OBJECTIVES: To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.

SEARCH METHODS: Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.Date of the last searches: 14 March 2016.

SELECTION CRITERIA: Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.

DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.

MAIN RESULTS: Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001).One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period.

OBJECTIVES: To determine the effectiveness of rapamycin or rapalogs in people with TSC for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.

SEARCH METHODS: We identified relevant studies from the Cochrane-Central-Register-of-Controlled-Trials (CENTRAL), Ovid MEDLINE and ongoing trials registries with no language restrictions. We searched conference proceedings and abstract books of conferences. Date of the last searches: 15 July 2022.

SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of rapamycin or rapalogs in people with TSC.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of each study; a third review author verified the extracted data and risk of bias decisions. We assessed the certainty of the evidence using GRADE.

MAIN RESULTS: The current update added seven RCTs, bringing the total number to 10 RCTs (with 1008 participants aged 3 months to 65 years; 484 males). All TSC diagnoses were by consensus criteria as a minimum. In parallel studies, 645 participants received active interventions and 340 placebo. Evidence is low-to-high certainty and study quality is mixed; mostly a low risk of bias across domains, but one study had a high risk of performance bias (lack of blinding) and three studies had a high risk of attrition bias. Manufacturers of the investigational products supported eight studies. Systemic administration Six studies (703 participants) administered everolimus (rapalog) orally. More participants in the intervention arm reduced renal angiomyolipoma size by 50% (risk ratio (RR) 24.69, 95% confidence interval (CI) 3.51 to 173.41; P = 0.001; 2 studies, 162 participants, high-certainty evidence). In the intervention arm, more participants in the intervention arm reduced SEGA tumour size by 50% (RR 27.85, 95% CI 1.74 to 444.82; P = 0.02; 1 study; 117 participants; moderate-certainty evidence) ,and reported more skin responses (RR 5.78, 95% CI 2.30 to 14.52; P = 0.0002; 2 studies; 224 participants; high-certainty evidence). In one 18-week study (366 participants), the intervention led to 25% fewer seizures (RR 1.63, 95% CI 1.27 to 2.09; P = 0.0001) or 50% fewer seizures (RR 2.28, 95% CI 1.44 to 3.60; P = 0.0004); but there was no difference in numbers being seizure-free (RR 5.30, 95% CI 0.69 to 40.57; P = 0.11) (moderate-certainty evidence). One study (42 participants) showed no difference in neurocognitive, neuropsychiatry, behavioural, sensory and motor development (low-certainty evidence). Total adverse events (AEs) did not differ between groups (RR 1.09, 95% CI 0.97 to 1.22; P = 0.16; 5 studies; 680 participants; high-certainty evidence). However, the intervention group experienced more AEs resulting in withdrawal, interruption of treatment, or reduced dose (RR 2.61, 95% CI 1.58 to 4.33; P = 0.0002; 4 studies; 633 participants; high-certainty evidence and also reported more severe AEs (RR 2.35, 95% CI 0.99 to 5.58; P = 0.05; 2 studies; 413 participants; high-certainty evidence). Topical (skin) administration Four studies (305 participants) administered rapamycin topically. More participants in the intervention arm showed a response to skin lesions (RR 2.72, 95% CI 1.76 to 4.18; P < 0.00001; 2 studies; 187 participants; high-certainty evidence) and more participants in the placebo arm reported a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; 1 study; 164 participants; high-certainty evidence). More participants in the intervention arm responded to facial angiofibroma at one to three months (RR 28.74, 95% CI 1.78 to 463.19; P = 0.02) and three to six months (RR 39.39, 95% CI 2.48 to 626.00; P = 0.009; low-certainty evidence). Similar results were noted for cephalic plaques at one to three months (RR 10.93, 95% CI 0.64 to 186.08; P = 0.10) and three to six months (RR 7.38, 95% CI 1.01 to 53.83; P = 0.05; low-certainty evidence). More participants on placebo showed a deterioration of skin lesions (RR 0.27, 95% CI 0.15 to 0.49; P < 0.0001; 1 study; 164 participants; moderate-certainty evidence). The intervention arm reported a higher general improvement score (MD -1.01, 95% CI -1.68 to -0.34; P < 0.0001), but no difference specifically in the adult subgroup (MD -0.75, 95% CI -1.58 to 0.08; P = 0.08; 1 study; 36 participants; moderate-certainty evidence). Participants in the intervention arm reported higher satisfaction than with placebo (MD -0.92, 95% CI -1.79 to -0.05; P = 0.04; 1 study; 36 participants; low-certainty evidence), although again with no difference among adults (MD -0.25, 95% CI -1.52 to 1.02; P = 0.70; 1 study; 18 participants; low-certainty evidence). Groups did not differ in change in quality of life at six months (MD 0.30, 95% CI -1.01 to 1.61; P = 0.65; 1 study; 62 participants; low-certainty evidence). Treatment led to a higher risk of any AE compared to placebo (RR 1.72, 95% CI 1.10, 2.67; P = 0.02; 3 studies; 277 participants; moderate-certainty evidence); but no difference between groups in severe AEs (RR 0.78, 95% CI 0.19 to 3.15; P = 0.73; 1 study; 179 participants; moderate-certainty evidence).

