Association of Food and Nonalcoholic Beverage Marketing With Children and Adolescents' Eating Behaviors and Health: A Systematic Review and Meta-analysis.

Importance: There is widespread interest in the effect of food marketing on children; however, the comprehensive global evidence reviews are now dated. Objective: To quantify the association of food and nonalcoholic beverage marketing with behavioral and health outcomes in children and adolescents to inform updated World Health Organization guidelines. Data Sources: Twenty-two databases were searched (including MEDLINE, CINAHL, Web of Science, Embase, and The Cochrane Library) with a publication date limit from January 2009 through March 2020. Study Selection: Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Inclusion criteria were primary studies assessing the association of food marketing with specified outcomes in children and adolescents (aged 0-19 years). Exclusion criteria were qualitative studies or those on advertising of infant formula. Of 31 063 articles identified, 96 articles were eligible for inclusion in the systematic review, and 80 articles in the meta-analysis (19 372 participants). Data Extraction and Synthesis: Two reviewers independently extracted data. Random-effects models were used for meta-analyses; meta-regressions, sensitivity analyses, and P curve analyses were also performed. Where appropriate, pooling was conducted using combining P values and vote counting by direction of effect. Grading of Recommendations Assessment, Development, and Evaluation was used to judge certainty of evidence. Main Outcomes and Measures: Critical outcomes were intake, choice, preference, and purchasing. Important outcomes were purchase requests, dental caries, body weight, and diet-related noncommunicable diseases. Results: Participants totaled 19 372 from 80 included articles. Food marketing was associated with significant increases in intake (standardized mean difference [SMD], 0.25; 95% CI, 0.15-0.35; P < .001), choice (odds ratio, 1.77; 95% CI, 1.26-2.50; P < .001), and preference (SMD, 0.30; 95% CI, 0.12-0.49; P = .001). Substantial heterogeneity (all >76%) was unexplained by sensitivity or moderator analyses. The combination of P values for purchase requests was significant but no clear evidence was found for an association of marketing with purchasing. Data on dental health and body weight outcomes were scarce. The certainty of evidence was graded as very low to moderate for intake and choice, and very low for preference and purchasing. Conclusions and Relevance: In this systematic review and meta-analysis, food marketing was associated with increased intake, choice, preference, and purchase requests in children and adolescents. Implementation of policies to restrict children's exposure is expected to benefit child health.

Systematic review of the effect of policies to restrict the marketing of foods and non-alcoholic beverages to which children are exposed.

This systematic review examined the effectiveness of policies restricting the marketing of foods and/or non-alcoholic beverages to children to inform updated World Health Organization (WHO) guidelines. Databases were searched to March 2020. Inclusion criteria were primary studies of any design assessing implemented policies to restrict food marketing to children (0-19 years). Critical outcomes were exposure to and power of marketing, dietary intake, choice, preference, and purchasing. Important outcomes were purchase requests, dental caries, body weight, diet-related noncommunicable diseases, product change, and unintended consequences. Forty-four observational studies met inclusion criteria; most were moderate quality. Pooling was conducted using vote counting by direction of effect, and GRADE was used to judge evidence certainty. Evidence suggests food marketing policies may result in reduced purchases of unhealthy foods and in unintended consequences favorable for public health. Desirable or potentially desirable (for public health) effects of policies on food marketing exposure and power were also found. Evidence on diet and product change was very limited. The certainty of evidence was very low for four outcomes (exposure, power, dietary intake, and product change) and low for two (purchasing and unintended consequences). Policies can effectively limit food marketing to children; policymakers should prioritize mandatory approaches aligned with WHO recommendations.

Prophylactic removal of impacted mandibular third molars: a systematic review and economic evaluation.

