Comparison of dietary macronutrient patterns of 14 popular named dietary programmes for weight and cardiovascular risk factor reduction in adults: systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To determine the relative effectiveness of dietary macronutrient patterns and popular named diet programmes for weight loss and cardiovascular risk factor improvement among adults who are overweight or obese. DESIGN: Systematic review and network meta-analysis of randomised trials. DATA SOURCES: Medline, Embase, CINAHL, AMED, and CENTRAL from database inception until September 2018, reference lists of eligible trials, and related reviews. STUDY SELECTION: Randomised trials that enrolled adults (≥18 years) who were overweight (body mass index 25-29) or obese (≥30) to a popular named diet or an alternative diet. OUTCOMES AND MEASURES: Change in body weight, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, systolic blood pressure, diastolic blood pressure, and C reactive protein at the six and 12 month follow-up. REVIEW METHODS: Two reviewers independently extracted data on study participants, interventions, and outcomes and assessed risk of bias, and the certainty of evidence using the GRADE (grading of recommendations, assessment, development, and evaluation) approach. A bayesian framework informed a series of random effects network meta-analyses to estimate the relative effectiveness of the diets. RESULTS: 121 eligible trials with 21 942 patients were included and reported on 14 named diets and three control diets. Compared with usual diet, low carbohydrate and low fat diets had a similar effect at six months on weight loss (4.63 v 4.37 kg, both moderate certainty) and reduction in systolic blood pressure (5.14 mm Hg, moderate certainty v 5.05 mm Hg, low certainty) and diastolic blood pressure (3.21 v 2.85 mm Hg, both low certainty). Moderate macronutrient diets resulted in slightly less weight loss and blood pressure reductions. Low carbohydrate diets had less effect than low fat diets and moderate macronutrient diets on reduction in LDL cholesterol (1.01 mg/dL, low certainty v 7.08 mg/dL, moderate certainty v 5.22 mg/dL, moderate certainty, respectively) but an increase in HDL cholesterol (2.31 mg/dL, low certainty), whereas low fat (-1.88 mg/dL, moderate certainty) and moderate macronutrient (-0.89 mg/dL, moderate certainty) did not. Among popular named diets, those with the largest effect on weight reduction and blood pressure in comparison with usual diet were Atkins (weight 5.5 kg, systolic blood pressure 5.1 mm Hg, diastolic blood pressure 3.3 mm Hg), DASH (3.6 kg, 4.7 mm Hg, 2.9 mm Hg, respectively), and Zone (4.1 kg, 3.5 mm Hg, 2.3 mm Hg, respectively) at six months (all moderate certainty). No diets significantly improved levels of HDL cholesterol or C reactive protein at six months. Overall, weight loss diminished at 12 months among all macronutrient patterns and popular named diets, while the benefits for cardiovascular risk factors of all interventions, except the Mediterranean diet, essentially disappeared. CONCLUSIONS: Moderate certainty evidence shows that most macronutrient diets, over six months, result in modest weight loss and substantial improvements in cardiovascular risk factors, particularly blood pressure. At 12 months the effects on weight reduction and improvements in cardiovascular risk factors largely disappear. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015027929.

Effect of Electronic Prescribing Strategies on Medication Error and Harm in Hospital: a Systematic Review and Meta-analysis.

BACKGROUND: Computerized physician order entry and clinical decision support systems are electronic prescribing strategies that are increasingly used to improve patient safety. Previous reviews show limited effect on patient outcomes. Our objective was to assess the impact of electronic prescribing strategies on medication errors and patient harm in hospitalized patients. METHODS: MEDLINE, EMBASE, CENTRAL, and CINAHL were searched from January 2007 to January 2018. We included prospective studies that compared hospital-based electronic prescribing strategies with control, and reported on medication error or patient harm. Data were abstracted by two reviewers and pooled using random effects model. Study quality was assessed using the Effective Practice and Organisation of Care and evidence quality was assessed using Grading of Recommendations Assessment, Development, and Evaluation. RESULTS: Thirty-eight studies were included; comprised of 11 randomized control trials and 27 non-randomized interventional studies. Electronic prescribing strategies reduced medication errors (RR 0.24 (95% CI 0.13, 0.46), I2 98%, n = 11) and dosing errors (RR 0.17 (95% CI 0.08, 0.38), I2 96%, n = 9), with both risk ratios significantly affected by advancing year of publication. There was a significant effect of electronic prescribing strategies on adverse drug events (ADEs) (RR 0.52 (95% CI 0.40, 0.68), I2 0%, n = 2), but not on preventable ADEs (RR 0.55 (95% CI 0.30, 1.01), I2 78%, n = 3), hypoglycemia (RR 1.03 (95% CI 0.62-1.70), I2 28%, n = 7), length of stay (MD - 0.18 (95% - 1.42, 1.05), I2 94%, n = 7), or mortality (RR 0.97 (95% CI 0.79, 1.19), I2 74%, n = 9). The quality of evidence was rated very low. DISCUSSION: Electronic prescribing strategies decrease medication errors and adverse drug events, but had no effect on other patient outcomes. Conservative interpretations of these findings are supported by significant heterogeneity and the preponderance of low-quality studies.

