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  1. Palaniappan SK, Than NN, Thein AW, van Mourik I
    Cochrane Database Syst Rev, 2020 03 30;3:CD012056.
    PMID: 32227478 DOI: 10.1002/14651858.CD012056.pub3
    BACKGROUND: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published 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    SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal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.

    AUTHORS' CONCLUSIONS: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.

  2. Sasongko TH, Ismail NF, Zabidi-Hussin Z
    Cochrane Database Syst Rev, 2016 Jul 13;7:CD011272.
    PMID: 27409709 DOI: 10.1002/14651858.CD011272.pub2
    BACKGROUND: Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.

    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.

    AUTHORS' CONCLUSIONS: We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.

  3. Pal S, Dixit R, Moe S, Godinho MA, Abas AB, Ballas SK, et al.
    Cochrane Database Syst Rev, 2020 03 03;3:CD012762.
    PMID: 32124977 DOI: 10.1002/14651858.CD012762.pub2
    BACKGROUND: Sickle cell disease (SCD), one of the most common inherited disorders, is associated with vaso-occlusive pain episodes and haemolysis leading to recurrent morbidity, hospital admissions and work or school absenteeism. The crises are conventionally treated with opioids, non-opioids and other adjuvants with the risk of developing complications, addictions and drug-seeking behaviour. Different non-pharmacological treatments, such as transcutaneous electrical nerve stimulation (TENS) have been used for managing pain in other painful conditions. Hence, the efficacy of TENS for managing pain in SCD needs to be reviewed.

    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.

    AUTHORS' CONCLUSIONS: Since we have only included one small and very low-quality trial, with a high risk of bias across several domains, we are unable to conclude whether TENS is harmful or beneficial for managing pain in people with SCD. There is a need for a well-designed, adequately-powered, RCT to evaluate the role of TENS in managing pain in people with SCD.

  4. Eachempati P, Kumbargere Nagraj S, Kiran Kumar Krishanappa S, Gupta P, Yaylali IE
    Cochrane Database Syst Rev, 2018 12 18;12:CD006202.
    PMID: 30562408 DOI: 10.1002/14651858.CD006202.pub2
    BACKGROUND: With the increased demand for whiter teeth, home-based bleaching products, either dentist-prescribed or over-the-counter products have been exponentially increasing in the past few decades. This is an update of a Cochrane Review first published in 2006.

    OBJECTIVES: To evaluate the effects of home-based tooth whitening products with chemical bleaching action, dispensed by a dentist or over-the-counter.

    SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 12 June 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6) in the Cochrane Library (searched 12 June 2018), MEDLINE Ovid (1946 to 12 June 2018), and Embase Ovid (1980 to 12 June 2018). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (12 June 2018) and the World Health Organization International Clinical Trials Registry Platform (12 June 2018) were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases.

    SELECTION CRITERIA: We included in our review randomised controlled trials (RCTs) which involved adults who were 18 years and above, and compared dentist-dispensed or over-the-counter tooth whitening (bleaching) products with placebo or other comparable products.Quasi-randomised trials, combination of in-office and home-based treatments, and home-based products having physical removal of stains were excluded.

    DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials. Two pairs of review authors independently extracted data and assessed risk of bias. We estimated risk ratios (RRs) for dichotomous data, and mean differences (MDs) or standardised mean difference (SMD) for continuous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach.

    MAIN RESULTS: We included 71 trials in the review with 26 studies (1398 participants) comparing a bleaching agent to placebo and 51 studies (2382 participants) comparing a bleaching agent to another bleaching agent. Two studies were at low overall risk of bias; two at high overall risk of bias; and the remaining 67 at unclear overall risk of bias.The bleaching agents (carbamide peroxide (CP) gel in tray, hydrogen peroxide (HP) gel in tray, HP strips, CP paint-on gel, HP paint-on gel, sodium hexametaphosphate (SHMP) chewing gum, sodium tripolyphosphate (STPP) chewing gum, and HP mouthwash) at different concentrations with varying application times whitened teeth compared to placebo over a short time period (from 2 weeks to 6 months), however the certainty of the evidence is low to very low.In trials comparing one bleaching agent to another, concentrations, application method and application times, and duration of use varied widely. Most of the comparisons were reported in single trials with small sample sizes and event rates and certainty of the evidence was assessed as low to very low. Therefore the evidence currently available is insufficient to draw reliable conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use.Tooth sensitivity and oral irritation were the most common side effects which were more prevalent with higher concentrations of active agents though the effects were mild and transient. Tooth whitening did not have any effect on oral health-related quality of life.

