Review Of Randomized Controlled Trials Research Articles

A programme of research to set priorities and reduce uncertainties for the prevention and treatment of skin disease

BackgroundSkin diseases are very common and can have a large impact on the quality of life of patients and caregivers. This programme addressed four diseases: (1) eczema, (2) vitiligo, (3) squamous cell skin cancer (SCC) and (4) pyoderma gangrenosum (PG).ObjectiveTo set priorities and reduce uncertainties for the treatment and prevention of skin disease in our four chosen diseases.DesignMixed methods including eight systematic reviews, three prioritisation exercises, two pilot randomised controlled trials (RCTs), three feasibility studies, two core outcome initiatives, four funding proposals for national RCTs and one completed national RCT.SettingSecondary care, primary care and the general population.ParticipantsPatients (and their caregivers) with eczema, vitiligo, SCC and PG, plus health-care professionals with an interest in skin disease.InterventionsOur three intervention studies included (1) barrier enhancement using emollients from birth to prevent eczema (pilot RCT); (2) handheld narrowband ultraviolet light B therapy for treating vitiligo (pilot RCT); and (3) oral ciclosporin (Neoral®, Novartis Pharmaceuticals) compared with oral prednisolone for managing PG (pragmatic national RCT).ResultsSystematic reviews included two overarching systematic reviews of RCTs of treatments for eczema and vitiligo, an umbrella review of systematic reviews of interventions for the prevention of eczema, two reviews of treatments for SCC (one included RCTs and the second included observational studies), and three reviews of outcome measures and outcome reporting. Three prioritisation partnership exercises identified 26 priority areas for future research in eczema, vitiligo and SCC. Two international consensus initiatives identified four core domains for future eczema trials and seven core domains for vitiligo trials. Two pilot RCTs and three feasibility studies critically informed development of four trial proposals for external funding, three of which are now funded and one is pending consideration by funders. Our pragmatic RCT tested the two commonly used systemic treatments for PG (prednisolone vs. ciclosporin) and found no difference in their clinical effectiveness or cost-effectiveness. Both drugs showed limited benefit. Only half of the participants’ ulcers had healed by 6 months. For those with healed ulcers, recurrence was common (30%). Different side effect profiles were noted for each drug, which can inform clinical decisions on an individual patient basis. Three researchers were trained to PhD level and a dermatology patient panel was established to ensure patient involvement in all aspects of the programme.ConclusionsFindings from this programme of work have already informed clinical guidelines and patient information resources. Feasibility studies have ensured that large national pragmatic trials will now be conducted on important areas of treatment uncertainty that address the needs of patients and the NHS. There is scope for considerable improvement in terms of trial design, conduct and reporting for RCTs of skin disease, which can be improved through wider collaboration, registration of trial protocols and complete reporting and international consensus over core outcome sets. Three national trials have now been funded as a result of this work. Two international initiatives to establish how best to measure the core outcome domains for eczema and vitiligo are ongoing.Trial registrationCurrent Controlled Trials Barrier Enhancement for Eczema Prevention (BEEP) (ISRCTN84854178 and NCT01142999), Study of Treatments fOr Pyoderma GAngrenosum Patients (STOP GAP) (ISRCTN35898459) and Hand Held NB-UVB for Early or Focal Vitiligo at Home (HI-Light Pilot Trial) (NCT01478945).FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 4, No. 18. See the NIHR Journals Library website for further project information.

A systematic review of the effect of yogurt consumption on chronic diseases risk markers in adults.

We reviewed randomised controlled trials (RCTs) that have assessed the effects of yogurt containing Lactobacillus bulgaricus and Streptococcus thermophilus (LBST) on metabolic risk markers of chronic diseases in adults. We performed a systematic search in July 2016 in the scientific databases PubMed, EMBASE and The Cochrane Library. Included studies were RCTs that assessed the impact of consuming yogurt containing LBST as a treatment, and that evaluated at least one metabolic risk marker for chronic diseases compared with a control diet or a diet supplemented in another food/ingredient in healthy or chronically ill adults. Seven RCTs involving 278 participants were included in the review. Studies were conducted in the USA, France, Spain, Iran and Canada. Five studies were undertaken in healthy adults, and two were conducted among lactose malabsorbers. All studies investigated changes in blood lipids and glucose homoeostasis, with different doses of yogurt, durations of the supplementation and risks markers assessed. Consumption of LBST yogurt significantly reduced total cholesterol concentrations, ratio of total cholesterol to HDL-C and plasma glucose compared to a control yogurt-free diet or diet supplemented in another food/ingredient in two out of the seven studies. The majority of included RCTs presented high to unclear methodological risks of bias, which raises questions about the validity of their findings. Data from this systematic review indicate that the consumption of LBST yogurt shows either favourable or neutral effects on metabolic risk markers when compared with a control treatment in controlled research settings. RCTs investigating the effect of LBST yogurt consumption on metabolic risk markers of chronic diseases are scarce and presented considerable variation in methodologies making comparison between studies difficult. Further large-scale, well-designed studies assessing the impact of LBST yogurt, in particular in comparison with a control yogurt-free diet, are warranted to effectively evaluate the effect of yogurt consumption per se on risk markers of chronic diseases.