Psychosocial and quality of life impact of scars in the surgical, traumatic and burn populations: a scoping review protocol.

INTRODUCTION: Despite the fact that millions of scars affect individuals annually, little is known about their psychosocial impact and overall quality of life (QOL) on individuals. Scars from multiple aetiologies may cause psychiatric and emotional disturbances, can limit physical functioning and increase costs to the healthcare system. The purpose of this protocol is to describe the methodological considerations that will guide the completion of a scoping review that will summarise the extent, range and nature of psychosocial health outcomes and QOL of scars of all aetiologies. METHODS AND ANALYSIS: A modified Arksey and O'Malley (2005) framework will be completed, namely having ongoing consultation between experts from the beginning of the process, then (1) identifying the research question/s, (2) identifying the relevant studies from electronic databases and grey literature, with (3) study selection and (4) charting of data by two independent coders, and (5) collating, summarising and reporting data. Experts will include a health information specialist (TAW), scar expert (JSF), scoping review consultant (SCK), as well as at least two independent coders (NZ, AM). ETHICS AND DISSEMINATION: Ethics approval will not be sought for this scoping review. We plan to disseminate this research through publications, presentations and meetings with relevant stakeholders.

Diagnostic Accuracy of MRI-Based Sacroiliitis Scoring Systems: A Systematic Review.

OBJECTIVE. Accurate and reproducible MRI assessment of the sacroiliac joint (SIJ) is challenging. Numerous scoring systems have been proposed to facilitate consistent SIJ assessment. The purpose of this article is to evaluate the diagnostic accuracy and reliability of existing MRI-based SIJ scoring systems for the evaluation of spondyloarthropathy. CONCLUSION. Among existing methods, there is fair (grade B) evidence to recommend the Spondyloarthropathy Research Consortium of Canada scoring systems as tools for MRI evaluation of the SIJ. However, limited data on criterion validity limit assessment of scoring system accuracy.

Comparative Effectiveness of Prophylactic Therapies for Necrotizing Enterocolitis in Preterm Infants: Protocol for a Network Meta-analysis of Randomized Trials.

Necrotizing enterocolitis (NEC) is a common and devastating disease with high morbidity and mortality in premature infants. Current literature on the prevention of NEC has limitations including lack of direct and indirect comparisons of available therapies. We will search MEDLINE, EMBASE, Science Citation Index Expanded, Social Sciences Citation Index, CINAHL, Scopus, ProQuest Dissertations and Theses database, and grey literature sources to identify eligible trials evaluating NEC preventive therapies. Eligible studies will (1) enroll preterm (gestational age <37 weeks) and/or low birth weight (birth weight <2500 g) infants, (2) randomize infants to any preventive intervention or a placebo, or alternative active or nonactive intervention. Our outcomes of interest are severe NEC (stage II or more, based on Bell's criteria), all-cause mortality, NEC-related mortality, late-onset sepsis, duration of hospitalization, weight gain, time to establish full enteral feeds, and treatment-related adverse events. Two reviewers will independently screen trials for eligibility, assess risk of bias, and extract data. All discrepancies will be resolved by discussion. We will specify a priori explanations for heterogeneity between studies. For available comparisons between treatment and no treatment, and direct comparisons of treatments, we will conduct conventional meta-analysis using a random effects model. We will conduct a network meta-analysis using a random effects model within the Bayesian framework using Markov chain Monte Carlo methods to assess relative effects of eligible interventions. We will assess the certainty in direct, indirect, and network estimates using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: We will disseminate our findings through a peer-reviewed publication and conference presentations.