    AUTHORS' CONCLUSIONS: We found low to very low-certainty evidence over short time periods to support the effectiveness of home-based chemically-induced bleaching methods compared to placebo for all the outcomes tested.We were unable to draw any conclusions regarding the superiority of home-based bleaching compositions or any particular method of application or concentration or application time or duration of use, as the overall evidence generated was of very low certainty. Well-planned RCTs need to be conducted by standardising methods of application, concentrations, application times, and duration of treatment.

  5. Moy FM, Ray A, Buckley BS, West HM
    Cochrane Database Syst Rev, 2017 06 11;6:CD009613.
    PMID: 28602020 DOI: 10.1002/14651858.CD009613.pub3
    BACKGROUND: Self-monitoring of blood glucose (SMBG) is recommended as a key component of the management plan for diabetes therapy during pregnancy. No existing systematic reviews consider the benefits/effectiveness of various techniques of blood glucose monitoring on maternal and infant outcomes among pregnant women with pre-existing diabetes. The effectiveness of the various monitoring techniques is unclear.

    OBJECTIVES: To compare techniques of blood glucose monitoring and their impact on maternal and infant outcomes among pregnant women with pre-existing diabetes.

    SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2016), searched reference lists of retrieved studies and contacted trial authors.

    SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing techniques of blood glucose monitoring including SMBG, continuous glucose monitoring (CGM) or clinic monitoring among pregnant women with pre-existing diabetes mellitus (type 1 or type 2). Trials investigating timing and frequency of monitoring were also included. RCTs using a cluster-randomised design were eligible for inclusion but none were identified.

    DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach.

    MAIN RESULTS: This review update includes at total of 10 trials (538) women (468 women with type 1 diabetes and 70 women with type 2 diabetes). The trials took place in Europe and the USA. Five of the 10 included studies were at moderate risk of bias, four studies were at low to moderate risk of bias, and one study was at high risk of bias. The trials are too small to show differences in important outcomes such as macrosomia, preterm birth, miscarriage or death of baby. Almost all the reported GRADE outcomes were assessed as being very low-quality evidence. This was due to design limitations in the studies, wide confidence intervals, small sample sizes, and few events. In addition, there was high heterogeneity for some outcomes.Various methods of glucose monitoring were compared in the trials. Neither pooled analyses nor individual trial analyses showed any clear advantages of one monitoring technique over another for primary and secondary outcomes. Many important outcomes were not reported.1. Self-monitoring versus standard care (two studies, 43 women): there was no clear difference for caesarean section (risk ratio (RR) 0.78, 95% confidence interval (CI) 0.40 to 1.49; one study, 28 women) or glycaemic control (both very low-quality), and not enough evidence to assess perinatal mortality and neonatal mortality and morbidity composite. Hypertensive disorders of pregnancy, large-for-gestational age, neurosensory disability, and preterm birth were not reported in either study.2. Self-monitoring versus hospitalisation (one study, 100 women): there was no clear difference for hypertensive disorders of pregnancy (pre-eclampsia and hypertension) (RR 4.26, 95% CI 0.52 to 35.16; very low-quality: RR 0.43, 95% CI 0.08 to 2.22; very low-quality). There was no clear difference in caesarean section or preterm birth less than 37 weeks' gestation (both very low quality), and the sample size was too small to assess perinatal mortality (very low-quality). Large-for-gestational age, mortality or morbidity composite, neurosensory disability and preterm birth less than 34 weeks were not reported.3. Pre-prandial versus post-prandial glucose monitoring (one study, 61 women): there was no clear difference between groups for caesarean section (RR 1.45, 95% CI 0.92 to 2.28; very low-quality), large-for-gestational age (RR 1.16, 95% CI 0.73 to 1.85; very low-quality) or glycaemic control (very low-quality). The results for hypertensive disorders of pregnancy: pre-eclampsia and perinatal mortality are not meaningful because these outcomes were too rare to show differences in a small sample (all very low-quality). The study did not report the outcomes mortality or morbidity composite, neurosensory disability or preterm birth.4. Automated telemedicine monitoring versus conventional system (three studies, 84 women): there was no clear difference for caesarean section (RR 0.96, 95% CI 0.62 to 1.48; one study, 32 women; very low-quality), and mortality or morbidity composite in the one study that reported these outcomes. There were no clear differences for glycaemic control (very low-quality). No studies reported hypertensive disorders of pregnancy, large-for-gestational age, perinatal mortality (stillbirth and neonatal mortality), neurosensory disability or preterm birth.5.CGM versus intermittent monitoring (two studies, 225 women): there was no clear difference for pre-eclampsia (RR 1.37, 95% CI 0.52 to 3.59; low-quality), caesarean section (average RR 1.00, 95% CI 0.65 to 1.54; I² = 62%; very low-quality) and large-for-gestational age (average RR 0.89, 95% CI 0.41 to 1.92; I² = 82%; very low-quality). Glycaemic control indicated by mean maternal HbA1c was lower for women in the continuous monitoring group (mean difference (MD) -0.60 %, 95% CI -0.91 to -0.29; one study, 71 women; moderate-quality). There was not enough evidence to assess perinatal mortality and there were no clear differences for preterm birth less than 37 weeks' gestation (low-quality). Mortality or morbidity composite, neurosensory disability and preterm birth less than 34 weeks were not reported.6. Constant CGM versus intermittent CGM (one study, 25 women): there was no clear difference between groups for caesarean section (RR 0.77, 95% CI 0.33 to 1.79; very low-quality), glycaemic control (mean blood glucose in the 3rd trimester) (MD -0.14 mmol/L, 95% CI -2.00 to 1.72; very low-quality) or preterm birth less than 37 weeks' gestation (RR 1.08, 95% CI 0.08 to 15.46; very low-quality). Other primary (hypertensive disorders of pregnancy, large-for-gestational age, perinatal mortality (stillbirth and neonatal mortality), mortality or morbidity composite, and neurosensory disability) or GRADE outcomes (preterm birth less than 34 weeks' gestation) were not reported.

