessment Questionnaire (HAQ; 0 to 3 scale, lower score means better function) ranged from 0 to 0.1 in the control group, and reduced by MD 0.33 in the Tai Chi group (95% CI -0.79 to 0.12); 11% absolute improvement (95% CI 26% improvement to 4% worsening); 2 studies, 63 participants; very low-quality evidence, downgraded for imprecision, blinding, and attrition. We are unsure of an important improvement, as the results were inconclusive.Participants in Tai Chi programs were less likely than those in a control group to withdraw from studies at 8 to 12 weeks (19/180 in intervention groups versus 49/165 in control groups; risk ratio (RR) 0.40 (95% CI 0.19 to 0.86); absolute difference 17% fewer (95% CI 30% fewer to 3% fewer); 7 studies, 289 participants; low-quality evidence, downgraded for imprecision and blinding.There were no data available for radiographic progression. Short-term adverse events were not reported by group, but in two studies there was some narrative description of joint and muscle soreness and cramps; long-term adverse events were not reported. AUTHORS' CONCLUSIONS: It is uncertain whether Tai Chi has any effect on clinical outcomes (joint pain, activity limitation, function) in RA, and important effects cannot be confirmed or excluded, since all outcomes had very low-quality evidence. Withdrawals from study were greater in the control groups than the Tai Chi groups, based on low-quality evidence. Although the incidence of adverse events is likely to be low with Tai Chi, we are uncertain, as studies failed to explicitly report such events. Few minor adverse events (joint and muscle soreness and cramps) were described qualitatively in the narrative of two of the studies. This updated review provides minimal change in the conclusions from the previous review, i.e. a pain outcome.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

BACKGROUND: Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. METHODS: We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. DISCUSSION: Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no.: CRD42018099591 .

Cannabis-based products for pediatric epilepsy: A systematic review.

OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Calcium channel blockers for primary and secondary Raynaud's phenomenon.

BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I² = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I² = 77%).Low-quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to -8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD -1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported.

Methodological Rigor in Preclinical Cardiovascular Studies: Targets to Enhance Reproducibility and Promote Research Translation.

RATIONALE: Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments. OBJECTIVE: To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research. METHODS AND RESULTS: All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months. CONCLUSIONS: Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.

The Ottawa panel clinical practice guidelines for the management of knee osteoarthritis. Part one: introduction, and mind-body exercise programs.

OBJECTIVE: To identify effective mind-body exercise programs and provide clinicians and patients with updated, high-quality recommendations concerning non-traditional land-based exercises for knee osteoarthritis. METHODS: A systematic search and adapted selection criteria included comparative controlled trials with mind-body exercise programs for patients with knee osteoarthritis. A panel of experts reached consensus on the recommendations using a Delphi survey. A hierarchical alphabetical grading system (A, B, C+, C, D, D+, D-) was used, based on statistical significance ( P < 0.5) and clinical importance (⩾15% improvement). RESULTS: The four high-quality studies identified demonstrated that various mind-body exercise programs are promising for improving the management of knee osteoarthritis. Hatha Yoga demonstrated significant improvement for pain relief (Grade B) and physical function (Grade C+). Tai Chi Qigong demonstrated significant improvement for quality of life (Grade B), pain relief (Grade C+) and physical function (Grade C+). Sun style Tai Chi gave significant improvement for pain relief (Grade B) and physical function (Grade B). CONCLUSION: Mind-body exercises are promising approaches to reduce pain, as well as to improve physical function and quality of life for individuals with knee osteoarthritis.

Mass deworming to improve developmental health and wellbeing of children in low-income and middle-income countries: a systematic review and network meta-analysis.

