Comparison of seven popular structured dietary programmes and risk of mortality and major cardiovascular events in patients at increased cardiovascular risk: systematic review and network meta-analysis.

OBJECTIVE: To determine the relative efficacy of structured named diet and health behaviour programmes (dietary programmes) for prevention of mortality and major cardiovascular events in patients at increased risk of cardiovascular disease. DESIGN: Systematic review and network meta-analysis of randomised controlled trials. DATA SOURCES: AMED (Allied and Complementary Medicine Database), CENTRAL (Cochrane Central Register of Controlled Trials), Embase, Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and ClinicalTrials.gov were searched up to September 2021. STUDY SELECTION: Randomised trials of patients at increased risk of cardiovascular disease that compared dietary programmes with minimal intervention (eg, healthy diet brochure) or alternative programmes with at least nine months of follow-up and reporting on mortality or major cardiovascular events (such as stroke or non-fatal myocardial infarction). In addition to dietary intervention, dietary programmes could also include exercise, behavioural support, and other secondary interventions such as drug treatment. OUTCOMES AND MEASURES: All cause mortality, cardiovascular mortality, and individual cardiovascular events (stroke, non-fatal myocardial infarction, and unplanned cardiovascular interventions). REVIEW METHODS: Pairs of reviewers independently extracted data and assessed risk of bias. A random effects network meta-analysis was performed using a frequentist approach and grading of recommendations assessment, development and evaluation (GRADE) methods to determine the certainty of evidence for each outcome. RESULTS: 40 eligible trials were identified with 35 548 participants across seven named dietary programmes (low fat, 18 studies; Mediterranean, 12; very low fat, 6; modified fat, 4; combined low fat and low sodium, 3; Ornish, 3; Pritikin, 1). At last reported follow-up, based on moderate certainty evidence, Mediterranean dietary programmes proved superior to minimal intervention for the prevention of all cause mortality (odds ratio 0.72, 95% confidence interval 0.56 to 0.92; patients at intermediate risk: risk difference 17 fewer per 1000 followed over five years), cardiovascular mortality (0.55, 0.39 to 0.78; 13 fewer per 1000), stroke (0.65, 0.46 to 0.93; 7 fewer per 1000), and non-fatal myocardial infarction (0.48, 0.36 to 0.65; 17 fewer per 1000). Based on moderate certainty evidence, low fat programmes proved superior to minimal intervention for prevention of all cause mortality (0.84, 0.74 to 0.95; 9 fewer per 1000) and non-fatal myocardial infarction (0.77, 0.61 to 0.96; 7 fewer per 1000). The absolute effects for both dietary programmes were more pronounced for patients at high risk. There were no convincing differences between Mediterranean and low fat programmes for mortality or non-fatal myocardial infarction. The five remaining dietary programmes generally had little or no benefit compared with minimal intervention typically based on low to moderate certainty evidence. CONCLUSIONS: Moderate certainty evidence shows that programmes promoting Mediterranean and low fat diets, with or without physical activity or other interventions, reduce all cause mortality and non-fatal myocardial infarction in patients with increased cardiovascular risk. Mediterranean programmes are also likely to reduce stroke risk. Generally, other named dietary programmes were not superior to minimal intervention. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016047939.

Integrative physiology and traditional naturopathic practice: Results of an international observational study.

BACKGROUND: Naturopathy is one of seven distinct traditional medical systems acknowledged by the World Health Organization. Naturopathic principles and philosophies encourage a focus on multiple body systems during case-taking and the design of treatments. Little is known about whether such teaching translates into practice. This study aimed to characterise naturopathic practice as it relates to the identification of multiple physiological systems in the diagnosis and treatment of patients. METHODS: A cross sectional study was conducted in collaboration with the World Naturopathic Federation. A survey capturing clinical diagnostic and treatment considerations for up to 20 consecutive patients was administered to naturopaths in 14 countries. RESULTS: Naturopaths (n = 56) were mostly female (62.5%), aged between 36 and 45 years (37.5%), in practice for 5-10 years (44.6%), and consulting between 11 and 20 patients per week (35.7%). Participants completed the survey for 851 patient cases. Naturopaths reported a greater number of physiological systems relevant to clinical cases where the patients were working age (18-65 years) (IRR 1.3, p = .042), elderly (65 years and over) (IRR 1.4, p = .046), or considered by the naturopath to have a chronic health condition (IRR 1.2, p = .003). The digestive system was weakly associated with patients based on chronicity of the health complaint (V = .1149, p = .004), or having a musculoskeletal complaint (V = .1067, p = .002) autoimmune pathophysiology (V = .1681, p < .001), and considered relevant in respiratory (V = .1042, p = .002), endocrine (V = .1023, p = .003), female reproductive (V = .1009, p = .003), and integumentary (V = .1382, p < .001) systems. CONCLUSION: Naturopaths across the world adopt an integrative physiological approach to the diagnosis and treatment of chronic and complex health care complaints..