    AUTHORS' CONCLUSIONS: This review found no evidence that any glucose monitoring technique is superior to any other technique among pregnant women with pre-existing type 1 or type 2 diabetes. The evidence base for the effectiveness of monitoring techniques is weak and additional evidence from large well-designed randomised trials is required to inform choices of glucose monitoring techniques.

  6. Aziz NA, Leonardi-Bee J, Phillips M, Gladman JR, Legg L, Walker MF
    PMID: 18425928 DOI: 10.1002/14651858.CD005952.pub2
    BACKGROUND: Current practice of rehabilitation intervention mainly concentrates on the first six months of stroke. At present, there is no agreed consensus about the benefits of such a service more than one year after stroke.

    OBJECTIVES: To ascertain whether therapy-based rehabilitation services can influence outcome one year or more after stroke.

    SEARCH STRATEGY: We searched the trials registers of the following Cochrane Review Groups: Stroke Group (last searched September 2007), Effective Practice and Organisation of Care Group (last searched October 2006) and Dementia and Cognitive Improvement Group (last searched October 2006). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2006), MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006), CINAHL (1982 to October 2006), AMED (1985 to October 2006), PEDro (1952 to October 2006), British Nursing Index (1993 to October 2006), DARE (1994 to October 2006), HMIC (1979 to October 2006) and NHS EED (1991 to October 2006). We also searched dissertation databases and ongoing trials and research registers, scanned reference lists and contacted researchers and experts in the field.

    SELECTION CRITERIA: All randomised controlled trials of community-based stroke patients, in which at least 75% were recruited one year after stroke and received a therapy-based rehabilitation intervention that was compared with conventional care.

    DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data on a number of pre-specified outcomes. The primary outcomes were the proportion of participants who had deteriorated or were dependent in personal activities of daily living at the end of scheduled follow up.

    MAIN RESULTS: We identified five trials of 487 participants that were eligible for the review. Overall, there was inconclusive evidence as to whether therapy-based rehabilitation intervention one year after stroke was able to influence any relevant patient or carer outcome. Trials varied in design, type of interventions provided, quality, and outcomes assessed.

    AUTHORS' CONCLUSIONS: This review highlights the dearth of evidence investigating long-term therapy-based rehabilitation interventions for patients with stroke.