Acute Appendicitis: A Meta-Analysis of the Diagnostic Accuracy of US, CT, and MRI as Second-Line Imaging Tests after an Initial US.

Purpose To evaluate the sensitivity, specificity, and diagnostic odds ratios of US, CT, and MRI as second-line imaging modalities after initial US for assessing acute appendicitis in children and adults. Materials and Methods A literature search was conducted in Medline and Embase to identify articles that used surgery or histopathologic examination alone or in combination with clinical follow-up or chart review to evaluate the diagnostic accuracy of second-line imaging modalities. The quality of articles was assessed by using the Quality Assessment of Diagnostic Accuracy Studies-2 and the Standards for Reporting of Diagnostic Accuracy tools. Results For studies of children, the number of studies and patients were as follows: US, six studies and 548 patients; CT, nine studies and 1498 patients; MRI, five studies and 287 patients. For studies of adults, the number of studies and patients were as follows: US, three studies and 169 patients; CT, 11 studies and 1027 patients; MRI, six studies and 427 patients. Pooled sensitivities and specificities of second-line US for diagnosis of appendicitis in children were 91.3% (95% confidence interval [CI]: 83.8%, 95.5%) and 95.2% (95% CI: 91.8%, 97.3%), respectively; and in adults, the pooled sensitivities and specificities were 83.1% (95% CI: 70.3%, 91.1%) and 90.9% (95% CI: 59.3%, 98.6%), respectively. Regarding second-line CT in children, the pooled sensitivities and specificities were 96.2% (95% CI: 93.2%, 97.8%) and 94.6% (95% CI: 92.8%, 95.9%); and in adults, the pooled sensitivities and specificities were 89.9% (95% CI: 85.4%, 93.2%) and 93.6% (95% CI: 91.2%, 95.3%), respectively. Regarding second-line MRI in children, pooled sensitivities and specificities were 97.4% (95% CI: 85.8%, 100%) and 97.1% (95% CI: 92.1%, 99.0%); and in adults, the pooled sensitivities and specificities were 89.9% (95% CI: 84.8%, 93.5%) and 93.6% (95% CI: 90.9%, 95.5%), respectively. Conclusion Second-line US, CT, and MRI have comparable and high accuracy in helping to diagnose appendicitis in children and adults, including pregnant women. All three modalities may be valid as second-line imaging in a clinical imaging pathway for diagnosis and management of appendicitis.

Platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis.

BACKGROUND: Current guidelines recommend screening of people with oesophageal varices via oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count-to-spleen length ratio are non-invasive tests proposed as triage tests for the diagnosis of oesophageal varices. OBJECTIVES: Primary objectives To determine the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non-invasive tests as triage or replacement of oesophago-gastro-duodenoscopy. Secondary objectives To compare the diagnostic accuracy of these same tests for the diagnosis of high-risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.We aimed to perform pair-wise comparisons between the three index tests, while considering predefined cut-off values.We investigated sources of heterogeneity. SEARCH METHODS: The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index - Expanded (Web of Science) (14 June 2016). We applied no language or document-type restrictions. SELECTION CRITERIA: Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count-to-spleen length ratio for the diagnosis of oesophageal varices via oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding. DATA COLLECTION AND ANALYSIS: Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews. MAIN RESULTS: We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross-sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut-off value for the three index tests; most included studies derived the best cut-off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm3)/mm cut-off value for platelet count-to-spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty-four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months. Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut-off value of around 150,000/mm3 from 140,000 to 150,000/mm3; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut-off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut-off value for platelet count-to-spleen length ratio of 909 (n/mm3)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001). Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut-off value of around 150,000/mm3 from 140,000 to 160,000/mm3; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut-off between studies (six studies, 883 participants). Platelet count-to-spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut-off value of around 909 (n/mm3)/mm; from 897 to 921 (n/mm3)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count-to-spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001). DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut-off value of around 115,000/mm3; four studies, 277 participants). Platelet count-to-spleen length z-score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut-off value of 25; two studies, 197 participants). AUTHORS' CONCLUSIONS: Platelet count-to-spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm3)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago-gastro-duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non-invasive tests should be examined.

Pregnancy Outcomes Following In Utero Exposure to Lamotrigine: A Systematic Review and Meta-Analysis.