Western herbal medicines in the treatment of irritable bowel syndrome: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of Western herbal medicines in the treatment of irritable bowel syndrome (IBS). DESIGN: A computer-based search of MEDLINE, EMBASE, CINAHL, AMED, GreenFILE, Health Source: Nursing/Academic Edition, and the Cochrane Library was conducted. A hand-search of the bibliographies of relevant papers and previous meta-analyses and reviews was also undertaken. Trials were included in the review if they were double-blind and placebo-controlled investigating the effects of Western herbal medicines on IBS-related symptoms or quality of life. There were no language restrictions. Eligibility assessment and data extraction were performed by two independent researchers. For herbal medicines where there was more than 1 trial of similar design, data were synthesised using relative risk of symptoms improving using the random effects model. RESULTS: Thirty-three trials were identified that met all eligibility criteria. Seventeen of these evaluated peppermint essential oil, fifteen other Western herbal medicines, and one trial evaluated peppermint oil in one arm and aniseed essential oil in the other arm. Eighteen different herbal preparations were evaluated in these trials. Data suggests that a number of Western herbal medicines may provide relief of IBS symptoms. Meta-analyses suggest that peppermint essential oil is both efficacious and well-tolerated in the short-term management of IBS. Aloe vera and asafoetida also demonstrated efficacy in reducing global IBS symptoms in meta-analyses. The herbal formulas STW 5, STW 5-II and Carmint, along with Ferula assa-foetida, Pimpenella anisum oil, the combination of Curcumin and Foeniculum vulgare oil, and the blend of Schinopsis lorentzii, Aesculus hippocastanum, and peppermint essential oil also demonstrated efficacy in rigorously-designed clinical trials. CONCLUSION: A number of Western herbal medicines show promise in the treatment of IBS. With the exception of peppermint essential oil, Aloe vera, and asafoetida, however, none of the positive trials have been replicated. This lack of replication limits the capacity to make definitive statements of efficacy for these herbal medicines.