An Overview of Challenges and Approaches to Minimize Bias in Randomized Controlled Trials in Perioperative Medicine

Purpose of Review Randomized controlled trials (RCT) are recognized as the most robust design to study the relationship between exposure and outcomes. The conventional RCT design is commonly used in pharmacological trials. Some surgical interventions are not be well suited to a conventional RCT design and may be associated with methodological challenges. Approaches have been proposed in non-pharmacological trials to overcome some of these challenges and minimize the risk of bias.

Oxytocin and Autism Spectrum Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Aim: Oxytocin presents an exciting potential to target the core symptoms of autism spectrum disorder (ASD) pharmacologically in an easily administered, cost-effective form with possibly minimal adverse effects. But, there are still major gaps in this area of research. This paper reviewed randomized controlled trials (RCTs) examining the effects of oxytocin administration on social cognition and restricted, repetitive behaviors in individuals with an ASD. Method: Electronic literature searches were conducted from PsycINFO, PubMed, Web of Knowledge, and EMBASE for RCTs published through June 2015. Results: 12 RCTs were included in this review. 7 out of the 11 studies that examined social cognition reported improvements. Additionally, one out of the 4 studies on restricted, repetitive behaviors, reported improvements following oxytocin administration. However, results from our meta-analyses suggest that oxytocin has no significant effect on these 2 domains. Conclusion: Previous evidence revealed mixed findings about the effects of oxytocin on ASD. Given the limited number of RCTs, our summary of findings on the effectiveness of oxytocin on ASD should still be considered tentative.

Theoretical, Critical, and Practical Reflections on the Long-Term Maintenance of Health Behavior Change.

This commentary is in response to Joseph, Daniel, Thind, Benitez and Pekmezi (2014). They reviewed randomized controlled trials (RCTs) that included long-term follow-up assessments at least 6 months post-intervention. Their main purpose was to understand which theory or model used by researchers could help explain the long-term maintenance of health behaviors once the intervention was withdrawn in trials focused on physical activity, dietary behavior, and excessive alcohol consumption. Results showed that social cognitive theory (SCT) and transtheoretical model (TTM) were used most often and associated with long-term behavior change compared to self-determination theory (SDT), theory of planned behavior (TPB), or the social-ecological model (SEM). SDT showed encouraging findings while the evidence was unclear for the TPB and the SEM. Here it is argued that scientists should continually reflect on the utility of theory over time and the efforts by Joseph and colleagues should be commended. It is also useful to distinguish theories, which are more specified and offer more generalized statements, than models. Models, such as the TPB and SEM, have incorporated elements of other theories but are typically viewed as tools to characterize behavior. For instance, in 10 studies reviewed by Joseph and colleagues the SCT and TTM were used in an integrative manner. An example of an integrated model is presented that incorporates elements of SDT, TPB, and SCT in an effort to highlight how integrating elements from multiple theories may be useful.

Acupuncture for heart failure: A systematic review of clinical studies

BackgroundAcupuncture has been used for treating heart failure mainly in combination with conventional treatments, but evidence for its effectiveness and safety has not been well established. Our aim was to review randomized controlled trials (RCTs) on acupuncture for heart failure and assess the clinical evidence. MethodsElectronic databases such as Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and certain Chinese & Korean databases were searched until October 2015. The main outcomes assessed were mortality, New York Heart Association (NYHA) function classifications, and acupuncture-related adverse events. The details of acupuncture intervention were also investigated. ResultsAmong 4107 publications, seven RCTs were included; most of them showed considerable methodological flaws. We could not conduct a meta-analysis because of the heterogeneity of the included studies. In one acute heart failure study, acupuncture shortened intensive care unit (ICU) stay by 2.2days (95% CI 1.26, 3.14) and reduced the risk ratio of re-admission to 0.53 (95% CI 0.28, 0.99). However, mortality was not affected. Hemodynamic parameters also showed improvement. Another study reported an improved left ventricular ejection fraction by 9.95% (95% CI 3.24, 16.66). In five chronic heart failure studies, acupuncture improved exercise capacity, quality of life, hemodynamic parameters, and time domain heart rate variability parameters. Acupuncture decreased NT-pro BNP levels by 292.20 (95% CI −567.36, −17.04). No adverse effects were reported. ConclusionsThe effectiveness of acupuncture as a therapy for heart failure is currently inconclusive. Further large and rigorous clinical trials are needed to establish its clinical utility.

Complementary and Alternative Medicine for Atopic Dermatitis: An Evidence-Based Review.