BACKGROUND: Impacted third molars are third molars that are blocked, by soft tissue or bone, from fully erupting through the gum. This can cause pain and disease. The treatment options for people with impacted third molars are removal or retention with standard care. If there are pathological changes, the current National Institute for Health and Care Excellence guidance states that the impacted third molar should be removed. OBJECTIVE: The objective of this study was to appraise the clinical effectiveness and cost-effectiveness of the prophylactic removal of impacted mandibular third molars compared with retention of, and standard care for, impacted third molars. METHODS: Five electronic databases were searched (1999 to 29 April 2016) to identify relevant evidence [The Cochrane Library (searched 4 April 2016 and 29 April 2016), MEDLINE (searched 4 April 2016 and 29 April 2016), EMBASE (searched 4 April 2016 and 29 April 2016), EconLit (searched 4 April 2016 and 29 April 2016) and NHS Economic Evaluation Database (searched 4 April 2016)]. Studies that compared the prophylactic removal of impacted mandibular third molars with retention and standard care or studies that assessed the outcomes from either approach were included. The clinical outcomes considered were pathology associated with retention, post-operative complications following extraction and adverse effects of treatment. Cost-effectiveness outcomes included UK costs and health-related quality-of-life measures. In addition, the assessment group constructed a de novo economic model to compare the cost-effectiveness of a prophylactic removal strategy with that of retention and standard care. RESULTS: The clinical review identified four cohort studies and nine systematic reviews. In the two studies that reported on surgical complications, no serious complications were reported. Pathological changes due to retention of asymptomatic impacted mandibular third molars were reported by three studies. In these studies, the extraction rate for retained impacted mandibular third molars varied from 5.5% to 31.4%; this variation can be explained by the differing follow-up periods (i.e. 1 and 5 years). The findings from this review are consistent with the findings from previous systematic reviews. Two published cost-effectiveness studies were identified. The authors of both studies concluded that, to their knowledge, there is currently no economic evidence to support the prophylactic removal of impacted mandibular third molars. The results generated by the assessment group's lifetime economic model indicated that the incremental cost-effectiveness ratio per quality-adjusted life-year gained for the comparison of a prophylactic removal strategy with a retention and standard care strategy is £11,741 for people aged 20 years with asymptomatic impacted mandibular third molars. The incremental cost per person associated with prophylactic extraction is £55.71, with an incremental quality-adjusted life-year gain of 0.005 per person. The base-case incremental cost-effectiveness ratio per quality-adjusted life-year gained was found to be robust when a range of sensitivity and scenario analyses were carried out. LIMITATIONS: Limitations of the study included that no head-to-head trials comparing the effectiveness of prophylactic removal of impacted mandibular third molars with retention and standard care were identified with the assessment group model that was built on observational data. Utility data on impacted mandibular third molars and their symptoms are lacking. CONCLUSIONS: The evidence comparing the prophylactic removal of impacted mandibular third molars with retention and standard care is very limited. However, the results from an exploratory assessment group model, which uses available evidence on symptom development and extraction rates of retained impacted mandibular third molars, suggest that prophylactic removal may be the more cost-effective strategy. FUTURE WORK: Effectiveness evidence is lacking. Head-to-head trials comparing the prophylactic removal of trouble-free impacted mandibular third molars with retention and watchful waiting are required. If this is not possible, routine clinical data, using common definitions and outcome reporting methods, should be collected. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016037776. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 30. See the NIHR Journals Library website for further project information.