OBJECTIVES: To assess the effectiveness of fibrin glue compared to sutures in conjunctival autografting for the surgical treatment of pterygium.

SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2016), Embase (January 1980 to October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 14 October 2016.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) in any setting where fibrin glue was compared with sutures to treat people with pterygium.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed trial quality, and extracted data using standard methodological procedures expected by Cochrane. Our primary outcome was recurrence of pterygium defined as any re-growth of tissue from the area of excision across the limbus onto the cornea. The secondary outcomes were surgical time and complication rate. We graded the certainty of the evidence using GRADE.

MAIN RESULTS: We included 14 RCTs conducted in Brazil, China, Egypt, India, Malaysia, New Zealand, Philippines, Saudi Arabia, Sweden and Turkey. The trials were published between 2004 and 2016, and were assessed as a mixture of unclear and low risk of bias with three studies at high risk of attrition bias. Only adults were enrolled in these studies.Using fibrin glue for the conjunctival autograft may result in less recurrence of pterygium compared with using sutures (risk ratio (RR) 0.47, 95% CI 0.27 to 0.82, 762 eyes, 12 RCTs; low-certainty evidence). If pterygium recurs after approximately 10 in every 100 surgeries with sutures, then using fibrin glue may result in approximately 5 fewer cases of recurrence in every 100 surgeries (95% CI 2 fewer to 7 fewer cases). Using fibrin glue may lead to more complications compared with sutures (RR 1.92; 95% CI 1.22 to 3.02, 11 RCTs, 673 eyes, low-certainty evidence). The most common complications reported were: graft dehiscence, graft retraction and granuloma. On average using fibrin glue may mean that surgery is quicker compared with suturing (mean difference (MD) -17.01 minutes 95% CI -20.56 to -13.46), 9 RCTs, 614 eyes, low-certainty evidence).

OBJECTIVES: The objective of this review is to compare SFH measurement with serial ultrasound measurement of fetal parameters or clinical palpation to detect abnormal fetal growth (IUGR and large-for-gestational age), and improving perinatal outcome.

SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (14 July 2015) and reference lists of retrieved articles.

SELECTION CRITERIA: Randomised controlled trials including quasi-randomised and cluster-randomised trials involving pregnant women with singleton fetuses at 20 weeks' gestation and above comparing tape measurement of SFH with serial ultrasound measurement of fetal parameters or clinical palpation using anatomical landmarks.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.

MAIN RESULTS: One trial involving 1639 women was included. It compared SFH measurement with clinical abdominal palpation.There was no difference in the two reported primary outcomes of incidence of small-for-gestational age (risk ratio (RR) 1.32; 95% confidence interval (CI) 0.92 to 1.90, low quality evidence) or perinatal death.(RR 1.25, 95% CI 0.38 to 4.07; participants = 1639, low quality evidence). There were no data on the neonatal detection of large-for-gestational age (variously defined by authors). There was no difference in the reported secondary outcomes of neonatal hypoglycaemia, admission to neonatal nursery, admission to the neonatal nursery for IUGR (low quality evidence), induction of labour and caesarean section (very low quality evidence). The trial did not address the other outcomes specified in the 'Summary of findings' table (intrauterine death; neurodevelopmental outcome in childhood). GRADEpro software was used to assess the quality of evidence, downgrading of evidence was based on including a small single study with unclear risk of bias and a wide confidence interval crossing the line of no effect.

OBJECTIVES: To evaluate the effects of sealants compared to no sealant or a different sealant in preventing pit and fissure caries on the occlusal surfaces of primary molars in children and to report the adverse effects and the retention of different types of sealants.

SEARCH METHODS: An information specialist searched four bibliographic databases up to 11 February 2021 and used additional search methods to identify published, unpublished and ongoing studies. Review authors scanned the reference lists of included studies and relevant systematic reviews for further studies.

SELECTION CRITERIA: We included parallel-group and split-mouth randomised controlled trials (RCTs) that compared a sealant with no sealant, or different types of sealants, for the prevention of caries in primary molars, with no restriction on follow-up duration. We included studies in which co-interventions such as oral health preventive measures, oral health education or tooth brushing demonstrations were used, provided that the same adjunct was used with the intervention and comparator. We excluded studies with complex interventions for the prevention of dental caries in primary teeth such as preventive resin restorations, or studies that used sealants in cavitated carious lesions.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, extracted data and assessed risk of bias of included studies. We presented outcomes for the development of new carious lesions on occlusal surfaces of primary molars as odds ratios (OR) with 95% confidence intervals (CIs). Where studies were similar in clinical and methodological characteristics, we planned to pool effect estimates using a random-effects model where appropriate. We used GRADE methodology to assess the certainty of the evidence.