Complementary and alternative interventions are becoming increasingly utilized as adjuncts to conventional treatment of atopic dermatitis (AD). While the number of studies continues to grow, the vastness of the subject coupled with the relatively poor quality and small size of the studies limit their usefulness to clinicians. Our aim was to comprehensively review randomized controlled trials (RCTs) of complementary and alternative therapies for AD. Searches were performed on PubMed, the Cochrane Central Register of Controlled Trials, EMBASE, and the Global Resource for EczemA Trial (GREAT) databases, focusing on RCTs of alternative or complementary AD therapies, with a sample size of ≥10, through March 2015 and limited to the English language. A total of 70 manuscripts met the inclusion criteria and were included in the final analysis. There is at least some levelI evidence to support the use of acupuncture and acupressure, stress-reducing techniques such as hypnosis, massage, and biofeedback, balneotherapy, herbal preparations (with many important caveats), certain botanical oils, oral evening primrose oil, vitamin D supplementation, and topical vitamin B12. Many other therapies either have sufficient data to suggest that they are ineffective, or simply do not have enough evidence to formulate a verdict. Careful review of the literature reveals several promising therapies in this domain; such findings may help direct further research that is necessary to bolster clinical recommendations for alternative or complementary treatments of AD.

Antidepressants for treating depression in adults with end-stage kidney disease treated with dialysis.

Depression affects approximately one-quarter of people treated with dialysis and is considered an important research uncertainty by patients and health professionals. Treatment for depression in dialysis patients may have different benefits and harms compared to the general population due to different clearances of antidepressant medication and the severity of somatic symptoms associated with end-stage kidney disease (ESKD). Guidelines suggest treatment of depression in dialysis patients with pharmacological therapy, preferably a selective serotonin reuptake inhibitor. This is an update of a review first published in 2005. To evaluate the benefit and harms of antidepressants for treating depression in adults with ESKD treated with dialysis. We searched Cochrane Kidney and Transplant's Specialised Register to 20 January 2016 through contact with the Information Specialist using search terms relevant to this review. Randomised controlled trials (RCTs) comparing antidepressant treatment with placebo or no treatment, or compared to another antidepressant medication or psychological intervention in adults with ESKD (estimated glomerular filtration rate < 15 mL/min/1.73 m(2)). Data were abstracted by two authors independently onto a standard form and subsequently entered into Review Manager. Risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data were calculated with 95% confidence intervals (95% CI). Four studies in 170 participants compared antidepressant therapy (fluoxetine, sertraline, citalopram or escitalopram) versus placebo or psychological training for 8 to 12 weeks. In generally very low or ungradeable evidence, compared to placebo, antidepressant therapy had no evidence of benefit on quality of life, had uncertain effects on increasing the risk of hypotension (3 studies, 144 participants: RR 1.72, 95% CI 0.75 to 3.92), headache (2 studies 56 participants: RR 2.91, 95% CI 0.73 to 11.57), and sexual dysfunction (2 studies, 101 participants: RR 3.83, 95% CI 0.63 to 23.34), and increased nausea (3 studies, 114 participants: RR 2.67, 95% CI 1.26 to 5.68). There were few or no data for hospitalisation, suicide or all-cause mortality resulting in inconclusive evidence. Antidepressant therapy may reduce depression scores during treatment compared to placebo (1 study, 43 participants: MD -7.50, 95% CI -11.94 to -3.06). Antidepressant therapy was not statistically different from group psychological therapy for effects on depression scores or withdrawal from treatment and a range of other outcomes were not measured. Despite the high prevalence of depression in dialysis patients and the relative priority that patients place on effective treatments, evidence for antidepressant medication in the dialysis setting is sparse and data are generally inconclusive. The relative benefits and harms of antidepressant therapy in dialysis patients are poorly known and large randomised studies of antidepressants versus placebo are required.

Decision aids to help older people make health decisions: a systematic review and meta-analysis.

BackgroundDecision aids have been overall successful in improving the quality of health decision making. However, it is unclear whether the impact of the results of using decision aids also apply to older people (aged 65+). We sought to systematically review randomized controlled trials (RCTs) and clinical controlled trials (CCTs) evaluating the efficacy of decision aids as compared to usual care or alternative intervention(s) for older adults facing treatment, screening or care decisions.MethodsA systematic search of (1) a Cochrane review of decision aids and (2) MEDLINE, Embase, PsycINFO, Cochrane library central registry of studies and Cinahl. We included published RCTs/CCTs of interventions designed to improve shared decision making (SDM) by older adults (aged 65+) and RCTs/CCTs that analysed the effect of the intervention in a subgroup with a mean age of 65+. Based on the International Patient Decision aid Standards (IPDAS), the primary outcomes were attributes of the decision and the decision process. Other behavioral, health, and health system effects were considered as secondary outcomes. If data could be pooled, a meta-analysis was conducted. Data for which meta-analysis was not possible were synthesized qualitatively.ResultsThe search strategy yielded 11,034 references. After abstract and full text screening, 22 papers were included. Decision aids performed better than control resp. usual care interventions by increasing knowledge and accurate risk perception in older people (decision attributes). With regard to decision process attributes, decision aids resulted in lower decisional conflict and more patient participation.ConclusionsThis review shows promising results on the effectiveness of decision aids for older adults. Decision aids improve older adults’ knowledge, increase their risk perception, decrease decisional conflict and seem to enhance participation in SDM. It must however be noted that the body of literature on the effectiveness of decision aids for older adults is still in its infancy. Only one decision aid was specifically developed for older adults, and the mean age in most studies was between 65 and 70, indicating that the oldest-old were not included. Future research should expand on the design, application and evaluation of decision aids for older, more vulnerable adults.Electronic supplementary materialThe online version of this article (doi:10.1186/s12911-016-0281-8) contains supplementary material, which is available to authorized users.