  7. Ni H, Moe S, Soe Z, Myint KT, Viswanathan KN
    Cochrane Database Syst Rev, 2018 Dec 11;12:CD011594.
    PMID: 30536566 DOI: 10.1002/14651858.CD011594.pub2
    BACKGROUND: Several dual bronchodilator combinations of long-acting beta2-agonist (LABA) and long-acting muscarinic antagonist (LAMA) have been approved for treatment of stable chronic obstructive pulmonary disease (COPD). The current GOLD (Global Initiative for Chronic Obstructive Lung Disease) recommendations suggest the use of LABA/LAMA combinations in people with group B COPD with persistent symptoms, group C COPD with further exacerbations on LAMA therapy alone and group D COPD with or without inhaled corticosteroids (ICS). Fixed-dose combination (FDC) of aclidinium/formoterol is one of the approved LABA/LAMA therapies for people with stable COPD.

    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.

    AUTHORS' CONCLUSIONS: FDC improved dyspnoea and lung function compared to aclidinium, formoterol or placebo, and this translated into an increase in the number of responders on combination treatment. Quality of life was better with combination compared to formoterol or placebo. There was no evidence of a difference between FDC and monotherapy or placebo for exacerbations, hospital admissions, mortality, non-fatal SAEs or adverse events. Studies reported a lower risk of moderate exacerbations and adverse events with FDC compared to formoterol; however, larger studies would yield a more precise estimate for these outcomes.

  8. Foong WC, Ho JJ, Loh CK, Viprakasit V
    Cochrane Database Syst Rev, 2016 Oct 18;10:CD011579.
    PMID: 27755646
    BACKGROUND: Non-transfusion dependent beta thalassaemia is a subset of inherited haemoglobin disorders characterised by reduced production of the beta globin chain of the haemoglobin molecule leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it is required when episodes of chronic anaemia occur. This chronic anaemia can impair growth and affect quality of life. People with non-transfusion dependent beta thalassaemia suffer from iron overload due to their body's increased capability of absorbing iron from food sources. Iron overload becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin level have been found to require fewer blood transfusions. Hydroxyurea has been used to increase foetal haemoglobin level; however, its efficacy in reducing transfusion, chronic anaemia complications and its safety need to be established.

    OBJECTIVES: To assess the effectiveness, safety and appropriate dose regimen of hydroxyurea in people with non-transfusion dependent beta thalassaemia (haemoglobin E combined with beta thalassaemia and beta thalassaemia intermedia).

    SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of relevant journals. We also searched ongoing trials registries and the reference lists of relevant articles and reviews.Date of last search: 30 April 2016.

    SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of hydroxyurea in people with non-transfusion dependent beta thalassaemia comparing hydroxyurea with placebo or standard treatment or comparing different doses of hydroxyurea.

    DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria in order to select trials for inclusion. Both authors assessed the risk of bias of trials and extracted the data. A third author verified these assessments.

    MAIN RESULTS: No trials comparing hydroxyurea with placebo or standard care were found. However, we included one randomised controlled trial (n = 61) comparing 20 mg/kg/day with 10 mg/kg/day of hydroxyurea for 24 weeks.Both haemoglobin and foetal haemoglobin levels were lower at 24 weeks in the 20 mg group compared with the 10 mg group, mean difference -2.39 (95% confidence interval - 2.8 to -1.98) and mean difference -1.5 (95% confidence interval -1.83 to -1.17), respectively. Major adverse effects were significantly more common in the 20 mg group, for neutropenia risk ratio 9.93 (95% confidence interval 1.34 to 73.97) and for thrombocytopenia risk ratio 3.68 (95% confidence interval 1.13 to 12.07). No difference was reported for minor adverse effects (gastrointestinal disturbances and raised liver enzymes). The effect of hydroxyurea on transfusion frequency was not reported.The overall quality for the outcomes reported was graded as very low mainly because the outcomes were derived from only one small study with an unclear method of allocation concealment.

    AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials to show whether hydroxyurea has any effect compared with controls on the need for blood transfusion. Administration of 10 mg/kg/day compared to 20 mg/kg/day of hydroxyurea resulted in higher haemoglobin levels and seems safer with fewer adverse effects. It has not been reported whether hydroxyurea is capable of reducing the need for blood transfusion. Large well-designed randomised controlled trials with sufficient duration of follow up are recommended.