Biofeedback for treatment of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a prevalent condition that currently lacks highly effective therapies for its management. Biofeedback has been proposed as a therapy that may help individuals learn to exert conscious control over sympatho-vagal balance as an indirect method of symptom management. OBJECTIVES: Our primary objective was to assess the efficacy and safety of biofeedback-based interventions for IBS in adults and children. SEARCH METHODS: We searched the Cochrane Inflammatory Bowel Disease (IBD) Group Specialized Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Allied and Complementary Medicine Database (AMED) from inception to 24 July 2019. We also searched reference lists from published trials, trial registries, device manufacturers, conference proceedings, theses, and dissertations. SELECTION CRITERIA: We judged randomized controlled trials to be eligible for inclusion if they met the Association for Applied Psychophysiology and Biofeedback definition of biofeedback, and if they compared a biofeedback intervention to an active, sham, or no-treatment control for the management of IBS. DATA COLLECTION AND ANALYSIS: Two authors independently screened trials for inclusion, extracted data, and assessed risk of bias. Primary outcomes were IBS global or clinical improvement scores and overall quality of life measures. Secondary outcome measures were adverse events, assessments of stool frequency and consistency, changes in abdominal pain, depression, and anxiety. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference (MD) and 95% CI. We used GRADE criteria to assess the overall certainty of the evidence. MAIN RESULTS: We identified eight randomized trials with a total of 300 adult participants for our analysis. We did not identify any trials in children. Four trials assessed thermal biofeedback. One trial assessed rectosigmoidal biofeedback. Two trials assessed heart rate variability biofeedback. Two trials assessed electrocutaneous biofeedback. Comparators were: no treatment (symptom monitoring group; three studies), attention control (pseudomeditation; two studies), relaxation control (one study), counseling (two studies), hypnotherapy (one study), standard therapy (one study), and sham biofeedback (one study). We judged all trials to have a high or unclear risk of bias. Global/Clinical improvement The clinical benefit of biofeedback plus standard therapy compared to standard therapy alone was uncertain (RR 4.20, 95% CI 1.40 to 12.58; 1 study, 20 participants; very low-certainty evidence). The same study also compared biofeedback plus standard therapy to sham biofeedback plus standard therapy. The clinical benefit in the biofeedback group was uncertain (RR 2.33, 95% CI 1.13 to 4.80; 1 study, 20 participants; very low-certainty evidence). The clinical benefit of heart rate biofeedback compared to hypnotherapy was uncertain when measured with the IBS severity scoring system (IBS-SSS) (MD -58.80, 95% CI -109.11 to -8.49; 1 study, 61 participants; low-certainty evidence). Compared to counseling, the effect of heart rate biofeedback was unclear when measured with a composite symptom reduction score (MD 7.03, 95% CI -51.07 to 65.13; 1 study, 29 participants; low-certainty evidence) and when evaluated for clinical response (50% improvement) (RR 1.09, 95% CI 0.48 to 2.45; 1 study, 29 participants; low-certainty evidence). The clinical benefit of thermal biofeedback used in a multi-component psychological intervention (MCPI) compared to no treatment was uncertain when measured with a composite clinical symptom reduction score (MD 30.34, 95% CI 8.47 to 52.21; 3 studies, 101 participants; very low-certainty evidence), and when evaluated as clinical response (50% improvement) (RR 2.12, 95% CI 1.24 to 3.62; 3 studies, 101 participants; very low-certainty evidence). Compared to attention control, the effects of thermal biofeedback within an MCPI were unclear when measured with a composite clinical symptom reduction score (MD 4.02, 95% CI -21.41 to 29.45; 2 studies, 80 participants; very low-certainty evidence) and when evaluated as clinical response (50% improvement) (RR 1.10, 95% CI 0.72 to 1.69, 2 studies, 80 participants; very low-certainty evidence). Quality of life A single trial used overall quality of life as an outcome measure, and reported that both the biofeedback and cognitive therapy groups improved after treatment. The trial did not note any between-group differences, and did not report any outcome data. Adverse events Only one of the eight trials explicitly reported adverse events. This study reported no adverse events in either the biofeedback or cognitive therapy groups (RD 0.00, 95% CI -0.12 to 0.12; 29 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is currently not enough evidence to assess whether biofeedback interventions are effective for controlling symptoms of IBS. Given the positive results reported in small trials to date, biofeedback deserves further study in people with IBS. Future research should include active control groups that use high provider-participant interaction, in an attempt to balance non-specific effects of interventions between groups, and report both commonly used outcome measures (e.g. IBS-SSS) and historical outcome measures (e.g. the composite primary symptom reduction (CPSR) score) to allow for meta-analysis with previous studies. Future studies should be explicit in their reporting of adverse events.

An examination of naturopathic treatment of non-specific gastrointestinal complaints: comparative analysis of two cases.

BACKGROUND: Functional gastrointestinal disorders (FGID) affect more than one-third of the general population and contribute a considerable burden on the health and wellbeing of the community and the economy. This study aims to examine the treatment approaches and outcomes of naturopathic management of individuals presenting with a non-specific FGID. METHODS: We report a comparison of two clinical case studies of patients being treated by a naturopath for a functional gastrointestinal disorder. The care was provided by two different student practitioners under the supervision of an industry qualified mentor within a multidisciplinary academic clinic at the Endeavour College of Natural Health. A student practitioner and student observer conduct consultations under the supervision of an industry qualified mentor. The outcomes of care were measured by the Gastrointestinal Symptom Rating Scale. RESULTS: Clinical notations partially correlate to Jane's outcomes measured by gastrointestinal rating scale scores, which remain stable. Significant changes in Rona's gastrointestinal rating scale scores equate to only generalizable minimal clinical notations. CONCLUSIONS: The holistic and individualised approach core to naturopathic medicine practice is also informed by traditional methods, research evidence and the pragmatic needs of the patient. The emphasis within naturopathic treatment approaches on dietary changes and lifestyle prescription alongside other ingestive therapies such as herbal and nutritional medicine underscores the need for clinical research designs which support evaluation of complex interventions in real-world settings.

Naturopathic Approaches to Irritable Bowel Syndrome-A Delphi Study.