MAIN RESULTS: We included nine studies that randomised 1120 children who ranged in age from 18 months to eight years at the start of the study. One study compared fluoride-releasing resin-based sealant with no sealant (139 tooth pairs in 90 children); two studies compared glass ionomer-based sealant with no sealant (619 children); two studies compared glass ionomer-based sealant with resin-based sealant (278 tooth pairs in 200 children); two studies compared fluoride-releasing resin-based sealant with resin-based sealant (113 tooth pairs in 69 children); one study compared composite with fluoride-releasing resin-based sealant (40 tooth pairs in 40 children); and one study compared autopolymerised sealant with light polymerised sealant (52 tooth pairs in 52 children). Three studies evaluated the effects of sealants versus no sealant and provided data for our primary outcome. Due to differences in study design such as age of participants and duration of follow-up, we elected not to pool the data. At 24 months, there was insufficient evidence of a difference in the development of new caries lesions for the fluoride-releasing sealants or no treatment groups (Becker Balagtas odds ratio (BB OR) 0.76, 95% CI 0.41 to 1.42; 1 study, 85 children, 255 tooth surfaces). For glass ionomer-based sealants, the evidence was equivocal; one study found insufficient evidence of a difference at follow-up between 12 and 30 months (OR 0.97, 95% CI 0.63 to 1.49; 449 children), while another with 12-month follow-up found a large, beneficial effect of sealants (OR 0.03, 95% CI 0.01 to 0.15; 107 children). We judged the certainty of the evidence to be low, downgrading two levels in total for study limitations, imprecision and inconsistency. We included six trials randomising 411 children that directly compared different sealant materials, four of which (221 children) provided data for our primary outcome. Differences in age of the participants and duration of follow-up precluded pooling of the data. The incidence of development of new caries lesions was typically low across the different sealant types evaluated. We judged the certainty of the evidence to be low or very low for the outcome of caries incidence. Only one study assessed and reported adverse events, the nature of which was gag reflex while placing the sealant material.

OBJECTIVES: To assess the effectiveness of healthcare interventions strategies to systematically improve identification of familial hypercholesterolaemia in primary care and other community settings compared to usual care (incidental approaches to identify familial hypercholesterolaemia in primary care and other community settings).

SEARCH METHODS: We searched the Cochrane Inborn Errors of Metabolism Trials Register. Date of last search: 13 September 2021. We also searched databases (Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, PubMed, Embase, CINAHL, Web of Science, and SCOPUS) as well as handsearching relevant conference proceedings, reference lists of included articles, and the grey literature. Date of last searches: 05 March 2020.  SELECTION CRITERIA: As per the Effective Practice and Organisation of Care (EPOC) Group guidelines, we planned to include randomised controlled trials (RCTs), cluster-RCTs and non-randomised studies of interventions (NRSI). Eligible NRSI were non-randomised controlled trials, prospective cohort studies, controlled before-and-after studies, and interrupted-time-series studies. We planned to selected studies with healthcare interventions strategies that aimed to systematically identify people with possible or definite clinical familial hypercholesterolaemia, in primary care and other community settings. These strategies would be compared with usual care or no intervention. We considered participants of any age from the general population who access primary care and other community settings.

DATA COLLECTION AND ANALYSIS: Two authors planned to independently select studies according to the inclusion criteria, to extract data and assess for risk of bias and the certainty of the evidence (according to the GRADE criteria). We contacted corresponding study authors in order to obtain further information for all the studies considered in the review.

MAIN RESULTS: No eligible RCTs or NRSIs were identified for inclusion, however, we excluded 28 studies.

OBJECTIVES: To assess the impact of antimalarial MDA on population asexual parasitaemia prevalence, parasitaemia incidence, gametocytaemia prevalence, anaemia prevalence, mortality and MDA-associated adverse events.

SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE+, EMBASE, to February 2013. We also searched CABS Abstracts, LILACS, reference lists, and recent conference proceedings.

SELECTION CRITERIA: Cluster-randomized trials and non-randomized controlled studies comparing therapeutic MDA versus placebo or no MDA, and uncontrolled before-and-after studies comparing post-MDA to baseline data were selected. Studies administering intermittent preventive treatment (IPT) to sub-populations (for example, pregnant women, children or infants) were excluded.

DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for inclusion, extracted data and assessed risk of bias. Studies were stratified by study design and then subgrouped by endemicity, by co-administration of 8-aminoquinoline plus schizonticide drugs and by plasmodium species. The quality of evidence was assessed using the GRADE approach.