  9. Ziganshina LE, Abakumova T, Vernay L
    Cochrane Database Syst Rev, 2017 04 21;4:CD007026.
    PMID: 28430363 DOI: 10.1002/14651858.CD007026.pub5
    BACKGROUND: Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries.

    OBJECTIVES: To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke.

    SEARCH METHODS: In May 2016 we searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian Databases. We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma).

    SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing cerebrolysin, started within 48 hours of stroke onset and continued for any time, with placebo or no treatment in people with acute ischaemic stroke.

    DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data.

    MAIN RESULTS: We identified six RCTs (1501 participants) that met the inclusion criteria.We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians.None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset).All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence).Serious adverse events (SAEs): there was no significant difference in the total number of SAEs with cerebrolysin (RR 1.16, 95% CI 0.81 to 1.67). This comprised no difference in fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the number of people with non-fatal SAEs (20/667 with cerebrolysin and 8/668 with placebo: RR 2.47, 95% CI 1.09 to 5.58, P = 0.03) (3 trials, 1335 participants, moderate-quality evidence).Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence).

    AUTHORS' CONCLUSIONS: The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence of an increase in non-fatal SAEs with cerebrolysin use but not in total SAEs.

  10. Kumbargere Nagraj S, Eachempati P, Uma E, Singh VP, Ismail NM, Varghese E
    Cochrane Database Syst Rev, 2019 12 11;12:CD012213.
    PMID: 31825092 DOI: 10.1002/14651858.CD012213.pub2
    BACKGROUND: Halitosis or bad breath is a symptom in which a noticeably unpleasant breath odour is present due to an underlying oral or systemic disease. 50% to 60% of the world population has experienced this problem which can lead to social stigma and loss of self-confidence. Multiple interventions have been tried to control halitosis ranging from mouthwashes and toothpastes to lasers. This new Cochrane Review incorporates Cochrane Reviews previously published on tongue scraping and mouthrinses for halitosis.

    OBJECTIVES: The objectives of this review were to assess the effects of various interventions used to control halitosis due to oral diseases only. We excluded studies including patients with halitosis secondary to systemic disease and halitosis-masking interventions.

    SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 8 April 2019), the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 3) in the Cochrane Library (searched 8 April 2019), MEDLINE Ovid (1946 to 8 April 2019), and Embase Ovid (1980 to 8 April 2019). We also searched LILACS BIREME (1982 to 19 April 2019), the National Database of Indian Medical Journals (1985 to 19 April 2019), OpenGrey (1992 to 19 April 2019), and CINAHL EBSCO (1937 to 19 April 2019). The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (8 April 2019), the World Health Organization International Clinical Trials Registry Platform (8 April 2019), the ISRCTN Registry (19 April 2019), the Clinical Trials Registry - India (19 April 2019), were searched for ongoing trials. We also searched the cross-references of included studies and systematic reviews published on the topic. No restrictions were placed on the language or date of publication when searching the electronic databases.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs) which involved adults over the age of 16, and any intervention for managing halitosis compared to another or placebo, or no intervention. The active interventions or controls were administered over a minimum of one week and with no upper time limit. We excluded quasi-randomised trials, trials comparing the results for less than one week follow-up, and studies including advanced periodontitis.

    DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently selected trials, extracted data, and assessed risk of bias. We estimated mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using the GRADE approach.