INTRODUCTION: Lamotrigine is used in pregnancy to control epilepsy and mood disorders. The reproductive safety of this widely used drug remains undefined and may represent a significant public health concern. OBJECTIVE: We aimed to perform a systematic review and meta-analysis of existing knowledge related to malformation rates and maternal-neonatal outcomes after in utero exposure to monotherapy with lamotrigine. METHODS: Relevant studies were identified through systematic searches conducted in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Ovid), and Web of Science (Thomson Reuters) from database inception to July 2016; no language or date restrictions were applied. All publications of clinically relevant outcomes of pregnancies following in utero exposure to lamotrigine were included in this systematic review and meta-analysis. RESULTS: A total of 21 studies describing immediate pregnancy outcomes and rates of congenital malformations fulfilled the inclusion criteria. Compared with disease-matched controls (n = 1412, total number of patients) and healthy controls (n = 774,571, total number of patients), in utero exposure to lamotrigine monotherapy was found to be associated with significantly decreased rates of inborn defects (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.62-2.16 and OR 1.25; 95% CI 0.89-1.74, respectively). Rates of miscarriages, stillbirths, preterm deliveries, and small for gestational age (SGA) neonates were not found to have been increased after in-utero exposure to LTG compared to the general population. Similarly, in utero exposure to lamotrigine monotherapy was not found to be associated with increased rates of inborn defects compared with in utero exposure to carbamazepine, and lamotrigine was found to be statistically significantly less teratogenic than valproic acid (n = 12,958 and 10,748; OR 0.84; 95% CI 0.68-1.03 and OR 0.32; 95% CI 0.26-0.39, respectively). CONCLUSION: No association was found between prenatal lamotrigine monotherapy and increased rates of birth defects and other explored variables related to adverse pregnancy outcomes.

PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

OBJECTIVES: To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). METHODS: Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. RESULTS: Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. CONCLUSIONS: The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.

BACKGROUND: Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy. METHODS AND FINDINGS: Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown. CONCLUSION: This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.

OBJECTIVES: To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs). STUDY DESIGN AND SETTING: We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies. RESULTS: Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups. CONCLUSIONS: Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials.

Sweet tasting solutions for reduction of needle-related procedural pain in children aged one to 16 years.