Third molars, commonly known as wisdom teeth, may come through the gum (erupt) without any problems, usually during young adulthood (aged 18­24 years). However, in some cases they are unable to erupt because they are poorly aligned or obstructed by other teeth, gums or bone. They are then referred to as 'impacted'. Historically, dentists often recommended that these teeth be removed, so as not to cause problems later in life. This is referred to as 'prophylactic' removal. In 2000, the National Institute for Health and Care Excellence reviewed this practice and recommended that these teeth should not be removed if they are not bothersome to the person. Many dentists and oral surgeons have disagreed with this decision, believing that it is more difficult to remove these teeth later in life, and that there are more complications for the patient if they are removed later in life. Our review group carried out a systematic review of the available clinical effectiveness and cost-effectiveness evidence of the prophylactic removal of impacted third molars. The review identified four clinical studies, none of which provided strong evidence for or against the prophylactic removal of these teeth. These findings are similar to those of nine previous reviews. There is also very little research reported that relates to the cost-effectiveness of the procedure, with only three studies identified. With the available evidence on the rates of extraction and the symptoms experienced by people who keep their impacted mandibular third molar, we built an exploratory economic model to assess the cost-effectiveness of recommending prophylactic removal compared with that of recommending watchful waiting. Results from the model suggested that a prophylactic removal strategy costs more than a watchful waiting strategy, but leads to improvements in quality of life. When the costs and quality-of-life measures that are associated with the two strategies are compared, the resulting statistic is £11,741 per quality-adjusted life-year gained, which would probably be good value for money for the NHS.

Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation.

BACKGROUND: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055516. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

WHAT WAS THE PROBLEM?: Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany), may be new treatment options. WHAT DID WE DO?: We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment. WHAT DID WE FIND?: Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects. WHAT DOES THIS MEAN?: At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

Topiramate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: The majority of people with epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies, and up to 30% from clinical series (not population-based), develop drug-resistant epilepsy, especially those with focal-onset seizures. In this review, we summarise the current evidence regarding topiramate, an antiepileptic drug first marketed in 1996, when used as an add-on treatment for drug-resistant focal epilepsy.This is an update of a Cochrane Review first published in 1999, and last updated in 2014. OBJECTIVES: To evaluate the efficacy and tolerability of topiramate when used as an add-on treatment for people with drug-resistant focal epilepsy. SEARCH METHODS: For the latest update of this review we searched the following databases on 2 July 2018: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (Ovid, 1946- ); ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We also contacted the manufacturers of topiramate and researchers in the field to identify any ongoing or unpublished studies. SELECTION CRITERIA: Randomised, placebo-controlled add-on trials of topiramate, recruiting people with drug-resistant focal epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (1) 50% or greater reduction in seizure frequency; (2) seizure freedom; (3) treatment withdrawal (any reason); (4) adverse effects. Primary analyses were intention-to-treat (ITT), and summary risk ratios (RRs) with 95% confidence intervals (95% CIs) are presented. We evaluated dose-response in regression models. We carried out a 'Risk of bias' assessment for each included study using the Cochrane 'Risk of bias' tool and assessed the overall certainty of evidence using the GRADE approach. MAIN RESULTS: We included 12 trials, representing 1650 participants. Baseline phases ranged from four to 12 weeks and double-blind phases ranged from 11 to 19 weeks. The RR for a 50% or greater reduction in seizure frequency with add-on topiramate compared to placebo was 2.71 (95% CI 2.05 to 3.59; 12 studies; high-certainty evidence). Dose regression analysis showed increasing effect with increasing topiramate dose demonstrated by an odds ratio (OR) of 1.45 (95% CI 1.28 to 1.64; P < 0.001) per 200 mg/d increase in topiramate dosage. The proportion of participants achieving seizure freedom was also significantly increased with add-on topiramate compared to placebo (RR 3.67, 95% CI 1.79 to 7.54; 8 studies; moderate-certainty evidence). Treatment withdrawal was significantly higher for add-on topiramate compared to placebo (RR 2.37, 95% CI 1.66 to 3.37; 12 studies; high-certainty evidence). The RRs for the following adverse effects indicate that they are significantly more prevalent with topiramate, compared to placebo: ataxia 2.29 (99% CI 1.10 to 4.77; 4 studies); concentration difficulties 7.81 (99% CI 2.08 to 29.29; 6 studies; moderate-certainty evidence); dizziness 1.52 (99% CI 1.07 to 2.16; 8 studies); fatigue 2.08 (99% CI 1.37 to 3.15; 10 studies); paraesthesia 3.65 (99% CI 1.58 to 8.39; 7 studies; moderate-certainty evidence); somnolence 2.44 (99% CI 1.61 to 3.68; 9 studies); 'thinking abnormally' 5.70 (99% CI 2.26 to 14.38; 4 studies; high-certainty evidence); and weight loss 3.99 (99% CI 1.82 to 8.72; 9 studies; low-certainty evidence). Evidence of publication bias for the primary outcome was found (Egger test, P = 0.001). We rated all studies included in the review as having either low or unclear risk of bias. Overall, we assessed the evidence as moderate to high certainty due to the evidence of publication bias, statistical heterogeneity and imprecision, which was partially compensated for by large effect sizes. AUTHORS' CONCLUSIONS: Topiramate has efficacy as an add-on treatment for drug-resistant focal epilepsy as it is almost three times more effective compared to a placebo in reducing seizures. The trials reviewed were of relatively short duration and provided no evidence for the long-term efficacy of topiramate. Short-term use of add-on topiramate was shown to be associated with several adverse events. The results of this review should only be applied to adult populations as only one study included children. Future research should consider further examining the effect of dose.