INTRODUCTION: Irritable bowel syndrome (IBS) affects 11% of the population, and up to 50% of patients report using complementary and alternative medicines (CAM) for it. To date, there is no research describing how providers of naturopathic medicine in North America, a well-defined CAM profession, approach IBS. METHODS: A Delphi study was conducted over a 17-month period in 4 rounds with 15 North American naturopathic medicine experts in IBS. Consensus was defined as a median value of 75% or greater agreement with the relevant statement. RESULTS: Consensus was met with 45 statements describing a "reasonable naturopathic approach" to IBS. These statements covered the domains of general, office visits, tracking progress, testing, interventions, and resources. CONCLUSION: These results represent the beginning of an evidence base depicting naturopathic interventions for IBS and should inform future randomized controlled clinical trials in this area. Future research should look to reflect on and revise these guidance consensus statements particularly extending to other stakeholders as well as geographic and regulatory jurisdictions in the naturopathic profession.

Naturopathic approaches to irritable bowel syndrome: protocol for a prospective observational study in academic teaching clinics.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional bowel disorder with a worldwide prevalence estimated between 10% and 20%. It has a significant impact on quality of life and societal expense. While there are pharmaceutical options available, few can be reliably recommended. Many IBS sufferers turn to complementary and alternative medicine including naturopathy. Naturopathic approaches to IBS are poorly studied to date. METHODS: We aim to describe naturopathic approaches to IBS as well as establish pilot data on before and after changes in validated IBS instruments. The study will employ a multi-centered, international, prospective, observational, naturalistic design. The uncontrolled before-and-after study will examine the outcomes associated with individualized, whole system naturopathic care as determined by each provider. We will recruit adult patients diagnosed with IBS and presenting to a participating naturopathic academic teaching clinic. Participants' IBS symptoms will be measured using validated instruments (IBS-SSS and IBS-AR). Quality of life will be measured by using the PROMIS-29 profile. Adverse events will be tracked, as followed for treatment descriptions. Our primary outcomes will be before-and-after differences using week twelve as the primary endpoint. A p values will be set at 0.05, and descriptive and summary data will be presented. DISCUSSION: This study is designed to plug significant evidence gaps and to gather preliminary evidence to guide the design of a follow-up randomized active controlled trial.Australia and New Zealand Clinical Trial Registration Number: ACTRN12617001413314Version 1.1.

North American naturopathic medicine in the 21st century: Time for a seventh guiding principle - Scientia Critica.

The World Health Organization strategy for global health includes a culturally-sensitive blending of western biomedicine with traditional forms of healing; in practical terms this approach is often referred to as integrative medicine. One distinct element within the systems of North American integrative healthcare is naturopathic medicine; while the basic premise of its fundamental approach to care - supporting healthy lifestyle behaviors - is as old as medicine itself, the early history of organized naturopathy in North America was heavy in theory and light on critical analysis. Dozens of questionable modalities and protocols have been housed under the rubric of naturopathy. It is our contention that the progression of professional naturopathic medicine in the 21st century - with goals of personal, public and planetary health - requires the active pursuit of critical analysis. We examine the primary guiding principles which drive the training and practice of North American naturopathic medicine; while these principles are laudable in the age of patient-centered care, we argue that there are shortcomings by absentia. We propose a seventh principle - Scientia Critica; that is, the ability to critically analyze accumulated knowledge - including scientific facts, knowledge about the self (critical consciousness) and values of the patient.