BACKGROUND: Extensive evidence exists showing analgesic effects of sweet solutions for newborns and infants. It is less certain if the same analgesic effects exist for children one year to 16 years of age. This is an updated version of the original Cochrane review published in Issue 10, 2011 (Harrison 2011) titled Sweet tasting solutions for reduction of needle-related procedural pain in children aged one to 16 years. OBJECTIVES: To determine the efficacy of sweet tasting solutions or substances for reducing needle-related procedural pain in children beyond one year of age. SEARCH METHODS: Searches were run to the end of June 2014. We searched the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Cochrane Methodology Register, Health Technology Assessment, the NHS Economic Evaluation Database, MEDLINE, EMBASE, PsycINFO, and ACP Journal Club (all via OvidSP), and CINAH (via EBSCOhost). We applied no language restrictions. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCT) in which children aged one year to 16 years, received a sweet tasting solution or substance for needle-related procedural pain. Control conditions included water, non-sweet tasting substances, pacifier, distraction, positioning/containment, breastfeeding, or no treatment. DATA COLLECTION AND ANALYSIS: Outcome measures included crying duration, composite pain scores, physiological or behavioral pain indicators, self-report of pain or parental or healthcare professional-report of the child's pain. We reported mean differences (MD), weighted mean difference (WMD), or standardized mean difference (SMD) with 95% confidence intervals (CI) using fixed-effect or random-effects models as appropriate for continuous outcome measures. We reported risk ratio (RR), risk difference (RD), and the number needed to treat to benefit (NNTB) for dichotomous outcomes. We used the I(2) statistic to assess between-study heterogeneity. MAIN RESULTS: We included one unpublished and seven published studies (total of 808 participants); four more studies and 478 more participants than the 2011 review. Six trials included young children aged one to four years receiving sucrose or candy lollypops for immunisation pain compared with water or no treatment. Usual care included topical anaesthetics, upright parental holding, and distraction. All studies were well designed blinded RCTs, however, five of the six studies had a high risk of bias based on small sample sizes.Two studies included school-aged children receiving sweet or unsweetened chewing gum before, or before and during, immunisation and blood collection. Both studies, conducted by the same author, had a high risk of bias based on small sample sizes.Results for the toddlers/pre-school children were conflicting. Duration of cry, using a random-effects model, was not significantly reduced by sweet taste (six trials, 520 children, WMD -15 seconds, 95% CI -54 to 24, I(2) = 94%).Composite pain score at time of first needle was reported in four studies (n = 121 children). The scores were not significantly different between the sucrose and control group (SMD -0.26, 95% CI -1.27 to 0.75, I(2) = 86%).A Children's Hospital of Eastern Ontario Pain Scale score > 4 was significantly less common in the sucrose group compared to the control group in one study (n = 472, RR 0.55, 95% CI 0.45 to 0.67; RD -0.29, 95% CI -0.37 to -0.20; NNTB 3, 95% CI 3 to 5; tests for heterogeneity not applicable.For school-aged children, chewing sweet gum before needle-related painful procedures (two studies, n = 111 children) or during the procedures (two studies, n = 103 children) did not significantly reduce pain scores. A comparison of the Faces Pain Scale scores in children chewing sweet gum before the procedures compared with scores of children chewing unsweetened gum revealed a WMD of -0.15 (95% CI -0.61 to 0.30). Similar results were found when comparing the chewing of sweet gum with unsweetened gum during the procedure (WMD 0.23, 95% CI -0.28 to 0.74). The Colored Analogue Scale for children chewing sweet gum compared to unsweetened gum before the procedure was not significantly different (WMD 0.24 (-0.69 to 1.18)) nor was it different when children chewed the gum during the procedure (WMD 0.86 (95% CI -0.12 to 1.83)). There was no heterogeneity for any of these analyses in school-aged children (I(2) = 0%). AUTHORS' CONCLUSIONS: Based on the eight studies included in this systematic review update, two of which were subgroups of small numbers of eligible toddlers from larger studies, and three of which were pilot RCTs with small numbers of participants, there is insufficient evidence of the analgesic effects of sweet tasting solutions or substances during acutely painful procedures in young children between one and four years of age. Further rigorously conducted, adequately powered RCTs are warranted in this population. Based on the two studies by the same author, there was no evidence of analgesic effects of sweet taste in school-aged children. As there are other effective evidence-based strategies available to use in this age group, further trials are not warranted.Despite the addition of four studies in this review, conclusions have not changed since the last version of the review.

Capsule endoscopy for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis.