A systematic review of the diagnostic accuracy of automated tests for cognitive impairment.

OBJECTIVE: The aim of this review is to determine whether automated computerised tests accurately identify patients with progressive cognitive impairment and, if so, to investigate their role in monitoring disease progression and/or response to treatment. METHODS: Six electronic databases (Medline, Embase, Cochrane, Institute for Scientific Information, PsycINFO, and ProQuest) were searched from January 2005 to August 2015 to identify papers for inclusion. Studies assessing the diagnostic accuracy of automated computerised tests for mild cognitive impairment (MCI) and early dementia against a reference standard were included. Where possible, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios were calculated. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess risk of bias. RESULTS: Sixteen studies assessing 11 diagnostic tools for MCI and early dementia were included. No studies were eligible for inclusion in the review of tools for monitoring progressive disease and response to treatment. The overall quality of the studies was good. However, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that statistical analysis was not possible. CONCLUSION: Some tests have shown promising results for identifying MCI and early dementia. However, concerns over small sample sizes, lack of replicability of studies, and lack of evidence available make it difficult to make recommendations on the clinical use of the computerised tests for diagnosing, monitoring progression, and treatment response for MCI and early dementia. Research is required to establish stable cut-off points for automated computerised tests used to diagnose patients with MCI or early dementia.

Drug-eluting stents versus bare-metal stents for acute coronary syndrome.