MAIN RESULTS: Two cluster-randomized trials, eight non-randomized controlled studies and 22 uncontrolled before-and-after studies are included in this review. Twenty-two studies (29 comparisons) compared MDA to placebo or no intervention of which two comparisons were conducted in areas of low endemicity (≤5%), 12 in areas of moderate endemicity (6-39%) and 15 in areas of high endemicity (≥ 40%). Ten studies evaluated MDA plus other vector control measures. The studies used a wide variety of MDA regimens incorporating different drugs, dosages, timings and numbers of MDA rounds. Many of the studies are now more than 30 years old. Areas of low endemicity (≤5%)Within the first month post-MDA, a single uncontrolled before-and-after study conducted in 1955 on a small Taiwanese island reported a much lower prevalence of parasitaemia following a single course of chloroquine compared to baseline (1 study, very low quality evidence). This lower parasite prevalence was still present after more than 12 months (one study, very low quality evidence). In addition, one cluster-randomized trial evaluating MDA in a low endemic setting reported zero episodes of parasitaemia at baseline, and throughout five months of follow-up in both the control and intervention arms (one study, very low quality evidence). Areas of moderate endemicity (6-39%)Within the first month post-MDA, the prevalence of parasitaemia was much lower in three non-randomized controlled studies from Kenya and India in the 1950s (RR 0.03, 95% CI 0.01 to 0.08, three studies, moderate quality evidence), and in three uncontrolled before-and-after studies conducted between 1954 and 1961 (RR 0.29, 95% CI 0.17 to 0.48, three studies,low quality evidence).The longest follow-up in these settings was four to six months. At this time point, the prevalence of parasitaemia remained substantially lower than controls in the two non-randomized controlled studies (RR 0.18, 95% CI 0.10 to 0.33, two studies, low quality evidence). In contrast, the two uncontrolled before-and-after studies found mixed results: one found no difference and one found a substantially higher prevalence compared to baseline (not pooled, two studies, very low quality evidence). Areas of high endemicity (≥40%)Within the first month post-MDA, the single cluster-randomized trial from the Gambia in 1999 found no significant difference in parasite prevalence (one study, low quality evidence). However, prevalence was much lower during the MDA programmes in three non-randomized controlled studies conducted in the 1960s and 1970s (RR 0.17, 95% CI 0.11 to 0.27, three studies, moderate quality evidence), and within one month of MDA in four uncontrolled before-and-after studies (RR 0.37, 95% CI 0.28 to 0.49, four studies,low quality evidence).Four trials reported changes in prevalence beyond three months. In the Gambia, the single cluster-randomized trial found no difference at five months (one trial, moderate quality evidence). The three uncontrolled before-and-after studies had mixed findings with large studies from Palestine and Cambodia showing sustained reductions at four months and 12 months, respectively, and a small study from Malaysia showing no difference after four to six months of follow-up (three studies,low quality evidence). 8-aminoquinolines We found no studies directly comparing MDA regimens that included 8-aminoquinolines with regimens that did not. In a crude subgroup analysis with a limited number of studies, we were unable to detect any evidence of additional benefit of primaquine in moderate- and high-transmission settings. Plasmodium species In studies that reported species-specific outcomes, the same interventions resulted in a larger impact on Plasmodium falciparum compared to P. vivax.

OBJECTIVES: To evaluate the effects of withdrawal or continuation of cholinesterase inhibitors or memantine, or both, in people with dementia on: cognitive, neuropsychiatric and functional outcomes, rates of institutionalisation, adverse events, dropout from trials, mortality, quality of life and carer-related outcomes.

SEARCH METHODS: We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register up to 17 October 2020 using terms appropriate for the retrieval of studies of cholinesterase inhibitors or memantine. The Specialised Register contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources.

SELECTION CRITERIA: We included all randomised, controlled clinical trials (RCTs) which compared withdrawal of cholinesterase inhibitors or memantine, or both, with continuation of the same drug or drugs.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed citations and full-text articles for inclusion, extracted data from included trials and assessed risk of bias using the Cochrane risk of bias tool. Where trials were sufficiently similar, we pooled data for outcomes in the short term (up to 2 months after randomisation), medium term (3-11 months) and long term (12 months or more). We assessed the overall certainty of the evidence for each outcome using GRADE methods.