BACKGROUND: Soil-transmitted helminthiasis and schistosomiasis, considered among the neglected tropical diseases by WHO, affect more than a third of the world's population, with varying intensity of infection. We aimed to evaluate the effects of mass deworming for soil-transmitted helminths (with or without deworming for schistosomiasis or co-interventions) on growth, educational achievement, cognition, school attendance, quality of life, and adverse effects in children in endemic helminth areas. METHODS: We searched 11 databases up to Jan 14, 2016, websites and trial registers, contacted authors, and reviewed reference lists. We included studies published in any language of children aged 6 months to 16 years, with mass deworming for soil-transmitted helminths or schistosomiasis (alone or in combination with other interventions) for 4 months or longer, that reported the primary outcomes of interest. We included randomised and quasi-randomised trials, controlled before-after studies, interrupted time series, and quasi-experimental studies. We screened in duplicate, then extracted data and appraised risk of bias in duplicate with a pre-tested form. We conducted random-effects meta-analysis and Bayesian network meta-analysis. FINDINGS: We included 52 studies of duration 5 years or less with 1 108 541 children, and four long-term studies 8-10 years after mass deworming programmes with more than 160 000 children. Overall risk of bias was moderate. Mass deworming for soil-transmitted helminths compared with controls led to little to no improvement in weight over a period of about 12 months (0·99 kg, 95% credible interval [CrI] -0·09 to 0·28; moderate certainty evidence) or height (0·07 cm, 95% CrI -0·10 to 0·24; moderate certainty evidence), little to no difference in proportion stunted (eight fewer per 1000 children, 95% CrI -48 to 32; high certainty evidence), cognition measured by short-term attention (-0·23 points on a 100 point scale, 95% CI -0·56 to 0·14; high certainty evidence), school attendance (1% higher, 95% CI -1 to 3; high certainty evidence), or mortality (one fewer per 1000 children, 95% CI -3 to 1; high certainty evidence). We found no data on quality of life and little evidence of adverse effects. Mass deworming for schistosomiasis might slightly increase weight (0·41 kg, 95% CrI -0·20 to 0·91) and has little to no effect on height (low certainty evidence) and cognition (moderate certainty evidence). Our analyses do not suggest indirect benefits for untreated children from being exposed to treated children in the community. We are uncertain about effects on long-term economic productivity (hours worked), cognition, literacy, and school enrolment owing to very low certainty evidence. Results were consistent across sensitivity and subgroup analyses by age, worm prevalence, baseline nutritional status, infection status, impact on worms, infection intensity, types of worms (ascaris, hookworm, or trichuris), risk of bias, cluster versus individual trials, compliance, and attrition. INTERPRETATION: Mass deworming for soil-transmitted helminths with or without deworming for schistosomiasis had little effect. For schistosomiasis, mass deworming might be effective for weight but is probably ineffective for height, cognition, and attendance. Future research should assess which subset of children do benefit from mass deworming, if any, using individual participant data meta-analysis. FUNDING: Canadian Institutes of Health Research and WHO.

Effects of aerobic training, resistance training, or both on psychological health in adolescents with obesity: The HEARTY randomized controlled trial.

OBJECTIVE: To determine the effects of aerobic training, resistance training, and combined training on mood, body image, and self-esteem in adolescents with obesity. METHOD: After a 4-week prerandomization treatment, 304 postpubertal adolescents (91 males, 213 females) with obesity ages 14-18 years were randomized to 1 of 4 groups for 22 weeks: aerobic training (n = 75), resistance training (n = 78), combined aerobic and resistance training (n = 75), or nonexercising control (n = 76). All participants received dietary counseling, with a daily energy deficit of 250 kcal. Mood was measured using the Brunel Mood Scale. Body image was assessed using the Multiple Body Self-Relations Questionnaire, and physical self-perceptions and global self-esteem were measured using the Harter Physical Self-Perceptions Questionnaire. RESULTS: Median adherence was 62%, 56%, and 64% in aerobic, resistance, and combined training, respectively. Resistance and combined training produced greater improvements than control on vigor, and resistance training reduced depressive symptoms. All groups improved on body image and physical self-perceptions, but combined showed greater increases than control on perceived physical conditioning, while only resistance training showed greater increases than controls on global self-esteem. Both combined and resistance training demonstrated greater increases in perceived strength than control. Psychological benefits were more related to better adherence and reductions in body fat than changes in strength or fitness. CONCLUSION: Resistance training, alone or in combination with aerobic training, may provide psychological benefits in adolescents with overweight or obesity, and therefore could be an alternative to aerobic training for some individuals in the biological and psychological management of adolescent obesity.

A prospective placebo controlled randomized study of caffeine in patients with supraventricular tachycardia undergoing electrophysiologic testing.

INTRODUCTION: Patients with cardiac arrhythmias are generally instructed to avoid caffeine intake. A comprehensive evaluation of the electrophysiological effects of caffeine on atrial and ventricular tissues in humans has not previously been performed. METHODS AND RESULTS: Eighty patients (31 men, mean age 49 ± 14 years) with symptomatic supraventricular tachycardia (SVT) undergoing an electrophysiologic study (EPS) prior to catheter ablation were randomized to receive oral caffeine or placebo. Caffeine at a dosage of 5 mg/kg (moderate intake) or placebo tablets were administered orally at a mean time of 57 ± 13 minutes prior to the EPS. The median (IQR) caffeine level in patients receiving caffeine was 7.4 µg/mL (4.7-8.7), as compared with 0.15 (0.00-0.61) in patients receiving placebo, P < 0.0001. Caffeine was associated with a significant increase in resting systolic and diastolic blood pressures as compared with placebo, while the resting heart rate was not significantly different between both groups. Caffeine was not associated with significant effects on the effective refractory period of the atrium or ventricle, as well as on AV node conduction. SVT was induced in all but 3 patients; there was no significant difference between groups receiving placebo or caffeine on SVT inducibility or the cycle length of induced tachycardias. CONCLUSIONS: Caffeine, at moderate intake, was associated with significant increases in systolic and diastolic blood pressures, but had no evidence of a significant effect on cardiac conduction and refractoriness. Furthermore, no effect of caffeine on SVT induction or more rapid rates of induced tachycardias was found.