BACKGROUND: Approximately 3.7 million people died from acute coronary syndrome worldwide in 2012. Acute coronary syndrome, also known as myocardial infarction or unstable angina pectoris, is caused by a sudden blockage of the blood supplied to the heart muscle. Percutaneous coronary intervention is often used for acute coronary syndrome, but previous systematic reviews on the effects of drug-eluting stents compared with bare-metal stents have shown conflicting results with regard to myocardial infarction; have not fully taken account of the risk of random and systematic errors; and have not included all relevant randomised clinical trials. OBJECTIVES: To assess the benefits and harms of drug-eluting stents versus bare-metal stents in people with acute coronary syndrome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, SCI-EXPANDED, and BIOSIS from their inception to January 2017. We also searched two clinical trials registers, the European Medicines Agency and the US Food and Drug Administration databases, and pharmaceutical company websites. In addition, we searched the reference lists of review articles and relevant trials. SELECTION CRITERIA: Randomised clinical trials assessing the effects of drug-eluting stents versus bare-metal stents for acute coronary syndrome. We included trials irrespective of publication type, status, date, or language. DATA COLLECTION AND ANALYSIS: We followed our published protocol and the methodological recommendations of Cochrane. Two review authors independently extracted data. We assessed the risks of systematic error by bias domains. We conducted Trial Sequential Analyses to control the risks of random errors. Our primary outcomes were all-cause mortality, major cardiovascular events, serious adverse events, and quality of life. Our secondary outcomes were angina, cardiovascular mortality, and myocardial infarction. Our primary assessment time point was at maximum follow-up. We assessed the quality of the evidence by the GRADE approach. MAIN RESULTS: We included 25 trials randomising a total of 12,503 participants. All trials were at high risk of bias, and the quality of evidence according to GRADE was low to very low. We included 22 trials where the participants presented with ST-elevation myocardial infarction, 1 trial where participants presented with non-ST-elevation myocardial infarction, and 2 trials where participants presented with a mix of acute coronary syndromes.Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of all-cause mortality or major cardiovascular events. The absolute risk of death was 6.97% in the drug-eluting stents group compared with 7.74% in the bare-metal stents group based on the risk ratio (RR) of 0.90 (95% confidence interval (CI) 0.78 to 1.03, 11,250 participants, 21 trials/22 comparisons, low-quality evidence). The absolute risk of a major cardiovascular event was 6.36% in the drug-eluting stents group compared with 6.63% in the bare-metal stents group based on the RR of 0.96 (95% CI 0.83 to 1.11, 10,939 participants, 19 trials/20 comparisons, very low-quality evidence). The results of Trial Sequential Analysis showed that we did not have sufficient information to confirm or reject our anticipated risk ratio reduction of 10% on either all-cause mortality or major cardiovascular events at maximum follow-up.Meta-analyses at maximum follow-up showed evidence of a benefit when comparing drug-eluting stents with bare-metal stents on the risk of a serious adverse event. The absolute risk of a serious adverse event was 18.04% in the drug-eluting stents group compared with 23.01% in the bare-metal stents group based on the RR of 0.80 (95% CI 0.74 to 0.86, 11,724 participants, 22 trials/23 comparisons, low-quality evidence), and Trial Sequential Analysis confirmed this result. When assessing each specific type of adverse event included in the serious adverse event outcome separately, the majority of the events were target vessel revascularisation. When target vessel revascularisation was analysed separately, meta-analysis showed evidence of a benefit of drug-eluting stents, and Trial Sequential Analysis confirmed this result.Meta-analyses at maximum follow-up showed no evidence of a difference when comparing drug-eluting stents with bare-metal stents on the risk of cardiovascular mortality (RR 0.91, 95% CI 0.76 to 1.09, 9248 participants, 14 trials/15 comparisons, very low-quality evidence) or myocardial infarction (RR 0.98, 95% CI 0.82 to 1.18, 10,217 participants, 18 trials/19 comparisons, very low-quality evidence). The results of the Trial Sequential Analysis showed that we had insufficient information to confirm or reject our anticipated risk ratio reduction of 10% on cardiovascular mortality and myocardial infarction.No trials reported results on quality of life or angina. AUTHORS' CONCLUSIONS: The current evidence suggests that drug-eluting stents may lead to fewer serious adverse events compared with bare-metal stents without increasing the risk of all-cause mortality or major cardiovascular events. However, our Trial Sequential Analysis showed that there currently was not enough information to assess a risk ratio reduction of 10% for all-cause mortality, major cardiovascular events, cardiovascular mortality, or myocardial infarction, and there were no data on quality of life or angina. The evidence in this review was of low to very low quality, and the true result may depart substantially from the results presented in this review.More randomised clinical trials with low risk of bias and low risks of random errors are needed if the benefits and harms of drug-eluting stents for acute coronary syndrome are to be assessed properly. More data are needed on the outcomes all-cause mortality, major cardiovascular events, quality of life, and angina to reduce the risk of random error.

Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child.