MAIN RESULTS: We included six trials investigating cholinesterase inhibitor withdrawal, and one trial investigating withdrawal of either donepezil or memantine. No trials assessed withdrawal of memantine only. Drugs were withdrawn abruptly in five trials and stepwise in two trials. All participants had dementia due to Alzheimer's disease, with severities ranging from mild to very severe, and were taking cholinesterase inhibitors without known adverse effects at baseline. The included trials randomised 759 participants to treatment groups relevant to this review. Study duration ranged from 6 weeks to 12 months. There were too few included studies to allow planned subgroup analyses. We considered some studies to be at unclear or high risk of selection, performance, detection, attrition or reporting bias. Compared to continuing cholinesterase inhibitors, discontinuing treatment may be associated with worse cognitive function in the short term (standardised mean difference (SMD) -0.42, 95% confidence interval (CI) -0.64 to -0.21; 4 studies; low certainty), but the effect in the medium term is very uncertain (SMD -0.40, 95% CI -0.87 to 0.07; 3 studies; very low certainty). In a sensitivity analysis omitting data from a study which only included participants who had shown a relatively poor prior response to donepezil, inconsistency was reduced and we found that cognitive function may be worse in the discontinuation group in the medium term (SMD -0.62; 95% CI -0.94 to -0.31). Data from one longer-term study suggest that discontinuing a cholinesterase inhibitor is probably associated with worse cognitive function at 12 months (mean difference (MD) -2.09 Standardised Mini-Mental State Examination (SMMSE) points, 95% CI -3.43 to -0.75; moderate certainty). Discontinuation may make little or no difference to functional status in the short term (SMD -0.25, 95% CI -0.54 to 0.04; 2 studies; low certainty), and its effect in the medium term is uncertain (SMD -0.38, 95% CI -0.74 to -0.01; 2 studies; very low certainty). After 12 months, discontinuing a cholinesterase inhibitor probably results in greater functional impairment than continuing treatment (MD -3.38 Bristol Activities of Daily Living Scale (BADLS) points, 95% CI -6.67 to -0.10; one study; moderate certainty). Discontinuation may be associated with a worsening of neuropsychiatric symptoms over the short term and medium term, although we cannot exclude a minimal effect (SMD - 0.48, 95% CI -0.82 to -0.13; 2 studies; low certainty; and SMD -0.27, 95% CI -0.47 to -0.08; 3 studies; low certainty, respectively). Data from one study suggest that discontinuing a cholinesterase inhibitor may result in little to no change in neuropsychiatric status at 12 months (MD -0.87 Neuropsychiatric Inventory (NPI) points; 95% CI -8.42 to 6.68; moderate certainty). We found no clear evidence of an effect of discontinuation on dropout due to lack of medication efficacy or deterioration in overall medical condition (odds ratio (OR) 1.53, 95% CI 0.84 to 2.76; 4 studies; low certainty), on number of adverse events (OR 0.85, 95% CI 0.57 to 1.27; 4 studies; low certainty) or serious adverse events (OR 0.80, 95% CI 0.46 to 1.39; 4 studies; low certainty), and on mortality (OR 0.75, 95% CI 0.36 to 1.55; 5 studies; low certainty). Institutionalisation was reported in one trial, but it was not possible to extract data for the groups relevant to this review.

OBJECTIVES: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020.

SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both).

DATA COLLECTION AND ANALYSIS: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review.

MAIN RESULTS: A comprehensive search of the literature did not identify any published eligible randomised controlled trials.

OBJECTIVES: To assess the benefits and harms of TENS for managing pain in people with SCD who experience pain crises or chronic pain (or both).

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries and the reference lists of relevant articles and reviews. Date of the last search: 26 Febraury 2020.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs, where TENS was evaluated for managing pain in people with SCD.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the trials identified by the literature searches according to the inclusion criteria. Two review authors then independently extracted data, assessed for risk of bias using the Cochrane standard tool and rated the quality of evidence using the GRADE guidelines.

MAIN RESULTS: One double-blind cross-over RCT with 22 participants with SCD (aged 12 to 27 years) was eligible for inclusion. Following stratification into four pain crises severity grades, participants were then randomised to receive TENS or placebo (sham TENS). The trial was concluded after 60 treatment episodes (30 treatment episodes of each treatment group). There is a lack of clarity regarding the trial design and the analysis of the cross-over data. If a participant was allocated to TENS treatment for an episode of pain and subsequently returned with a further episode of a similar degree of pain, they would then receive the sham TENS treatment (cross-over design). For those experiencing a pain episode of a different severity, it is not clear whether they were re-randomised or given the alternate treatment. Reporting and analysis was based on the total number pain events and not on the number of participants. It is unclear how many participants were crossed over from the TENS group to the sham TENS group and vice versa. The trial had a high risk of bias regarding random sequence generation and allocation concealment; an unclear risk regarding the blinding of participants and personnel; and a low risk regarding the blinding of the outcome assessors and selective outcome reporting. The trial was small and of very low quality; furthermore, given the issue with trial design we were unable to quantitatively analyse the data. Therefore, we present only a narrative summary and caution is advised in interpreting the results. In relation to our pre-defined primary outcomes, the included trial did not report pain relief at two to four weeks post intervention. The trial authors reported that no difference was found in the changes in pain ratings (recorded at one hour and four hours post intervention) between the TENS and the placebo groups. In relation to our secondary outcomes, the analgesic usage during the trial also did not show any difference between groups. Given the quality of the evidence, we are uncertain whether TENS improves overall satisfaction as compared to sham TENS. The ability to cope with activities of daily living was not evaluated. Regarding adverse events, although one case of itching was reported in the TENS group, the site and nature of itching was not clearly stated; hence it cannot be clearly attributed to TENS. Also, two participants receiving 'sham' TENS reported a worsening of pain with the intervention.

OBJECTIVES: To assess the effects of sweet potato for type 2 diabetes mellitus.

SEARCH METHODS: We searched several electronic databases, including The Cochrane Library (2013, Issue 1), MEDLINE, EMBASE, CINAHL, SIGLE and LILACS (all up to February 2013), combined with handsearches. No language restrictions were used.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared sweet potato with a placebo or a comparator intervention, with or without pharmacological or non-pharmacological interventions.

DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials and extracted the data. We evaluated risk of bias by assessing randomisation, allocation concealment, blinding, completeness of outcome data, selective reporting and other potential sources of bias.