Laparoscopic versus open distal pancreatectomy for pancreatic cancer.

Laparoscopic versus open distal pancreatectomy for pancreatic cancer.

Pharmacotherapy for opioid dependence in jails and prisons: research review update and future directions.

PurposeThe World Health Organization recommends the initiation of opioid agonists prior to release from incarceration to prevent relapse or overdose. Many countries in the world employ these strategies. This paper considers the evidence to support these recommendations and the factors that have slowed their adoption in the US.MethodsWe reviewed randomized controlled trials (RCTs) and longitudinal/observational studies that examine participant outcomes associated with the initiation or continuation of opioid agonists (methadone, buprenorphine) or antagonists (naltrexone) during incarceration. Papers were identified through a literature search of PubMed with an examination of their references and were included if they reported outcomes for methadone, buprenorphine, or naltrexone continued during incarceration or initiated prior to release in a correctional institution.ResultsFourteen studies were identified, including eight RCTs and six observational studies. One RCT found that patients treated with methadone who were continued on versus tapered off methadone during brief incarceration were more likely to return to treatment upon release. A second RCT found that the group starting methadone treatment in prison versus a waiting list was less likely to report using heroin and sharing syringes during incarceration. A third RCT found no differences in postrelease heroin use or reincarceration between individuals initiating treatment with methadone versus those initiating treatment with buprenorphine during relatively brief incarcerations. Findings from four additional RCTs indicate that starting opioid agonist treatment during incarceration versus after release was associated with higher rates of entry into community treatment and reduced heroin use. Finally, one pilot RCT showed that providing extended-release naltrexone prior to discharge resulted in significantly lower rates of opioid relapse compared to no medication.ConclusionReasons why uptake of these pharmacotherapies is limited in the US and relatively widespread in Europe are discussed. Recommendations for future research are outlined.

Laser-assisted subepithelial keratectomy (LASEK) versus photorefractive keratectomy (PRK) for correction of myopia.

Laser-assisted subepithelial keratectomy (LASEK) versus photorefractive keratectomy (PRK) for correction of myopia.

Irinotecan chemotherapy combined with fluoropyrimidines versus irinotecan alone for overall survival and progression-free survival in patients with advanced and/or metastatic colorectal cancer.

Chemotherapy is the treatment of choice in patients with advanced or metastatic colorectal cancer (CRC) where surgical resection of metastases is not an option. Both irinotecan (IRI) and fluoropyrimidines are often included in first- or second- line chemotherapy treatment regimens in such patients. However, it is not clear whether combining these agents is superior to irinotecan alone. To compare the efficacy and safety of two chemotherapeutic regimens, irinotecan monotherapy or irinotecan in combination with fluoropyrimidines, for patients with advanced CRC when administered in the first or second-line settings. We searched the following electronic databases to identify randomized controlled trials: Cochrane Colorectal Cancer Group Specialised Register (January 13, 2016), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library Issue 12, 2016), Ovid MEDLINE (1950 to January 13, 2016), Ovid EMBASE (1974 to January 13, 2016), registers of controlled trials in progress, references cited in relevant publications and conference proceedings in related fields (BioMed Central and Medscape's Conference). The key authors or investigators of all eligible studies, and professionals in the field were contacted when necessary. The search from January 2016 identified one eligible study, an ongoing trial currently presented as an abstract, to be considered in an update of this review. Randomized controlled trials (RCTs) investigating the efficacy and safety of IRI chemotherapy combined with fluoropyrimidine compared with IRI alone for the treatment of patients with advanced CRC, regardless of treatment line settings. Study eligibility and methodological quality were assessed independently by the two authors, and any disagreement was solved by a third author. The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.3. Five studies were included in this review with a total of 1,726 patients. The top-up search resulted in an additional ongoing trial, the results of which have not been incorporated in this review. Among five included studies, no reduction in all-cause mortality was observed in the combination arm, with a summary hazard ratio (HR) of 0.91 (95% CI: 0.81-1.02). Longer progression-free survival was observed in those treated with the combination chemotherapy (HR: 0.68, 95% CI: 0.53-0.87), however, this result may have been driven by findings from the single first-line treatment setting study.The quality of evidence for overall survival was low and for progression-free survival was moderate, mainly due to study limitation from the lack of information on randomisation methods and allocation concealment.There were higher risks of toxicity outcomes grade 3 or 4 diarrhoea and grade 1 or 2 alopecia, and a lower risk of grade 3 or 4 neutropenia in controls compared to the invervention group. Evidence for toxicity has been assessed to be low to moderate quality. There was no overall survival benefit of the irinotecan and fluoropyrimidine treatment over irinotecan alone, thus both regimens remain reasonable options in treating patients with advanced or metastatic CRC. Given the low and moderate quality of the evidence, future studies with sufficient numbers of patients in each treatment arms are needed to clarify the benefit observed in progression-free survival with combination irinotecan and fluoropyrimidines.

Systematic Review of Anthocyanins and Markers of Cardiovascular Disease.