BACKGROUND: There is evidence that certain antiepileptic drugs (AEDs) are teratogenic and are associated with an increased risk of congenital malformation. The majority of women with epilepsy continue taking AEDs throughout pregnancy; therefore it is important that comprehensive information on the potential risks associated with AED treatment is available. OBJECTIVES: To assess the effects of prenatal exposure to AEDs on the prevalence of congenital malformations in the child. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (September 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 11), MEDLINE (via Ovid) (1946 to September 2015), EMBASE (1974 to September 2015), Pharmline (1978 to September 2015), Reprotox (1983 to September 2015) and conference abstracts (2010-2015) without language restriction. SELECTION CRITERIA: We included prospective cohort controlled studies, cohort studies set within pregnancy registries and randomised controlled trials. Participants were women with epilepsy taking AEDs; the two control groups were women without epilepsy and women with epilepsy who were not taking AEDs during pregnancy. DATA COLLECTION AND ANALYSIS: Three authors independently selected studies for inclusion. Five authors completed data extraction and risk of bias assessments. The primary outcome was the presence of a major congenital malformation. Secondary outcomes included specific types of major congenital malformations. Where meta-analysis was not possible, we reviewed included studies narratively. MAIN RESULTS: We included 50 studies, with 31 contributing to meta-analysis. Study quality varied, and given the observational design, all were at high risk of certain biases. However, biases were balanced across the AEDs investigated and we believe that the results are not explained by these biases.Children exposed to carbamazepine (CBZ) were at a higher risk of malformation than children born to women without epilepsy (N = 1367 vs 2146, risk ratio (RR) 2.01, 95% confidence interval (CI) 1.20 to 3.36) and women with untreated epilepsy (N = 3058 vs 1287, RR 1.50, 95% CI 1.03 to 2.19). Children exposed to phenobarbital (PB) were at a higher risk of malformation than children born to women without epilepsy (N = 345 vs 1591, RR 2.84, 95% CI 1.57 to 5.13). Children exposed to phenytoin (PHT) were at an increased risk of malformation compared with children born to women without epilepsy (N = 477 vs 987, RR 2.38, 95% CI 1.12 to 5.03) and to women with untreated epilepsy (N = 640 vs 1256, RR 2.40, 95% CI 1.42 to 4.08). Children exposed to topiramate (TPM) were at an increased risk of malformation compared with children born to women without epilepsy (N = 359 vs 442, RR 3.69, 95% CI 1.36 to 10.07). The children exposed to valproate (VPA) were at a higher risk of malformation compared with children born to women without epilepsy (N = 467 vs 1936, RR 5.69, 95% CI 3.33 to 9.73) and to women with untreated epilepsy (N = 1923 vs 1259, RR 3.13, 95% CI 2.16 to 4.54). There was no increased risk for major malformation for lamotrigine (LTG). Gabapentin (GBP), levetiracetam (LEV), oxcarbazepine (OXC), primidone (PRM) or zonisamide (ZNS) were not associated with an increased risk, however, there were substantially fewer data for these medications.For AED comparisons, children exposed to VPA had the greatest risk of malformation (10.93%, 95% CI 8.91 to 13.13). Children exposed to VPA were at an increased risk of malformation compared with children exposed to CBZ (N = 2529 vs 4549, RR 2.44, 95% CI 2.00 to 2.94), GBP (N = 1814 vs 190, RR 6.21, 95% CI 1.91 to 20.23), LEV (N = 1814 vs 817, RR 5.82, 95% CI 3.13 to 10.81), LTG (N = 2021 vs 4164, RR 3.56, 95% CI 2.77 to 4.58), TPM (N = 1814 vs 473, RR 2.35, 95% CI 1.40 to 3.95), OXC (N = 676 vs 238, RR 3.71, 95% CI 1.65 to 8.33), PB (N = 1137 vs 626, RR 1.59, 95% CI 1.11 to 2.29, PHT (N = 2319 vs 1137, RR 2.00, 95% CI 1.48 to 2.71) or ZNS (N = 323 vs 90, RR 17.13, 95% CI 1.06 to 277.48). Children exposed to CBZ were at a higher risk of malformation than those exposed to LEV (N = 3051 vs 817, RR 1.84, 95% CI 1.03 to 3.29) and children exposed to LTG (N = 3385 vs 4164, RR 1.34, 95% CI 1.01 to 1.76). Children exposed to PB were at a higher risk of malformation compared with children exposed to GBP (N = 204 vs 159, RR 8.33, 95% CI 1.04 to 50.00), LEV (N = 204 vs 513, RR 2.33, 95% CI 1.04 to 5.00) or LTG (N = 282 vs 1959, RR 3.13, 95% CI 1.64 to 5.88). Children exposed to PHT had a higher risk of malformation than children exposed to LTG (N = 624 vs 4082, RR 1.89, 95% CI 1.19 to 2.94) or to LEV (N = 566 vs 817, RR 2.04, 95% CI 1.09 to 3.85); however, the comparison to LEV was not significant in the random-effects model. Children exposed to TPM were at a higher risk of malformation than children exposed to LEV (N = 473 vs 817, RR 2.00, 95% CI 1.03 to 3.85) or LTG (N = 473 vs 3975, RR 1.79, 95% CI 1.06 to 2.94). There were no other significant differences, or comparisons were limited to a single study.We found significantly higher rates of specific malformations associating PB exposure with cardiac malformations and VPA exposure with neural tube, cardiac, oro-facial/craniofacial, and skeletal and limb malformations in comparison to other AEDs. Dose of exposure mediated the risk of malformation following VPA exposure; a potential dose-response association for the other AEDs remained less clear. AUTHORS' CONCLUSIONS: Exposure in the womb to certain AEDs carried an increased risk of malformation in the foetus and may be associated with specific patterns of malformation. Based on current evidence, LEV and LTG exposure carried the lowest risk of overall malformation; however, data pertaining to specific malformations are lacking. Physicians should discuss both the risks and treatment efficacy with the patient prior to commencing treatment.