Deep transverse friction massage for treating lateral elbow or lateral knee tendinitis.

Background Deep transverse friction massage, one of several physical therapy interventions suggested for the management of tendinitis pain, was first demonstrated in the 1930s by Dr James Cyriax, a renowned orthopedic surgeon in England. Its goal is to prevent abnormal fibrous adhesions and abnormal scarring. This is an update of a Cochrane review first published in 2001.Objectives To assess the benefits and harms of deep transverse friction massage for treating lateral elbow or lateral knee tendinitis.Search methods We searched the following electronic databases: the specialized central registry of the Cochrane Field of Physical and Related Therapies,the Cochrane Central Register of Controlled Trials (CENTRAL),MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Clinicaltrials.gov, and the Physiotherapy Evidence Database (PEDro), up until July 2014. The reference lists of these trials were consulted for additional studies.Selection criteria All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing deep transverse friction massage with control or other active interventions for study participants with two eligible types of tendinitis (ie, extensor carpi radialis tendinitis (lateral elbow tendinitis, tennis elbow or lateral epicondylitis or lateralis epicondylitis humeri) and iliotibial band friction syndrome (lateral knee tendinitis)) were selected. Only studies published in English and French languages were included.Data collection and analysis Two review authors independently assessed the studies on the basis of inclusion and exclusion criteria. Results of individual trials were extracted from the included study using extraction forms prepared by two independent review authors before the review was begun.Data were cross-checked by a third review author. Risk of bias of the included studies was assessed using the "Risk of bias"tool of The Cochrane Collaboration. A pooled analysis was performed using mean difference (MD) for continuous outcomes and risk ratio (RR)for dichotomous outcomes with 95% confidence intervals (CIs).Main results Two RCTs (no new additional studies in this update) with 57 participants met the inclusion criteria. These studies demonstrated high risk of performance and detection bias, and the risk of selection, attrition, and reporting bias was unclear.The first study included 40 participants with lateral elbow tendinitis and compared (1) deep transverse friction massage combined with therapeutic ultrasound and placebo ointment (n = 11) versus therapeutic ultrasound and placebo ointment only (n = 9) and (2)deep transverse friction massage combined with phonophoresis (n = 10) versus phonophoresis only (n = 10). No statistically significant differences were reported within five weeks for mean change in pain on a 0 to 100 visual analog scale (VAS) (MD -6.60, 95%CI -28.60 to 15.40; 7% absolute improvement), grip strength measured in kilograms of force (MD 0.10, 95% CI -0.16 to 0.36) and function ona 0 to 100 VAS (MD -1.80, 95% CI -0.18.64 to 15.04; 2% improvement), pain-free function index measured as the number of painfree items (MD 1.10, 95% CI -1.00 to 3.20) and functional status (RR 3.3, 95% CI 0.4 to 24.3) for deep transverse friction massage,and therapeutic ultrasound and placebo ointment compared with therapeutic ultrasound and placebo ointment only. Likewise for deep transverse friction massage and phonophoresis compared with phonophoresis alone, no statistically significant differences were found for pain (MD -1.2, 95% CI -20.24 to 17.84; 1% improvement), grip strength (MD -0.20, 95% CI -0.46 to 0.06) and function (MD3.70, 95% CI -14.13 to 21.53; 4% improvement). In addition, the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach was used to evaluate the quality of evidence for the pain outcome, which received a score of "very low".Pain relief of 30% or greater, quality of life, patient global assessment, adverse events, and withdrawals due to adverse events were not assessed or reported.The second study included 17 participants with iliotibial band friction syndrome (knee tendinitis) and compared deep transverse friction massage with physical therapy intervention versus physical therapy intervention alone, at two weeks. Deep transverse friction massage with physical therapy intervention showed no statistically significant differences in the three measures of pain relief on a 0 to 10 VAS when compared with physical therapy alone: daily pain (MD -0.40, 95% CI -0.80 to -0.00; absolute improvement 4%), pain while running (scale from 0 to 150) (MD -3.00, 95% CI -11.08 to 5.08), and percentage of maximum pain while running (MD -0.10, 95% CI -3.97 to 3.77). For the pain outcome, absolute improvement showed a 4% reduction in pain. However, the quality of the body of evidence received a grade of "very low."Pain relief of 30% or greater, function, quality of life, patient global assessment of success, adverse events, and withdrawals due to adverse events were not assessed or reported.Authors' conclusions We do not have sufficient evidence to determine the effects of deep transverse friction on pain, improvement in grip strength, and functional status for patients with lateral elbow tendinitis or knee tendinitis, as no evidence of clinically important benefits was found.The confidence intervals of the estimate of effects overlapped the null value for deep transverse friction massage in combination with physical therapy compared with physical therapy alone in the treatment of lateral elbow tendinitis and knee tendinitis. These conclusions are limited by the small sample size of the included randomized controlled trials. Future trials, utilizing specific methods and adequate sample sizes, are needed before conclusions can be drawn regarding the specific effects of deep transverse friction massage on lateral elbow tendinitis.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