BACKGROUND: Current guidelines recommend performance of oesophago-gastro-duodenoscopy at the time of diagnosis of hepatic cirrhosis to screen for oesophageal varices. These guidelines require people to undergo an unpleasant invasive procedure repeatedly with its attendant risks, despite the fact that half of the people do not have identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Video capsule endoscopy is a non-invasive test proposed as an alternative method for the diagnosis of oesophageal varices. OBJECTIVES: To determine the diagnostic accuracy of capsule endoscopy for the diagnosis of oesophageal varices in children or adults with chronic liver disease or portal vein thrombosis, irrespective of the aetiology. To investigate the accuracy of capsule endoscopy as triage or replacement of oesophago-gastro-duodenoscopy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register (October 2013), MEDLINE (Ovid SP) (1950 to October 2013), EMBASE (Ovid SP) (1980 to October 2013), ACP Journal Club (Ovid SP) (1991 to October 2013), Database of Abstracts of Reviews of Effects (DARE) (Ovid SP) (third quarter), Health Technology Assessment (HTA) (Ovid SP) (third quarter), NHS Economic Evaluation Database (NHSEED) (Ovid SP) (third quarter), and Science Citation Index Expanded (SCI-EXPANDED) (ISI Web of Knowledge) (1955 to October 2013). We applied no language or document type restrictions. SELECTION CRITERIA: Studies that evaluated the diagnostic accuracy of capsule endoscopy for the diagnosis of oesophageal varices using oesophago-gastro-duodenoscopy as the reference standard in children or adults of any age, with chronic liver disease or portal vein thrombosis. DATA COLLECTION AND ANALYSIS: We followed the available guidelines provided in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews. We calculated the pooled estimates of sensitivity and specificity using the bivariate model due to the absence of a negative correlation in the receiver operating characteristic (ROC) space and of a threshold effect. MAIN RESULTS: The search identified 16 eligible studies, in which only adults with cirrhosis were included. In one study, people with portal thrombosis were also included. We classified most of the studies at high risk of bias for the 'Participants selection' and the 'Flow and timing' domains. One study assessed the accuracy of capsule endoscopy for the diagnosis of large (high-risk) oesophageal varices. In the remaining15 studies that assessed the accuracy of capsule endoscopy for the diagnosis of oesophageal varices of any size in people with cirrhosis, 936 participants were included; the pooled estimate of sensitivity was 84.8% (95% confidence interval (CI) 77.3% to 90.2%) and of specificity 84.3% (95% CI 73.1% to 91.4%). Eight of these studies included people with suspected varices or people with already diagnosed or even treated varices, or both, introducing a selection bias. Seven studies including only people with suspected but unknown varices were at low risk of bias; the pooled estimate of sensitivity was 79.7% (95% CI 73.1% to 85.0%) and of specificity 86.1% (95% CI 64.5% to 95.5%). Six studies assessed the diagnostic accuracy of capsule endoscopy for the diagnosis of large oesophageal varices, associated with a higher risk of bleeding; the pooled sensitivity was 73.7% (95% CI 52.4% to 87.7%) and of specificity 90.5% (95% CI 84.1% to 94.4%). Two studies also evaluated the presence of red marks, which are another marker of high risk of bleeding; the estimates of sensitivity and specificity varied widely. Two studies obtained similar results with the use of a modified device as index test (string capsule). Due to the absence of data, we could not perform all planned subgroup analyses. Interobserver agreement in the interpretation of capsule endoscopy results and any adverse event attributable to capsule endoscopy were poorly assessed and reported. Only four studies evaluated the interobserver agreement in the interpretation of capsule endoscopy results: the concordance was moderate. The participants' preferences for capsule endoscopy or oesophago-gastro-duodenoscopy were reported differently but seemed in favour of capsule endoscopy in nine of 10 studies. In 10 studies, participants reported some minor discomfort on swallowing the capsule. Only one study identified other significant adverse events, including impaction of the capsule due to previously unidentified oesophageal strictures in two participants. No adverse events were reported as a consequence of the reference standard. AUTHORS' CONCLUSIONS: We cannot support the use of capsule endoscopy as a triage test in adults with cirrhosis, administered before oesophago-gastro-duodenoscopy, despite the low incidence of adverse events and participant reports of being better tolerated. Thus, we cannot conclude that oesophago-gastro-duodenoscopy can be replaced by capsule endoscopy for the detection of oesophageal varices in adults with cirrhosis. We found no data assessing capsule endoscopy in children and in people with portal thrombosis.

A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates.

BACKGROUND: Sucrose has been demonstrated to provide analgesia for minor painful procedures in infants. However, results of trials investigating other sweet solutions for neonatal pain relief have not yet been synthesized. OBJECTIVE: To establish the efficacy of nonsucrose sweet-tasting solutions for pain relief during painful procedures in neonates. METHOD: The present article is a systematic review and meta-analyses of the literature. Standard methods of the Cochrane Neonatal Collaborative Review Group were used. Literature searches were reviewed for randomized controlled trials investigating the use of sweet solutions, except sucrose, for procedural pain management in neonates. Outcomes assessed included validated pain measures and behavioural and physiological indicators. RESULTS: Thirty-eight studies (3785 neonates) were included, 35 of which investigated glucose. Heel lancing was performed in 21/38 studies and venipuncture in 11/38 studies. A 3.6-point reduction in Premature Infant Pain Profile scores during heel lances was observed in studies comparing 20% to 30% glucose with no intervention (two studies, 124 neonates; mean difference -3.6 [95% CI -4.6 to -2.6]; P<0.001; I2=54%). A significant reduction in the incidence of cry after venipuncture for infants receiving 25% to 30% glucose versus water or no intervention was observed (three studies, 130 infants; risk difference -0.18 [95% CI -0.31 to -0.05]; P=0.008, number needed to treat = 6 [95% CI 3 to 20]; I2=63%). CONCLUSIONS: The present systematic review and meta-analyses demonstrate that glucose reduces pain scores and crying during single heel lances and venipunctures. Results indicate that 20% to 30% glucose solutions have analgesic effects and can be recommended as an alternative to sucrose for procedural pain reduction in healthy term and preterm neonates.

Do antipyretics prevent the recurrence of febrile seizures in children? A systematic review of randomized controlled trials and meta-analysis.