Automated tests for diagnosing and monitoring cognitive impairment: a diagnostic accuracy review.

BACKGROUND: Cognitive impairment is a growing public health concern, and is one of the most distinctive characteristics of all dementias. The timely recognition of dementia syndromes can be beneficial, as some causes of dementia are treatable and are fully or partially reversible. Several automated cognitive assessment tools for assessing mild cognitive impairment (MCI) and early dementia are now available. Proponents of these tests cite as benefits the tests' repeatability and robustness and the saving of clinicians' time. However, the use of these tools to diagnose and/or monitor progressive cognitive impairment or response to treatment has not yet been evaluated. OBJECTIVES: The aim of this review was to determine whether or not automated computerised tests could accurately identify patients with progressive cognitive impairment in MCI and dementia and, if so, to investigate their role in monitoring disease progression and/or response to treatment. DATA SOURCES: Five electronic databases (MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science and PsycINFO), plus ProQuest, were searched from 2005 to August 2015. The bibliographies of retrieved citations were also examined. Trial and research registers were searched for ongoing studies and reviews. A second search was run to identify individual test costs and acquisition costs for the various tools identified in the review. REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. The results of the data extraction and quality assessment for each study are presented in structured tables and as a narrative summary. RESULTS: The electronic searching of databases, including ProQuest, resulted in 13,542 unique citations. The titles and abstracts of these were screened and 399 articles were shortlisted for full-text assessment. Sixteen studies were included in the diagnostic accuracy review. No studies were eligible for inclusion in the review of tools for monitoring progressive disease. Eleven automated computerised tests were assessed in the 16 included studies. The overall quality of the studies was good; however, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that meaningful synthesis or statistical analysis was not possible. LIMITATIONS: The main limitation of this review is the substantial heterogeneity of the tests assessed in the included studies. As a result, no meta-analyses could be undertaken. CONCLUSION: The quantity of information available is insufficient to be able to make recommendations on the clinical use of the computerised tests for diagnosing and monitoring MCI and early dementia progression. The value of these tests also depends on the costs of acquisition, training, administration and scoring. FUTURE WORK: Research is required to establish stable cut-off points for automated computerised tests that are used to diagnose patients with MCI or early dementia. Additionally, the costs associated with acquiring and using these tests in clinical practice should be estimated. STUDY REGISTRATION: The study is registered as PROSPERO CRD42015025410. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Nitrous oxide-based versus nitrous oxide-free general anaesthesia and accidental awareness during general anaesthesia in surgical patients.