MAIN RESULTS: Three RCTs met our inclusion criteria: these investigated a total of 140 participants and ranged from six weeks to five months in duration. All three studies were performed by the same trialist. Overall, the risk of bias of these trials was unclear or high. All RCTs compared the effect of sweet potato preparations with placebo on glycaemic control in type 2 diabetes mellitus. There was a statistically significant improvement in glycosylated haemoglobin A1c (HbA1c) at three to five months with 4 g/day sweet potato preparation compared to placebo (mean difference -0.3% (95% confidence interval -0.6 to -0.04); P = 0.02; 122 participants; 2 trials). No serious adverse effects were reported. Diabetic complications and morbidity, death from any cause, health-related quality of life, well-being, functional outcomes and costs were not investigated.

OBJECTIVES: To assess the effects of colesevelam for type 2 diabetes mellitus.

SEARCH METHODS: Several electronic databases were searched, among these The Cochrane Library (Issue 1, 2012), MEDLINE, EMBASE, CINAHL, LILACS, OpenGrey and Proquest Dissertations and Theses database (all up to January 2012), combined with handsearches. No language restriction was used.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared colesevelam with or without other oral hypoglycaemic agents with a placebo or a control intervention with or without oral hypoglycaemic agents.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected the trials and extracted the data. We evaluated risk of bias of trials using the parameters of randomisation, allocation concealment, blinding, completeness of outcome data, selective reporting and other potential sources of bias.

MAIN RESULTS: Six RCTs ranging from 8 to 26 weeks investigating 1450 participants met the inclusion criteria. Overall, the risk of bias of these trials was unclear or high. All RCTs compared the effects of colesevelam with or without other antidiabetic drug treatments with placebo only (one study) or combined with antidiabetic drug treatments. Colesevelam with add-on antidiabetic agents demonstrated a statistically significant reduction in fasting blood glucose with a mean difference (MD) of -15 mg/dL (95% confidence interval (CI) -22 to - 8), P < 0.0001; 1075 participants, 4 trials, no trial with low risk of bias in all domains. There was also a reduction in glycosylated haemoglobin A1c (HbA1c) in favour of colesevelam (MD -0.5% (95% CI -0.6 to -0.4), P < 0.00001; 1315 participants, 5 trials, no trial with low risk of bias in all domains. However, the single trial comparing colesevelam to placebo only (33 participants) did not reveal a statistically significant difference between the two arms - in fact, in both arms HbA1c increased. Colesevelam with add-on antidiabetic agents demonstrated a statistical significant reduction in low-density lipoprotein (LDL)-cholesterol with a MD of -13 mg/dL (95% CI -17 to - 9), P < 0.00001; 886 participants, 4 trials, no trial with low risk of bias in all domains. Non-severe hypoglycaemic episodes were infrequently observed. No other serious adverse effects were reported. There was no documentation of complications of the disease, morbidity, mortality, health-related quality of life and costs.

OBJECTIVES: To assess the effects of mormodica charantia for type 2 diabetes mellitus.

SEARCH METHODS: Several electronic databases were searched, among these were The Cochrane Library (Issue 1, 2012), MEDLINE, EMBASE, CINAHL, SIGLE and LILACS (all up to February 2012), combined with handsearches. No language restriction was used.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared momordica charantia with placebo or a control intervention, with or without pharmacological or non-pharmacological interventions.

DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Risk of bias of the trials was evaluated using the parameters of randomisation, allocation concealment, blinding, completeness of outcome data, selective reporting and other potential sources of bias. A meta-analysis was not performed given the quality of data and the variability of preparations of momordica charantia used in the interventions (no similar preparation was tested twice).

MAIN RESULTS: Four randomised controlled trials with up to three months duration and investigating 479 participants met the inclusion criteria. Risk of bias of these trials (only two studies were published as a full peer-reviewed publication) was generally high. Two RCTs compared the effects of preparations from different parts of the momordica charantia plant with placebo on glycaemic control in type 2 diabetes mellitus. There was no statistically significant difference in the glycaemic control with momordica charantia preparations compared to placebo. When momordica charantia was compared to metformin or glibenclamide, there was also no significant change in reliable parameters of glycaemic control. No serious adverse effects were reported in any trial. No trial investigated death from any cause, morbidity, health-related quality of life or costs.

OBJECTIVES: To assess the effectiveness of carbohydrates in improving cognitive function in older adults.

SEARCH STRATEGY: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register on 22 June 2010 using the terms: carbohydrates OR carbohydrate OR monosaccharides OR disaccharides OR oligosaccharides OR polysaccharides OR CARBS. ALOIS contains records from all major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trial databases and grey literature sources.

SELECTION CRITERIA: All randomised controlled trials (RCT) that have examined the efficacy of any form of carbohydrates in normal cognition and MCI.

DATA COLLECTION AND ANALYSIS: One review author selected and retrieved relevant articles for further assessment. The remaining authors independently assessed whether any of the retrieved trials should be included. Disagreements were resolved by discussion. 

MAIN RESULTS: There is no suitable RCT of any form of carbohydrates involving independent-living older adults with normal cognition or mild cognitive impairment.