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

BACKGROUND: Antibiotics are frequently prescribed in children. They alter the microbial balance within the gastrointestinal tract, commonly resulting in antibiotic-associated diarrhea (AAD). Probiotics may prevent AAD via restoration of the gut microflora. OBJECTIVES: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. SEARCH METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to November 2014) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors of included trials, nutraceutical and pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched. SELECTION CRITERIA: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. DATA COLLECTION AND ANALYSIS: Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled risk ratio (RR) or risk difference (RD), and continuous data (mean duration of diarrhea, mean daily stool frequency) as mean difference (MD), along with their corresponding 95% confidence interval (95% CI). For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, as well as risk of bias. We also conducted post hoc subgroup analyses by patient diagnosis, single versus multi-strain, industry sponsorship, and inpatient status. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Twenty-three studies (3938 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Clostridium butyricum, Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., orStreptococcus spp., alone or in combination. Eleven studies used a single strain probiotic, four combined two probiotic strains, three combined three probiotic strains, one combined four probiotic strains, two combined seven probiotic strains, one included ten probiotic strains, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high or unclear in 13 studies and low in 10 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 22/23 trials reporting on the incidence of diarrhea show a precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 8% (163/1992) compared to 19% (364/1906) in the control group (RR 0.46, 95% CI 0.35 to 0.61; I(2) = 55%, 3898 participants). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate. This benefit remained statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) sensitivity analysis, where the incidence of AAD in the probiotic group was 14% (330/2294) compared to 19% (426/2235) in the control group (RR 0.69; 95% CI 0.54 to 0.89; I(2) = 63%, 4529 participants). None of the 16 trials (n = 2455) that reported on adverse events documented any serious adverse events attributable to probiotics. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.01). The majority of adverse events were in placebo, standard care or no treatment group. Adverse events reported in the studies include rash, nausea, gas, flatulence, abdominal bloating, abdominal pain, vomiting, increased phlegm, chest pain, constipation, taste disturbance, and low appetite. AUTHORS' CONCLUSIONS: Moderate quality evidence suggests a protective effect of probiotics in preventing AAD. Our pooled estimate suggests a precise (RR 0.46; 95% CI 0.35 to 0.61) probiotic effect with a NNT of 10. Among the various probiotics evaluated, Lactobacillus rhamnosus or Saccharomyces boulardii at 5 to 40 billion colony forming units/day may be appropriate given the modest NNT and the likelihood that adverse events are very rare. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Although no serious adverse events were observed among otherwise healthy children, serious adverse events have been observed in severely debilitated or immuno-compromised children with underlying risk factors including central venous catheter use and disorders associated with bacterial/fungal translocation. Until further research has been conducted, probiotic use should be avoided in pediatric populations at risk for adverse events. Future trials would benefit from a standard and valid outcomes to measure AAD.

Probiotics for the prevention of Clostridium difficile-associated diarrhea: a systematic review and meta-analysis.

BACKGROUND: Antibiotic treatment may disturb the resistance of gastrointestinal flora to colonization. This may result in complications, the most serious of which is Clostridium difficile­associated diarrhea (CDAD). PURPOSE: To assess the efficacy and safety of probiotics for the prevention of CDAD in adults and children receiving antibiotics. DATA SOURCES: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Allied and Complementary Medicine Database, Web of Science, and 12 gray-literature sources. STUDY SELECTION: Randomized, controlled trials including adult or pediatric patients receiving antibiotics that compared any strain or dose of a specified probiotic with placebo or with no treatment control and reported the incidence of CDAD. DATA EXTRACTION: Two reviewers independently screened potentially eligible articles; extracted data on populations, interventions, and outcomes; and assessed risk of bias. The Grading of Recommendations Assessment, Development and Evaluation guidelines were used to independently rate overall confidence in effect estimates for each outcome. DATA SYNTHESIS: Twenty trials including 3818 participants met the eligibility criteria. Probiotics reduced the incidence of CDAD by 66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I(2) = 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1000 persons. Of probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I(2) = 17%). LIMITATIONS: In 13 trials, data on CDAD were missing for 5% to 45% of patients. The results were robust to worst-plausible assumptions regarding event rates in studies with missing outcome data. CONCLUSION: Moderate-quality evidence suggests that probiotic prophylaxis results in a large reduction in CDAD without an increase in clinically important adverse events. PRIMARY FUNDING SOURCE: None.

Probiotics for the prevention of pediatric antibiotic-associated diarrhea.