BACKGROUND: Accidental awareness during general anaesthesia (AAGA) is when a patient unintentionally becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event. Incidence estimates for AAGA vary, with the most common estimate being one to two cases per 1000 general anaesthetics. Evidence linking nitrous oxide use and an increased risk of AAGA has come from observational studies data but the literature is contradictory, with some studies finding a protective effect of nitrous oxide. OBJECTIVES: To assess the effect of general anaesthesia including nitrous oxide on the risk of AAGA in patients aged five years and over. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registers ((www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/network/en/) and Current Controlled Trials (www.isrctn.com/)) for eligible studies on December 9 2015. In addition, we conducted forward and backward citation searching using key identified papers. SELECTION CRITERIA: We considered all randomized controlled trials (RCTs), including quasi-randomized studies and cluster-randomized studies, of participants aged five years or older receiving general anaesthesia for any type of surgery.We included trials in which participants receiving general anaesthesia that included nitrous oxide for maintenance at a concentration of at least 30% were compared with participants receiving no nitrous oxide during general anaesthesia. The intervention group must have received nitrous oxide in conjunction with an additional anaesthetic. We excluded studies where the depth of anaesthesia differed between the study arms. For inclusion in the review, studies needed to state in their methods that they planned to assess AAGA. We defined this as when a patient becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane to identify studies. We extracted data and conducted 'Risk of bias' assessment using the Covidence database. MAIN RESULTS: We included 15 studies. The total number of participants included in the analyses was 3520. Most studies were small with fewer than 120 participants, although two larger studies with 2012 and 671 participants were included. There was considerable variation in many of the study characteristics, including the anaesthetics used. The concentrations of nitrous oxide varied between 50% and 70%, and half of the studies used clinical signs and haemodynamic changes to monitor depth of anaesthesia.As it was not possible to blind the anaesthetist to the anaesthetic used, we rated all studies at high risk of performance bias and we therefore downgraded the quality of evidence by one level for risk of bias using the GRADE approach. Other types of bias were generally low, or were rated unclear due to missing information.No studies were designed to measure AAGA as the primary outcome, and were therefore statistically underpowered to answer this review question. Despite the inclusion of 3520 participants, only three awareness events were reported by two studies. In one study the event was due to technical failure. Due to the rarity of the events, we did not consider it appropriate to pool the data, and we therefore downgraded the quality of evidence by a further level for imprecision using GRADE. AUTHORS' CONCLUSIONS: It is not possible to draw any conclusions from this review. The included studies were mainly small (fewer than 120 participants) and there were limited estimates of effect, with only two studies reporting any events. We cannot therefore determine whether the use of nitrous oxide in general anaesthesia increases, decreases or has no effect on the risk of accidental awareness.

The importance of appropriate allocation to offending behavior programs.

This study examined the impact on reconviction of appropriate allocation to three general offending behavior programs involving adult male offenders in the English and Welsh Probation Service. Appropriate allocation was defined by level of risk for reconviction. There were three allocation groups: too low, appropriate, and too high. Using a quasi-experimental design, the reconviction rates of offenders who were allocated to and completed a program, offenders allocated to a program who failed to start, and a comparison group were compared. It was found that the appropriateness of allocation affected reconviction independently of treatment group. Furthermore, in line with the risk principle, there was an interaction between treatment group and the appropriateness of allocation.