OBJECTIVES: To determine the effectiveness of antipyretics use in prevention of subsequent febrile seizures in children. DATA SOURCES: A search for all available electronic databases (MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, ACP Journal Club, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials, Cochrane Methodology Register) from 1950 to July 2011 was done. No language restrictions were applied, but English abstract required. STUDY SELECTION: We included randomized controlled trials comparing the efficacy of antipyretic drugs to placebo in reducing the recurrence rate of febrile seizures in children (6-72 months) with previous febrile seizures. We excluded reviews, letters, and uncontrolled or non-randomized studies. DATA EXTRACTION AND SYNTHESIS: The literature search was performed by a professional medical librarian. Based of the preliminary search, two reviewers independently pooled studies for detailed manual review per the inclusion criteria. We used the Cochrane Review Manager software (Revman 5) to calculate the odds ratio and 95% confidence intervals (CI) for seizure recurrence, assuming a random-effects model. RESULTS: Initial search identified 479 citations, five articles underwent further rigorous evaluation by two reviewers and three papers met the inclusion criteria. In these three studies, 540 children were included, of whom 348 received antipyretics (acetaminophen (15 mg/kg), ibuprofen (5-10mg/kg) or diclofenac (1.5mg/kg)) and 192 received placebo for prevention of subsequent febrile seizures during a 1-2 year follow-up period. Seventy-nine patients (22.7%) in the antipyretics group and forty-seven patients (24.4%) in the placebo group had febrile seizure recurrence during follow up. No statistically significant difference was found between the antipyretics and the placebo groups in the recurrence rate of febrile seizures (OR 0.9, 95% CI: 0.57-1.43). CONCLUSION: Antipyretics were ineffective in reducing the recurrence of febrile seizures.

Folate Intake, MTHFR Polymorphisms, and the Risk of Colorectal Cancer: A Systematic Review and Meta-Analysis.

Background. The objective was to determine whether relationships exist between the methylene-tetrahydrofolate reductase (MTHFR) polymorphisms and risk of colorectal cancer (CRC) and examine whether the risk is modified by level of folate intake. Methods. MEDLINE, Embase, and SCOPUS were searched to May 2012 using the terms "folic acid," "folate," "colorectal cancer," "methylenetetrahydrofolate reductase," "MTHFR." Observational studies were included which (1) assessed the risk of CRC for each polymorphism and/or (2) had defined levels of folate intake for each polymorphism and assessed the risk of CRC. Results. From 910 references, 67 studies met our criteria; hand searching yielded 10 studies. The summary risk estimate comparing the 677CT versus CC genotype was 1.02 (95% CI 0.95-1.10) and for 677TT versus CC was 0.88 (95% CI 0.80-0.96) both with heterogeneity. The summary risk estimates for A1298C polymorphisms suggested no reduced risk. The summary risk estimate for high versus low total folate for the 677CC genotype was 0.70 (95% CI 0.56-0.89) and the 677TT genotype 0.63 (95% CI 0.41-0.97). Conclusion. These results suggest that the 677TT genotype is associated with a reduced risk of developing CRC, under conditions of high total folate intake, and this associated risk remains reduced for both MTHFR 677 CC and TT genotypes.

Sweet tasting solutions for reduction of needle-related procedural pain in children aged one to 16 years.