Anthocyanins are dietary flavonoids commonly consumed in the diet, which have been suggested to have a preventative effect on cardiovascular disease (CVD) development among epidemiological studies. We systematically reviewed randomized controlled trials (RCTs) testing the effects of purified anthocyanins and anthocyanin-rich extracts on markers of CVD (triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and blood pressure) in both healthy and diseased populations. Eligible studies included RCTs of adults published in English. We searched PubMed, Web of Science Core Collection, and BIOSIS Previews for relevant articles from inception until 1 July 2014. Twelve RCTs representing 10 studies were included in this review. Supplementation with anthocyanins significantly improved LDL cholesterol among diseased individuals or those with elevated biomarkers. Supplementation did not significantly affect other markers of CVD in either healthy individuals or those with elevated markers. No adverse effects of anthocyanins were reported across studies at levels up to 640 mg/day. Limitations of trials in the qualitative analyses include short trial duration and large variability in the dose administered within the trials. Longer-duration trials assessing dose response are needed to adequately determine whether an effect of supplementation exists.

The impact of equol-producing status in modifying the effect of soya isoflavones on risk factors for CHD: a systematic review of randomised controlled trials.

Recent studies suggest that the ability to produce equol, a metabolite of the soya isoflavone daidzein, is beneficial to coronary health. Equol, generated by bacterial action on isoflavones in the human gut, is biologically more potent than dietary sources of isoflavones. Not all humans are equol producers. We investigated whether equol-producing status is favourably associated with risk factors for CHD following an intervention by dietary soya isoflavones. We systematically reviewed randomised controlled trials (RCT) that evaluated the effect of soya isoflavones on risk factors for CHD and that reported equol-producing status. We searched PubMed, EMBASE, Ovid Medline and the Cochrane Central Register for Controlled Trials published up to April 2015 and hand-searched bibliographies to identify the RCT. Characteristics of participants and outcomes measurements were extracted and qualitatively analysed. From a total of 1671 studies, we identified forty-two articles that satisfied our search criteria. The effects of equol on risk factors for CHD were mainly based on secondary analyses in these studies, thus with inadequate statistical power. Although fourteen out of the forty-two studies found that equol production after a soya isoflavone intervention significantly improved a range of risk factors including cholesterol and other lipids, inflammation and blood pressure variables, these results need further verification by sufficiently powered studies. The other twenty-eight studies primarily reported null results. RCT of equol, which has recently become available as a dietary supplement, on CHD and its risk factors are awaited.

Probiotics for preventing urinary tract infections in adults and children.

Urinary tract infection (UTI) is a common bacterial infection that can lead to significant morbidity including stricture, abscess formation, fistula, bacteraemia, sepsis, pyelonephritis and kidney dysfunction. Mortality rates are reported to be as high as 1% in men and 3% in women due to development of pyelonephritis. Because probiotic therapy is readily available without a prescription, a review of their efficacy in the prevention of UTI may aid consumers in making informed decisions about potential prophylactic therapy. Institutions and caregivers also need evidence-based synopses of current evidence to make informed patient care decisions. Compared to placebo or no therapy, did probiotics (any formulation) provide a therapeutic advantage in terms of morbidity and mortality, when used to prevent UTI in susceptible patient populations?Compared to other prophylactic interventions, including drug and non-drug measures (e.g. continuous antibiotic prophylaxis, topical oestrogen, cranberry juice), did probiotics (any formulation) provide a therapeutic advantage in terms of morbidity and mortality when used to prevent UTIs in susceptible patient populations? We searched the Cochrane Kidney and Transplant Specialised Register to 21 September 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Randomised controlled trials (RCTs) of susceptible patients (e.g. past history of UTI) or healthy people in which any strain, formulation, dose or frequency of probiotic was compared to placebo or active comparators were included. All RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at comparing probiotics to no therapy, placebo, or other prophylactic interventions were included. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. We included nine studies that involved 735 people in this review. Four studies compared probiotic with placebo, two compared probiotic with no treatment, two compared probiotics with antibiotics in patients with UTI, and one study compared probiotic with placebo in healthy women. All studies aimed to measure differences in rates of recurrent UTI.Our risk of bias assessment found that most studies had small sample sizes and reported insufficient methodological detail to enable robust assessment. Overall, there was a high risk of bias in the included studies which lead to inability to draw firm conclusions and suggesting that any reported treatment effects may be misleading or represent overestimates.We found no significant reduction in the risk of recurrent symptomatic bacterial UTI between patients treated with probiotics and placebo (6 studies, 352 participants: RR 0.82, 95% CI 0.60 to 1.12; I(2) = 23%) with wide confidence intervals, and statistical heterogeneity was low. No significant reduction in the risk of recurrent symptomatic bacterial UTI was found between probiotic and antibiotic treated patients (1 study, 223 participants: RR 1.12, 95% CI 0.95 to 1.33).The most commonly reported adverse effects were diarrhoea, nausea, vomiting, constipation and vaginal symptoms. None of the included studies reported numbers of participants with at least one asymptomatic bacterial UTI, all-cause mortality or those with at least one confirmed case of bacteraemia or fungaemia. Two studies reported study withdrawal due to adverse events and the number of participants who experienced at least one adverse event. One study reported withdrawal occurred in six probiotic participants (5.2%), 15 antibiotic participants (12.2%), while the second study noted one placebo group participant discontinued treatment due to an adverse event. No significant benefit was demonstrated for probiotics compared with placebo or no treatment, but a benefit cannot be ruled out as the data were few, and derived from small studies with poor methodological reporting.There was limited information on harm and mortality with probiotics and no evidence on the impact of probiotics on serious adverse events. Current evidence cannot rule out a reduction or increase in recurrent UTI in women with recurrent UTI who use prophylactic probiotics. There was insufficient evidence from one RCT to comment on the effect of probiotics versus antibiotics.