    MAIN RESULTS: We included 44 trials in the review with 1809 participants comparing an intervention with a placebo or a control. The age of participants ranged from 17 to 77 years. Most of the trials reported on short-term follow-up (ranging from one week to four weeks). Only one trial reported long-term follow-up (three months). Three studies were at low overall risk of bias, 16 at high overall risk of bias, and the remaining 25 at unclear overall risk of bias. We compared different types of interventions which were categorised as mechanical debridement, chewing gums, systemic deodorising agents, topical agents, toothpastes, mouthrinse/mouthwash, tablets, and combination methods. Mechanical debridement: for mechanical tongue cleaning versus no tongue cleaning, the evidence was very uncertain for the outcome dentist-reported organoleptic test (OLT) scores (MD -0.20, 95% CI -0.34 to -0.07; 2 trials, 46 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Chewing gums: for 0.6% eucalyptus chewing gum versus placebo chewing gum, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.10, 95% CI -0.31 to 0.11; 1 trial, 65 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Systemic deodorising agents: for 1000 mg champignon versus placebo, the evidence was very uncertain for the outcome patient-reported visual analogue scale (VAS) scores (MD -1.07, 95% CI -14.51 to 12.37; 1 trial, 40 participants; very low-certainty evidence). No data were reported for dentist-reported OLT score or adverse events. Topical agents: for hinokitiol gel versus placebo gel, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.27, 95% CI -1.26 to 0.72; 1 trial, 18 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Toothpastes: for 0.3% triclosan toothpaste versus control toothpaste, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -3.48, 95% CI -3.77 to -3.19; 1 trial, 81 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Mouthrinse/mouthwash: for mouthwash containing chlorhexidine and zinc acetate versus placebo mouthwash, the evidence was very uncertain for the outcome dentist-reported OLT scores (MD -0.20, 95% CI -0.58 to 0.18; 1 trial, 44 participants; very low-certainty evidence). No data were reported for patient-reported OLT score or adverse events. Tablets: no data were reported on key outcomes for this comparison. Combination methods: for brushing plus cetylpyridium mouthwash versus brushing, the evidence was uncertain for the outcome dentist-reported OLT scores (MD -0.48, 95% CI -0.72 to -0.24; 1 trial, 70 participants; low-certainty evidence). No data were reported for patient-reported OLT score or adverse events.

    AUTHORS' CONCLUSIONS: We found low- to very low-certainty evidence to support the effectiveness of interventions for managing halitosis compared to placebo or control for the OLT and patient-reported outcomes tested. We were unable to draw any conclusions regarding the superiority of any intervention or concentration. Well-planned RCTs need to be conducted by standardising the interventions and concentrations.

  11. Ngim CF, Lai NM, Hong JY, Tan SL, Ramadas A, Muthukumarasamy P, et al.
    Cochrane Database Syst Rev, 2017 09 18;9:CD012284.
    PMID: 28921500 DOI: 10.1002/14651858.CD012284.pub2
    BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency.

    OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia.

    SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Our database and trial registry searches are current to 10 August 2017 and 08 August 2017, respectively.

    SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity.

    DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The quality of the evidence was assessed using GRADE criteria.

    MAIN RESULTS: One parallel trial conducted in Turkey was included. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The quality of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate quality evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate quality evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period.

    AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate quality that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.

  12. Ngim CF, Lai NM, Hong JY, Tan SL, Ramadas A, Muthukumarasamy P, et al.
    Cochrane Database Syst Rev, 2020 05 28;5:CD012284.
    PMID: 32463488 DOI: 10.1002/14651858.CD012284.pub3
    BACKGROUND: Thalassaemia is a recessively-inherited blood disorder that leads to anaemia of varying severity. In those affected by the more severe forms, regular blood transfusions are required which may lead to iron overload. Accumulated iron from blood transfusions may be deposited in vital organs including the heart, liver and endocrine organs such as the pituitary glands which can affect growth hormone production. Growth hormone deficiency is one of the factors that can lead to short stature, a common complication in people with thalassaemia. Growth hormone replacement therapy has been used in children with thalassaemia who have short stature and growth hormone deficiency. This review on the role of growth hormone was originally published in September 2017 and updated in April 2020.

    OBJECTIVES: To assess the benefits and safety of growth hormone therapy in people with thalassaemia.

    SEARCH METHODS: We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of latest search: 14 November 2019. We also searched the reference lists of relevant articles, reviews and clinical trial registries. Date of latest search: 06 January 2020.

    SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing the use of growth hormone therapy to placebo or standard care in people with thalassaemia of any type or severity.

    DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion. Data extraction and assessment of risk of bias were also conducted independently by two authors. The certainty of the evidence was assessed using GRADE criteria.