BACKGROUND: Antibiotics alter the microbial balance within the gastrointestinal tract. Probiotics may prevent antibiotic-associated diarrhea (AAD) via restoration of the gut microflora. Antibiotics are prescribed frequently in children and AAD is common in this population. OBJECTIVES: The primary objectives were to assess the efficacy and safety of probiotics (any specified strain or dose) used for the prevention of AAD in children. SEARCH METHODS: MEDLINE, EMBASE, CENTRAL, CINAHL, AMED, and the Web of Science (inception to May 2010) were searched along with specialized registers including the Cochrane IBD/FBD review group, CISCOM (Centralized Information Service for Complementary Medicine), NHS Evidence, the International Bibliographic Information on Dietary Supplements as well as trial registries. Letters were sent to authors of included trials, nutra/pharmaceutical companies, and experts in the field requesting additional information on ongoing or unpublished trials. Conference proceedings, dissertation abstracts, and reference lists from included and relevant articles were also searched. SELECTION CRITERIA: Randomized, parallel, controlled trials in children (0 to 18 years) receiving antibiotics, that compare probiotics to placebo, active alternative prophylaxis, or no treatment and measure the incidence of diarrhea secondary to antibiotic use were considered for inclusion. DATA COLLECTION AND ANALYSIS: Study selection, data extraction as well as methodological quality assessment using the risk of bias instrument was conducted independently and in duplicate by two authors. Dichotomous data (incidence of diarrhea, adverse events) were combined using a pooled relative risk and risk difference (adverse events), and continuous data (mean duration of diarrhea, mean daily stool frequency) as weighted mean differences, along with their corresponding 95% confidence intervals. For overall pooled results on the incidence of diarrhea, sensitivity analyses included available case versus extreme-plausible analyses and random- versus fixed-effect models. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain, dose, definition of antibiotic-associated diarrhea, antibiotic agent as well as risk of bias. MAIN RESULTS: Sixteen studies (3432 participants) met the inclusion criteria. Trials included treatment with either Bacillus spp., Bifidobacterium spp., Lactobacilli spp., Lactococcus spp., Leuconostoc cremoris, Saccharomyces spp., or Streptococcus spp., alone or in combination. Nine studies used a single strain probiotic agent, four combined two probiotic strains, one combined three probiotic strains, one product included ten probiotic agents, and one study included two probiotic arms that used three and two strains respectively. The risk of bias was determined to be high in 8 studies and low in 8 studies. Available case (patients who did not complete the studies were not included in the analysis) results from 15/16 trials reporting on the incidence of diarrhea show a large, precise benefit from probiotics compared to active, placebo or no treatment control. The incidence of AAD in the probiotic group was 9% compared to 18% in the control group (2874 participants; RR 0.52; 95% CI 0.38 to 0.72; I(2) = 56%). This benefit was not statistically significant in an extreme plausible (60% of children loss to follow-up in probiotic group and 20% loss to follow-up in the control group had diarrhea) intention to treat (ITT) sensitivity analysis. The incidence of AAD in the probiotic group was 16% compared to 18% in the control group (3392 participants; RR 0.81; 95% CI 0.63 to 1.04; I(2) = 59%). An a priori available case subgroup analysis exploring heterogeneity indicated that high dose (≥5 billion CFUs/day) is more effective than low probiotic dose (< 5 billion CFUs/day), interaction P value = 0.010. For the high dose studies the incidence of AAD in the probiotic group was 8% compared to 22% in the control group (1474 participants; RR 0.40; 95% CI 0.29 to 0.55). For the low dose studies the incidence of AAD in the probiotic group was 8% compared to 11% in the control group (1382 participants; RR 0.80; 95% CI 0.53 to 1.21). An extreme plausible ITT subgroup analysis was marginally significant for high dose probiotics. For the high dose studies the incidence of AAD in the probiotic group was 17% compared to 22% in the control group (1776 participants; RR 0.72; 95% CI 0.53 to 0.99; I(2) = 58%). None of the 11 trials (n = 1583) that reported on adverse events documented any serious adverse events. Meta-analysis excluded all but an extremely small non-significant difference in adverse events between treatment and control (RD 0.00; 95% CI -0.01 to 0.02). AUTHORS' CONCLUSIONS: Despite heterogeneity in probiotic strain, dose, and duration, as well as in study quality, the overall evidence suggests a protective effect of probiotics in preventing AAD. Using 11 criteria to evaluate the credibility of the subgroup analysis on probiotic dose, the results indicate that the subgroup effect based on dose (≥5 billion CFU/day) was credible. Based on high-dose probiotics, the number needed to treat (NNT) to prevent one case of diarrhea is seven (NNT 7; 95% CI 6 to 10). However, a GRADE analysis indicated that the overall quality of the evidence for the primary endpoint (incidence of diarrhea) was low due to issues with risk of bias (due to high loss to follow-up) and imprecision (sparse data, 225 events). The benefit for high dose probiotics (Lactobacillus rhamnosus or Saccharomyces boulardii) needs to be confirmed by a large well-designed randomized trial. More refined trials are also needed that test strain specific probiotics and evaluate the efficacy (e.g. incidence and duration of diarrhea) and safety of probiotics with limited losses to follow-up. It is premature to draw conclusions about the efficacy and safety of other probiotic agents for pediatric AAD. Future trials would benefit from a standard and valid outcomes to measure AAD.