RANDOMISED CONTROLLED TRIALS OF CHRONIC PAIN IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW

BackgroundApproximately 15 to 30% of children and adolescents suffer from daily pain persistent over more than 3 months and there is evidence supporting that the prevalence of chronic pain is steadily increasing in this population. Chronic pain is known to have a negative impact on children's development and social behaviour, leading often to severe psychological distress and physical disability. We reviewed medical literature to assess the characteristics and quality of randomized controlled trials (RCTs) on pharmacological and non-pharmacological therapies in chronic and recurrent pain in the paediatric population.MethodsWe performed a systematic search of PubMed, Embase and the Cochrane Library up to March 2014. Bibliographies of relevant articles were also hand-searched. We included all RCTs that involved children and adolescents (age 0 to 18 years) and evaluated the use of a pharmacological agent or a non-pharmacological approach in the context of chronic or recurrent pain. The latter was defined as pain persisting for more than 3 months. Methodological quality was evaluated using the Cochrane Risk of Bias Tool. Two reviewers independently assessed studies for inclusion and evaluated methodological quality.ResultsA total of 52 randomized controlled trials were selected and included in the analysis. The majority were conducted in single hospital institutions, with no information on study funding. Median sample size was 45 (34–57) participants. Almost 50% of the RCTs included both adults and children with a median age at inclusion of 13 years. Non-pharmacological approaches were more commonly tested whereas evaluation of pharmacological agents concerned less than 30% of RCTs. Abdominal pain and headache were the most common types of chronic pain experienced among trial participants. Overall, the methodological quality was poor and did not parallel the number of RCTs that increased over the years. The risk of bias was high or unclear in 70% of the trials.ConclusionsThis is the first systematic review of RCTs conducted to evaluate pharmacological and non-pharmacological therapies in chronic and recurrent pain in children and adolescents. Although, management of pain in adults has significantly improved over the years due to the evaluation of numerous analgesic therapies, our results highlight the existing knowledge gap with regards to children and adolescents. Therapeutic strategies, in particular pharmacological agents, applied to relieve chronic or recurrent pain in children and adolescents are not evaluated through high quality RCTs. The need to improve analgesic therapy in children and adolescents with chronic pain is still unmet. We discuss possible research constraints and challenges related to this fact as well as adequate methodologies to circumvent them.

Structured telephone support or non-invasive telemonitoring for patients with heart failure.