OBJECTIVES: To assess the effectiveness of influenza vaccine in reducing the occurrence of acute otitis media (AOM) in infants and children.

SEARCH METHODS: We searched CENTRAL (2014, Issue 6), MEDLINE (1946 to July week 1, 2014), EMBASE (2010 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014), Web of Science (1955 to July 2014) and reference lists of articles to July 2014.

SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing influenza vaccine with placebo or no treatment in infants and children aged younger than six years old. We included children of either sex and of any ethnicity, with or without a history of recurrent AOM.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, assessed trial quality and extracted data. We performed statistical analyses using the random-effects and fixed-effect models and expressed the results as risk ratio (RR), risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, with 95% confidence intervals (CI).

MAIN RESULTS: We included 10 trials (six trials in high-income countries and four multicentre trials in high-, middle- and low-income countries) involving 16,707 children aged six months to six years. Eight trials recruited participants from a healthcare setting. Nine trials (and all five trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment and nine trials reported adequate blinding of participants and personnel. Attrition was low for all trials included in the analysis.The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (five trials, 4736 participants: RR 0.80, 95% CI 0.67 to 0.96; RD -0.04, 95% CI -0.07 to -0.02; NNTB 25, 95% CI 15 to 50).The subgroup analyses (i.e. number of courses, settings, seasons or types of vaccine administered) showed no differences.There was a reduction in the use of antibiotics in vaccinated children (two trials, 1223 participants: RR 0.70, 95% CI 0.59 to 0.83; RD -0.15, 95% CI -0.30 to -0.00).There was no significant difference in the utilisation of health care for the one trial that provided sufficient information to be included. The use of influenza vaccine resulted in a significant increase in fever (six trials, 10,199 participants: RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI -0.00 to 0.05) and rhinorrhoea (six trials, 10,563 children: RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16) but no difference in pharyngitis. No major adverse events were reported.Compared to the protocol, the review included a subgroup analysis of AOM episodes by season, and changed the types of influenza vaccine from a secondary outcome to a subgroup analysis.

OBJECTIVES: To assess the effectiveness of influenza vaccine in reducing the occurrence of acute otitis media in infants and children.

SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, LILACS, Web of Science, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov (15 February 2017). We also searched the reference lists of included studies to identify any additional trials.

SELECTION CRITERIA: Randomised controlled trials comparing influenza vaccine with placebo or no treatment in infants and children aged younger than six years. We included children of either sex and of any ethnicity, with or without a history of recurrent AOM.

DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, assessed trial quality, and extracted data. We performed statistical analyses using the random-effects and fixed-effect models and expressed the results as risk ratio (RR), risk difference (RD), and number needed to treat for an additional beneficial outcome (NNTB) for dichotomous outcomes, with 95% confidence intervals (CI).

MAIN RESULTS: We included 11 trials (6 trials in high-income countries and 5 multicentre trials in high-, middle-, and low-income countries) involving 17,123 children aged 6 months to 6 years. Eight trials recruited participants from a healthcare setting. Ten trials (and all four trials that contributed to the primary outcome) declared funding from vaccine manufacturers. Four trials reported adequate allocation concealment, and 10 trials reported adequate blinding of participants and personnel. Attrition was low for eight trials included in the analysis.The primary outcome showed a small reduction in at least one episode of AOM over at least six months of follow-up (4 trials, 3134 children; RR 0.84, 95% CI 0.69 to 1.02; RD -0.04, 95% CI -0.08 to -0.00; NNTB 25, 95% CI 12.5 to 100; low-quality evidence).The subgroup analyses (i.e. number of courses and types of vaccine administered) showed no differences.There was a reduction in the use of antibiotics in vaccinated children (2 trials, 1223 children; RR 0.70, 95% CI 0.59 to 0.83; RD -0.11, 95% CI -0.16 to -0.06; moderate-quality evidence).We were unable to demonstrate whether there was any difference in the utilisation of health care. The use of influenza vaccine resulted in a significant increase in fever (7 trials, 10,615 children; RR 1.15, 95% CI 1.06 to 1.24; RD 0.02, 95% CI 0.00 to 0.04; low-quality evidence), rhinorrhoea (6 trials, 10,563 children; RR 1.17, 95% CI 1.07 to 1.29; RD 0.09, 95% CI 0.01 to 0.16; low-quality evidence), but no difference in pharyngitis. No major adverse events were reported.Differing from the protocol, the original publication of the review included a subgroup analysis of AOM episodes by season, and the secondary outcome 'types of influenza vaccine' was changed to a subgroup analysis. For this update, we removed the subgroup analyses for trial setting, season, and utilisation of health care due to the small number of trials involved. We removed Belshe 2000 from primary and secondary outcomes (courses of vaccine and types of vaccine) because it reported episodes of AOM per person. We did not perform a subgroup analysis by type of adverse event. We have reported each type of adverse event as a separate analysis.

OBJECTIVES: To assess the efficacy and safety of combined aclidinium bromide and long-acting beta2-agonists in stable COPD.

SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, World Health Organization (WHO) trials portal, United States Food and Drug Administration (FDA) and manufacturers' websites as well as the reference list of published trials up to 12 October 2018.

SELECTION CRITERIA: Parallel-group randomised controlled trials (RCTs) assessing combined aclidinium bromide and LABAs in people with stable COPD.

DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane for data collection and analysis. The primary outcomes were exacerbations requiring a short course of an oral steroid or antibiotic, or both; quality of life measured by a validated scale and non-fatal serious adverse events (SAEs). Where the outcome or study details were not reported, we contacted the study investigators or pharmaceutical company trial co-ordinators (or both) for missing data.

MAIN RESULTS: We identified RCTs comparing aclidinium/formoterol FDC versus aclidinium, formoterol or placebo only. We included seven multicentre trials of four to 52 weeks' duration conducted in outpatient settings. There were 5921 participants, whose mean age ranged from 60.7 to 64.7 years, mostly men with a mean smoking pack-years of 46.4 to 61.3 of which 43.9% to 63.4% were current smokers. They had a moderate-to-severe degree of COPD with a mean postbronchodilator forced expiratory volume in one second (FEV1) between 50.5% and 61% of predicted normal and the baseline mean FEV1 of 1.23 L to 1.43 L. We assessed performance and detection biases as low for all studies whereas selection, attrition and reporting biases were either low or unclear.FDC versus aclidiniumThere was no evidence of a difference between FDC and aclidinium for exacerbations requiring steroids or antibiotics, or both (OR 0.95, 95% CI 0.71 to 1.27; 2 trials, 2156 participants; moderate-certainty evidence); quality of life measured by St George's Respiratory Questionnaire (SGRQ) total score (MD -0.92, 95% CI -2.15 to 0.30); participants with significant improvement in SGRQ score (OR 1.17, 95% CI 0.97 to 1.41; 2 trials, 2002 participants; moderate-certainty evidence); non-fatal SAE (OR 1.19, 95% CI 0.79 to 1.80; 3 trials, 2473 participants; moderate-certainty evidence); hospital admissions due to severe exacerbations (OR 0.62, 95% CI 0.29 to 1.29; 2 trials, 2156 participants; moderate-certainty evidence) or adverse events (OR 0.95, 95% CI 0.76 to 1.18; 3 trials, 2473 participants; moderate-certainty evidence). Compared with aclidinium, FDC improved symptoms (Transitional Dyspnoea Index (TDI) focal score: MD 0.37, 95% CI 0.07 to 0.68; 2 trials, 2013 participants) with a higher chance of achieving a minimal clinically important difference (MCID) of at least one unit improvement (OR 1.34, 95% CI 1.11 to 1.62; high-certainty evidence); the number needed to treat for an additional beneficial outcome (NNTB) being 14 (95% CI 9 to 39).FDC versus formoterolWhen compared to formoterol, combination therapy reduced exacerbations requiring steroids or antibiotics, or both (OR 0.78, 95% CI 0.62 to 0.99; 3 trials, 2694 participants; high-certainty evidence); may decrease SGRQ total score (MD -1.88, 95% CI -3.10 to -0.65; 2 trials, 2002 participants; low-certainty evidence; MCID for SGRQ is 4 units); increased TDI focal score (MD 0.42, 95% CI 0.11 to 0.72; 2 trials, 2010 participants) with more participants attaining an MCID (OR 1.30, 95% CI 1.07 to 1.56; high-certainty evidence) and an NNTB of 16 (95% CI 10 to 60). FDC lowered the risk of adverse events compared to formoterol (OR 0.78, 95% CI 0.65 to 0.93; 5 trials, 3140 participants; high-certainty evidence; NNTB 22). However, there was no difference between FDC and formoterol for hospital admissions, all-cause mortality and non-fatal SAEs.FDC versus placeboCompared with placebo, FDC demonstrated no evidence of a difference in exacerbations requiring steroids or antibiotics, or both (OR 0.82, 95% CI 0.60 to 1.12; 2 trials, 1960 participants; moderate-certainty evidence) or hospital admissions due to severe exacerbations (OR 0.55, 95% CI 0.25 to 1.18; 2 trials, 1960 participants; moderate-certainty evidence), although estimates were uncertain. Quality of life measure by SGRQ total score was significantly better with FDC compared to placebo (MD -2.91, 95% CI -4.33 to -1.50; 2 trials, 1823 participants) resulting in a corresponding increase in SGRQ responders who achieved at least four units decrease in SGRQ total score (OR 1.72, 95% CI 1.39 to 2.13; high-certainty evidence) with an NNTB of 7 (95% CI 5 to 12). FDC also improved symptoms measured by TDI focal score (MD 1.32, 95% CI 0.96 to 1.69; 2 studies, 1832 participants) with more participants attaining at least one unit improvement in TDI focal score (OR 2.51, 95% CI 2.02 to 3.11; high-certainty evidence; NNTB 4). There were no differences in non-fatal SAEs, adverse events and all-cause mortality between FDC and placebo.Combination therapy significantly improved trough FEV1 compared to aclidinium, formoterol or placebo.