    MAIN RESULTS: We included one parallel trial conducted in Turkey. The trial recruited 20 children with homozygous beta thalassaemia who had short stature; 10 children received growth hormone therapy administered subcutaneously on a daily basis at a dose of 0.7 IU/kg per week and 10 children received standard care. The overall risk of bias in this trial was low except for the selection criteria and attrition bias which were unclear. The certainty of the evidence for all major outcomes was moderate, the main concern was imprecision of the estimates due to the small sample size leading to wide confidence intervals. Final height (cm) (the review's pre-specified primary outcome) and change in height were not assessed in the included trial. The trial reported no clear difference between groups in height standard deviation (SD) score after one year, mean difference (MD) -0.09 (95% confidence interval (CI) -0.33 to 0.15 (moderate-certainty evidence). However, modest improvements appeared to be observed in the following key outcomes in children receiving growth hormone therapy compared to control (moderate-certainty evidence): change between baseline and final visit in height SD score, MD 0.26 (95% CI 0.13 to 0.39); height velocity, MD 2.28 cm/year (95% CI 1.76 to 2.80); height velocity SD score, MD 3.31 (95% CI 2.43 to 4.19); and change in height velocity SD score between baseline and final visit, MD 3.41 (95% CI 2.45 to 4.37). No adverse effects of treatment were reported in either group; however, while there was no clear difference between groups in the oral glucose tolerance test at one year, fasting blood glucose was significantly higher in the growth hormone therapy group compared to control, although both results were still within the normal range, MD 6.67 mg/dL (95% CI 2.66 to 10.68). There were no data beyond the one-year trial period.

    AUTHORS' CONCLUSIONS: A small single trial contributed evidence of moderate certainty that the use of growth hormone for a year may improve height velocity of children with thalassaemia although height SD score in the treatment group was similar to the control group. There are no randomised controlled trials in adults or trials that address the use of growth hormone therapy over a longer period and assess its effect on final height and quality of life. The optimal dosage of growth hormone and the ideal time to start this therapy remain uncertain. Large well-designed randomised controlled trials over a longer period with sufficient duration of follow up are needed.

  13. Jahanfar S, Ng CJ, Teng CL
    PMID: 19160255 DOI: 10.1002/14651858.CD005458.pub2
    BACKGROUND: Mastitis can be caused by ineffective positioning of the baby at the breast or restricted feeding. Infective mastitis is commonly caused by Staphylococcus Aureus. Incidence of mastitis in breastfeeding women may reach 33%. Effective milk removal, pain medication and antibiotic therapy have been the mainstays of treatment.

    OBJECTIVES: This review aims to examine the effectiveness of antibiotic therapies in relieving symptoms for breastfeeding women with mastitis with or without laboratory investigation.

    SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (December 2007), the Cochrane Central Register of Clinical Trials (The Cochrane Library 2007, Issue 4), MEDLINE (1996 to 2007) and EMBASE (January 1985 to 2007). We contacted investigators and other content experts known to us for unpublished trials and scanned the reference lists of retrieved articles

    SELECTION CRITERIA: Randomized and quasi-randomized clinical trials comparing the effectiveness of various types of antibiotic therapies or antibiotic therapy versus alternative therapies for the treatment of mastitis were selected.

    DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. When in dispute, we consulted a third author.

    MAIN RESULTS: Two trials met the inclusion criteria. One small trial (n = 25) compared amoxicillin with cephradine and found no significant difference between the two antibiotics in terms of symptom relief and abscess formation. Another, older study compared breast emptying alone as "supportive therapy" versus antibiotic therapy plus supportive therapy, and no therapy. The findings of the latter study suggested faster clearance of symptoms for women using antibiotics, although the study design was problematic.

    AUTHORS' CONCLUSIONS: There is insufficient evidence to confirm or refute the effectiveness of antibiotic therapy for the treatment of lactational mastitis. There is an urgent need to conduct high-quality, double-blinded randomized clinical trials to determine whether antibiotics should be used in this common postpartum condition.
  14. Tan ML, Ho JJ, Teh KH
    Cochrane Database Syst Rev, 2016 Sep 28;9:CD009398.
    PMID: 27678554 DOI: 10.1002/14651858.CD009398.pub3
    BACKGROUND: About 5% of school children have a specific learning disorder, defined as unexpected failure to acquire adequate abilities in reading, writing or mathematics that is not a result of reduced intellectual ability, inadequate teaching or social deprivation. Of these events, 80% are reading disorders. Polyunsaturated fatty acids (PUFAs), in particular, omega-3 and omega-6 fatty acids, which normally are abundant in the brain and in the retina, are important for learning. Some children with specific learning disorders have been found to be deficient in these PUFAs, and it is argued that supplementation of PUFAs may help these children improve their learning abilities.