Specialised disease management programmes for heart failure aim to improve care, clinical outcomes and/or reduce healthcare utilisation. Since the last version of this review in 2010, several new trials of structured telephone support and non-invasive home telemonitoring have been published which have raised questions about their effectiveness.To review randomised controlled trials (RCTs) of structured telephone support or non-invasive home telemonitoring compared to standard practice for people with heart failure, in order to quantify the effects of these interventions over and above usual care.We updated the searches of the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Health Technology AsseFssment Database (HTA) on the Cochrane Library; MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index- Science (CPCI-S) on Web of Science (Thomson Reuters), AMED, Proquest Theses and Dissertations, IEEE Xplore and TROVE in January 2015. We handsearched bibliographies of relevant studies and systematic reviews and abstract conference proceedings. We applied no language limits.We included only peer-reviewed, published RCTs comparing structured telephone support or non-invasive home telemonitoring to usual care of people with chronic heart failure. The intervention or usual care could not include protocol-driven home visits or more intensive than usual (typically four to six weeks) clinic follow-up.We present data as risk ratios (RRs) with 95% confidence intervals (CIs). Primary outcomes included all-cause mortality, all-cause and heart failure-related hospitalisations, which we analysed using a fixed-effect model. Other outcomes included length of stay, health-related quality of life, heart failure knowledge and self care, acceptability and cost; we described and tabulated these. We performed meta-regression to assess homogeneity (the null hypothesis) in each subgroup analysis and to see if the effect of the intervention varied according to some quantitative variable (such as year of publication or median age).We include 41 studies of either structured telephone support or non-invasive home telemonitoring for people with heart failure, of which 17 were new and 24 had been included in the previous Cochrane review. In the current review, 25 studies evaluated structured telephone support (eight new studies, plus one study previously included but classified as telemonitoring; total of 9332 participants), 18 evaluated telemonitoring (nine new studies; total of 3860 participants). Two of the included studies trialled both structured telephone support and telemonitoring compared to usual care, therefore 43 comparisons are evident.Non-invasive telemonitoring reduced all-cause mortality (RR 0.80, 95% CI 0.68 to 0.94; participants = 3740; studies = 17; I² = 24%, GRADE: moderate-quality evidence) and heart failure-related hospitalisations (RR 0.71, 95% CI 0.60 to 0.83; participants = 2148; studies = 8; I² = 20%, GRADE: moderate-quality evidence). Structured telephone support reduced all-cause mortality (RR 0.87, 95% CI 0.77 to 0.98; participants = 9222; studies = 22; I² = 0%, GRADE: moderate-quality evidence) and heart failure-related hospitalisations (RR 0.85, 95% CI 0.77 to 0.93; participants = 7030; studies = 16; I² = 27%, GRADE: moderate-quality evidence).Neither structured telephone support nor telemonitoring demonstrated effectiveness in reducing the risk of all-cause hospitalisations (structured telephone support: RR 0.95, 95% CI 0.90 to 1.00; participants = 7216; studies = 16; I² = 47%, GRADE: very low-quality evidence; non-invasive telemonitoring: RR 0.95, 95% CI 0.89 to 1.01; participants = 3332; studies = 13; I² = 71%, GRADE: very low-quality evidence).Seven structured telephone support studies reported length of stay, with one reporting a significant reduction in length of stay in hospital. Nine telemonitoring studies reported length of stay outcome, with one study reporting a significant reduction in the length of stay with the intervention. One telemonitoring study reported a large difference in the total number of hospitalisations for more than three days, but this was not an analysis of length of stay per hospitalisation. Nine of 11 structured telephone support studies and five of 11 telemonitoring studies reported significant improvements in health-related quality of life. Nine structured telephone support studies and six telemonitoring studies reported costs of the intervention or cost effectiveness. Three structured telephone support studies and one telemonitoring study reported a decrease in costs and two telemonitoring studies reported increases in cost, due both to the cost of the intervention and to increased medical management. Adherence was rated between 55.1% and 98.5% for those structured telephone support and telemonitoring studies which reported this outcome. Participant acceptance of the intervention was reported in the range of 76% to 97% for studies which evaluated this outcome. Seven of nine studies that measured these outcomes reported significant improvements in heart failure knowledge and self-care behaviours.For people with heart failure, structured telephone support and non-invasive home telemonitoring reduce the risk of all-cause mortality and heart failure-related hospitalisations; these interventions also demonstrated improvements in health-related quality of life and heart failure knowledge and self-care behaviours. Studies also demonstrated participant satisfaction with the majority of the interventions which assessed this outcome.

Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP).

Henoch-Schönlein purpura (HSP) is the most common vasculitis of childhood but may occur in adults. This small vessel vasculitis is characterised by palpable purpura, abdominal pain, arthritis or arthralgia and kidney involvement. This is an update of a review first published in 2009. To evaluate the benefits and harms of different agents (used singularly or in combination) compared with placebo, no treatment or any other agent for: (1) the prevention of severe kidney disease in patients with HSP without kidney disease at presentation; (2) the prevention of severe kidney disease in patients with HSP and minor kidney disease (microscopic haematuria, mild proteinuria) at presentation; (3) the treatment of established severe kidney disease (macroscopic haematuria, proteinuria, nephritic syndrome, nephrotic syndrome with or without acute kidney failure) in HSP; and (4) the prevention of recurrent episodes of HSP-associated kidney disease. We searched the Cochrane Kidney and Transplant's Specialised Register to 13 July 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Randomised controlled trials (RCTs) comparing interventions used to prevent or treat kidney disease in HSP compared with placebo, no treatment or other agents were included. Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random effects model and the results were expressed as risk ratio (RR) or risk difference (RD) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Thirteen studies (1403 enrolled patients) were identified. Risks of bias attributes were frequently poorly performed. Low risk of bias was reported in six studies (50%) for sequence generation (selection bias) and in seven (58%) for allocation concealment (selection bias). Blinding of participants and personnel (performance bias) and of outcome assessment (detection bias) was at low risk of bias in three studies. Five studies reported complete outcome data (attrition bias) while eight studies reported expected outcomes so were at low risk of reporting bias.Eight studies evaluated therapy to prevent persistent kidney disease in HSP. There was no significant difference in the risk of persistent kidney disease any time after treatment (5 studies, 746 children: RR 0.74, 95% CI 0.42 to 1.32), or at one, three, six and 12 months in children given prednisone for 14 to 28 days at presentation of HSP compared with placebo or supportive treatment. There were no significant differences in the risk of persistent kidney disease with antiplatelet therapy in children with or without kidney disease at entry. Heparin significantly reduced the risk of persistent kidney disease by three months compared with placebo (1 study, 228 children: RR 0.27, 95% CI 0.14 to 0.55); no significant bleeding occurred. Four studies examined the treatment of severe HSP-associated kidney disease. Two studies (one involving 56 children and the other involving 54 adults) compared cyclophosphamide with placebo or supportive treatment and found no significant benefit of cyclophosphamide. There were no significant differences in adverse effects. In one study comparing cyclosporin with methylprednisolone (15 children) there was no significant difference in remission at final follow-up at a mean of 6.3 years (RR 1.37, 95% CI 0.74 to 2.54). In one study (17 children) comparing mycophenolate mofetil with azathioprine, there was no significant difference in the remission of proteinuria at one year (RR 1.32, 95% CI 0.86 to 2.03). No studies were identified which evaluated the efficacy of therapy on kidney disease in participants with recurrent episodes of HSP. There are no substantial changes in conclusions from this update compared with the initial review. From generally low quality evidence, we found no evidence of benefit from RCTs for the use of prednisone or antiplatelet agents to prevent persistent kidney disease in children with HSP. Though heparin appeared effective, this potentially dangerous therapy is not justified to prevent serious kidney disease when fewer than 2% of children with HSP develop severe kidney disease. No evidence of benefit has been found for cyclophosphamide treatment in children or adults with HSP and severe kidney disease. Because of small patient numbers and events leading to imprecision in results, it remains unclear whether cyclosporin and mycophenolate mofetil have any roles in the treatment of children with HSP and severe kidney disease.