BACKGROUND: Large numbers of studies have shown that oral sucrose or glucose, with or without non-nutritive sucking given prior to painful procedures result in a significant reduction in behavioral pain responses during or following painful procedures compared with placebo, no treatment or non-nutritive sucking alone, in newborns and infants up to 12 months of age. It is not known if these pain-reducing effects exist for older infants and children one year to 16 years of age. OBJECTIVES: To determine the efficacy of sweet tasting solutions or substances for reducing needle-related procedural pain in children beyond one year of age. SEARCH STRATEGY: We searched the following databases: the Cochrane Register of Controlled Trials (CCTR), MEDLINE, EMBASE, PsycINFO, ACP Journal Club, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Cochrane Methodology Register, Health Technology Assessment, and the NHS Economic Evaluation Database, and on the EBSCOhost interface: CINAHL. We applied no language or document type restrictions. We used the standard methods of The Cochrane Collaboration. The last date of the search was June 30, 2011. SELECTION CRITERIA: Randomized controlled trials (RCTs) in which children from one year up to 16 years of age, received a sweet tasting solution or substance for needle-related procedural pain. Control conditions included water, non-sweet tasting substances, pacifier, distraction, no treatment, positioning/containment or breastfeeding. DATA COLLECTION AND ANALYSIS: Outcome measures included composite pain scores, physiological or behavioral pain indicators, self-report of pain or parental- or healthcare professional-report of child's pain. We reported mean differences (MD) with 95% confidence intervals (CI) using fixed-effect or random-effects models as appropriate for continuous outcome measures. We planned to report risk ratio (RR) and risk difference (RD) for dichotomous outcomes. We used the Chi(2) test and I(2) statistic to assess between-study heterogeneity. MAIN RESULTS: We included four studies (330 participants). Two studies focused on toddlers and pre-school children receiving sucrose for immunization pain compared with water or no treatment and two studies included school-aged children receiving sweet or unsweetened chewing gum before, or, before and during immunization and blood collection. Results for the toddlers/pre-school children were conflicting. Participants in the sucrose group in one study had significantly lower cry duration and behavioral pain scores, compared with the no intervention group, while crying time did not differ between the sucrose and the no intervention group in the other study. For school-aged children, chewing sweet gum either before, or during the procedure, did not significantly reduce pain scores. AUTHORS' CONCLUSIONS: Based on these four studies, two of which were subgroups of small numbers of eligible toddlers from larger studies, there is insufficient evidence of the analgesic effects of sweet tasting solutions or substances during acute painful procedures in children over one year of age. Further well-conducted RCTs are warranted in this population.

Analgesic effects of sweet-tasting solutions for infants: current state of equipoise.

OBJECTIVE: The goal was to review published studies of analgesic effects of sweet solutions, to ascertain areas with sufficient evidence of effectiveness and areas of uncertainty. METHODS: Databases searched included Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature database, and PsycINFO, using the terms pain*, infant*, neonat*, newborn*, sucrose, glucose, and alternative sugars. Publications were sorted according to type, year, painful procedure studied, placebo/no-treatment groups, population studied, and country of publication. RESULTS: A total of 298 relevant unique publications involving human infants were identified; 125 (42%) were primary research studies, of which 116 (93%) were randomized controlled trials. Healthy preterm or term newborns were included in 82 studies (65%), and sick or very low birth weight infants were included in 22 (18%). Most studies included single episodes of painful procedures, with only 3 (2%) conducted over long periods. Procedures investigated most frequently were heel lance (49%), venipuncture (14%), and intramuscular injection (14%). Placebo or no-treatment groups were included in 111 studies (89%); in 103 (93%) of those studies, sweet solutions reduced behavioral responses, compared with placebo/ no treatment. CONCLUSION: Clinical equipoise relating to analgesic effects of sweet solutions no longer exists for single episodes of procedures for healthy preterm and term newborn infants. Uncertainties include outcomes after prolonged use of sweet solutions, concomitant use of other analgesics, and effectiveness beyond the newborn period. Future research should focus on addressing these knowledge and research gaps.

Efficacy of sweet solutions for analgesia in infants between 1 and 12 months of age: a systematic review.

OBJECTIVE: To compare the efficacy of oral sweet solutions to water or no treatment in infants aged 1-12 months during immunisation. METHODS: Randomised controlled trials (RCTs) were retrieved through internet searches or manual searches of reference lists. Search terms included newborn, infant, pain, sucrose and alternative names for sweet solutions. Summary estimates with 95% CIs were calculated and included relative risk (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, and weighted mean differences (WMD) for continuous outcomes. Where pooling of results was not possible, a narrative summary of study results is presented. RESULTS: Of the 695 studies identified, 14 RCTs with 1674 injections met the inclusion criteria. Sucrose or glucose, compared to water or no treatment decreased crying during or following immunisation in 13 of the 14 studies. Infants receiving 30% glucose (three trials, 243 infants) had a decreased RR in crying incidence following immunisation (typical RR 0.80, 95% CI 0.69 to 0.93; RD -0.17, 95% CI -0.29 to -0.05; NNTB 6, 95% CI 3 to 20). With sucrose or glucose, there was a 10% WMD reduction in proportion of crying time (95% CI -18 to -2) and a 12 s reduction in crying duration (95% CI -23 to -0.7 s). An optimal dose of sucrose or glucose could not be ascertained due to the varied volumes and concentrations used. CONCLUSION: Infants aged 1-12 months administered sucrose or glucose before immunisation had moderately reduced incidence and duration of crying. Healthcare professionals should consider using sucrose or glucose before and during immunisation.