OBJECTIVE: To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001]. CONCLUSION: The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.

Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

BACKGROUND: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. OBJECTIVES: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. SEARCH METHODS: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. SELECTION CRITERIA: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly). DATA COLLECTION AND ANALYSIS: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. MAIN RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). AUTHORS' CONCLUSIONS: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation.

OBJECTIVES: The primary objective was to assess the cost-effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagulants stratified by center-specific time in therapeutic range, age, and CHADS2 score. METHODS: Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Analysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta-analysis. Utility values and costs were obtained from published data. Numerous deterministic sensitivity analyses and probabilistic analysis were conducted. RESULTS: The incremental cost per QALY gained for dabigatran 150 mg versus warfarin was $20,797. Apixaban produced equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban were dominated by dabigatran 150 mg and apixaban. Results were sensitive to the drug costs of apixaban, the time horizon adopted, and the consequences from major and minor bleeds with dabigatran. Results varied by a center's average time in therapeutic range, a patient's CHADS2 score, and patient age, with either dabigatran 150 mg or apixaban being optimal. CONCLUSIONS: Results were highly sensitive to patient characteristics. Rivaroxaban and dabigatran 110 mg were unlikely to be cost-effective. For different characteristics, apixaban or dabigatran 150 mg were optimal. Thus, the choice between these two options may come down to the price of apixaban and further evidence on the impact of major and minor bleeds with dabigatran.

WITHDRAWN: Therapeutic ultrasound for treating patellofemoral pain syndrome.

BACKGROUND: Therapeutic ultrasound is one of several rehabilitation interventions suggested for the management of pain due to patellofemoral knee pain syndrome. OBJECTIVES: To assess the effectiveness and side effects of ultrasound therapy for treating patellofemoral knee pain syndrome. SEARCH METHODS: We searched the Cochrane Musculoskeletal Review Group register, Cochrane Field of Physical and Related Therapies register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, HealthSTAR, Sports Discus, CINAHL,and PEDro databases (to December 2000) according to the sensitive search strategy for RCTs designed for the Cochrane Collaboration. The search was complemented with handsearching of the reference lists. Key experts in the area were contacted for any further articles. SELECTION CRITERIA: All randomized controlled trials (RCTs), controlled clinical trials (CCTs), case-control and cohort studies comparing therapeutic ultrasound against placebo or another active intervention in people with patellofemoral pain syndrome were selected according to an a priori protocol. DATA COLLECTION AND ANALYSIS: Two reviewers determined the studies to be included based on a priori inclusion criteria. Data were independently extracted by the same two reviewers and checked by a third reviewer (BS) using a previously developed form. The same two reviewers independently assessed the methodological quality of the RCTs and CCTs using a validated scale. The data analysis was performed using Peto odds ratios. MAIN RESULTS: The search retrieved 85 articles. Of the eight that were potentially relevant, only one RCT, including 53 participants with patellofemoral pain syndrome, was identified for this review. All participants received an exercise program as concurrent therapy. Ultrasound combined with ice massage contrast (n of 13), where n equals the number of participants, was not statistically different from ice massage alone (n = 16) in terms of participant-rated pain relief or quadriceps and hamstring strengthening. In the ultrasound and ice massage group, 46% (6 of 13) reported improved pain relief compared to 31% (4 of 13) in the ice massage alone group. This difference of 15% does not meet international standards for clinically important improvements in osteoarthritis, which is 20%. Side effects were not reported. AUTHORS' CONCLUSIONS: Ultrasound therapy was not shown to have a clinically important effect on pain relief for people with patellofemoral pain syndrome. These conclusions are limited by the poor reporting of the therapeutic application of the ultrasound and low methodological quality of the one trial included. No conclusions can be drawn concerning the use, or non-use, of ultrasound for treating patellofemoral pain syndrome. More well-designed studies are needed.