Interventions for pain with intrauterine device insertion.

Fear of pain during insertion of intrauterine contraception (IUC) is a barrier to use of this method. IUC includes copper-containing intrauterine devices and levonorgestrel-releasing intrauterine systems. Interventions for pain control during IUC insertion include non-steroidal anti-inflammatory drugs (NSAIDs), local cervical anesthetics, and cervical ripening agents such as misoprostol. To review randomized controlled trials (RCTs) of interventions for reducing IUC insertion-related pain We searched for trials in CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP. The most recent search was 22 June 2015. We examined reference lists of pertinent articles. For the initial review, we wrote to investigators to find other published or unpublished trials. We included RCTs that evaluated an intervention for preventing IUC insertion-related pain. The comparison could have been a placebo, no intervention, or another active intervention. The primary outcomes were self-reported pain at tenaculum placement, during IUC insertion, and after IUC insertion (up to six hours). Two authors extracted data from eligible trials. For dichotomous variables, we calculated the Mantel-Haenszel odds ratio (OR) with 95% confidence interval (CI). For continuous variables, we computed the mean difference (MD) with 95% CI. In meta-analysis of trials with different measurement scales, we used the standardized mean difference (SMD). We included 33 trials with 5710 participants total; 29 were published from 2010 to 2015. Studies examined lidocaine, misoprostol, NSAIDs, and other interventions. Here we synthesize results from trials with sufficient outcome data and moderate- or high-quality evidence.For lidocaine, meta-analysis showed topical 2% gel had no effect on pain at tenaculum placement (two trials) or on pain during IUC insertion (three trials). Other formulations were effective compared with placebo in individual trials. Mean score for IUC-insertion pain was lower with lidocaine and prilocaine cream (MD -1.96, 95% CI -3.00 to -0.92). Among nulliparous women, topical 4% formulation showed lower scores for IUC-insertion pain assessed within 10 minutes (MD -15.90, 95% CI -22.77 to -9.03) and at 30 minutes later (MD -11.10, 95% CI -19.05 to -3.15). Among parous women, IUC-insertion pain was lower with 10% spray (median 1.00 versus 3.00). Compared with no intervention, pain at tenaculum placement was lower with 1% paracervical block (median 12 versus 28).For misoprostol, meta-analysis showed a higher mean score for IUC insertion compared with placebo (SMD 0.27, 95% CI 0.07 to 0.46; four studies). In meta-analysis, cramping was more likely with misoprostol (OR 2.64, 95% CI 1.46 to 4.76; four studies). A trial with nulliparous women found a higher score for IUC-insertion pain with misoprostol (median 46 versus 34). Pain before leaving the clinic was higher for misoprostol in two trials with nulliparous women (MD 7.60, 95% CI 6.48 to 8.72; medians 35.5 versus 20.5). In one trial with nulliparous women, moderate or severe pain at IUC insertion was less likely with misoprostol (OR 0.30, 95% CI 0.16 to 0.55). In the same trial, the misoprostol group was more likely to rate the experience favorably. Within two trials of misoprostol plus diclofenac, shivering, headache, or abdominal pain were more likely with misoprostol. Participants had no vaginal delivery. One trial showed the misoprostol group less likely to choose or recommend the treatment.Among multiparous women, mean score for IUC-insertion pain was lower for tramadol 50 mg versus naproxen 550 mg (MD -0.63, 95% CI -0.94 to -0.32) and for naproxen versus placebo (MD -1.94, 95% CI -2.35 to -1.53). The naproxen group was less likely than the placebo group to report the insertion experience as unpleasant and not want the medication in the future. An older trial showed repeated doses of naproxen 300 mg led to lower pain scores at one hour (MD -1.04, 95% CI -1.67 to -0.41) and two hours (MD -0.98, 95% CI -1.64 to -0.32) after insertion. Most women were nulliparous and also had lidocaine paracervical block. Nearly all trials used modern IUC. Most effectiveness evidence was of moderate quality, having come from single trials. Lidocaine 2% gel, misoprostol, and most NSAIDs did not help reduce pain. Some lidocaine formulations, tramadol, and naproxen had some effect on reducing IUC insertion-related pain in specific groups. The ineffective interventions do not need further research.