    OBJECTIVES: 1. To assess effects on learning outcomes of supplementation of polyunsaturated fatty acids (PUFAs) for children with specific learning disorders.2. To determine whether adverse effects of supplementation of PUFAs are reported in these children.

    SEARCH METHODS: In November 2015, we searched CENTRAL, Ovid MEDLINE, Embase, PsycINFO, 10 other databases and two trials registers. We also searched the reference lists of relevant articles.

    SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing PUFAs with placebo or no treatment in children younger than 18 years with specific learning disabilities, as diagnosed in accordance with the fifth (or earlier) edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-5), or the 10th (or earlier) revision of the International Classification of Diseases (ICD-10) or equivalent criteria. We included children with coexisting developmental disorders such as attention deficit hyperactivity disorder (ADHD) or autism.

    DATA COLLECTION AND ANALYSIS: Two review authors (MLT and KHT) independently screened the titles and abstracts of articles identified by the search and eliminated all studies that did not meet the inclusion criteria. We contacted study authors to ask for missing information and clarification, when needed. We used the GRADE approach to assess the quality of evidence.

    MAIN RESULTS: Two small studies involving 116 children, mainly boys between 10 and 18 years of age, met the inclusion criteria. One study was conducted in a school setting, the other at a specialised clinic. Both studies used three months of a combination of omega-3 and omega-6 supplements as the intervention compared with placebo. Although both studies had generally low risk of bias, we judged the risk of reporting bias as unclear in one study, and as high in the other study. In addition, one of the studies was funded by industry and reported active company involvement in the study.None of the studies reported data on the primary outcomes of reading, writing, spelling and mathematics scores, as assessed by standardised tests.Evidence of low quality indicates that supplementation of PUFAs did not increase the risk of gastrointestinal disturbances (risk ratio 1.43, 95% confidence interval 0.25 to 8.15; two studies, 116 children). Investigators reported no other adverse effects.Both studies reported attention deficit hyperactivity disorder (ADHD)-related behaviour outcomes. We were unable to combine the results in a meta-analysis because one study reported findings as a continuous outcome, and the other as a dichotomous outcome. No other secondary outcomes were reported.We excluded one study because it used a cointervention (carnosine), and five other studies because they did not provide a robust diagnosis of a specific learning disorder. We identified one ongoing study and found three studies awaiting classification.

    AUTHORS' CONCLUSIONS: Evidence is insufficient to permit any conclusions about the effect of PUFAs on the learning abilities of children with specific learning disorders. Well-designed RCTs with clearly defined populations of children with specific learning disorders who have been diagnosed by standardised diagnostic criteria are needed.

  15. Lai NM, Rajadurai SV, Tan KH
    PMID: 16856077
    Preterm infants with bronchopulmonary dysplasia/chronic lung disease have nutritional deficits that may contribute to short and long term morbidity and mortality. Increasing the daily energy intake for these infants may improve their respiratory, growth and neurodevelopmental outcomes.
  16. Lai NM, Foong SC, Foong WC, Tan K
    Cochrane Database Syst Rev, 2016 Apr 14;4:CD008313.
    PMID: 27075527 DOI: 10.1002/14651858.CD008313.pub3
    BACKGROUND: The increased birth rate of twins during recent decades and the improved prognosis of preterm infants have resulted in the need to explore measures that could optimize their growth and neurodevelopmental outcomes. It has been postulated that co-bedding simulates twins' intrauterine experiences in which co-regulatory behaviors between them are observed. These behaviors are proposed to benefit twins by reducing their stress, which may promote growth and development. However, in practice, uncertainty surrounds the benefit-risk profile of co-bedding.

    OBJECTIVES: We aimed to assess the effectiveness of co-bedding compared with separate (individual) care for stable preterm twins in the neonatal nursery in promoting growth and neurodevelopment and reducing short- and long-term morbidities, and to determine whether co-bedding is associated with significant adverse effects.As secondary objectives, we sought to evaluate effects of co-bedding via the following subgroup analyses: twin pairs with different weight ranges (very low birth weight [VLBW] < 1500 grams vs non-VLBW), twins with versus without significant growth discordance at birth, preterm versus borderline preterm twins, twins co-bedded in incubator versus cot at study entry, and twins randomized by twin pair versus neonatal unit.

    SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG). We used keywords and medical subject headings (MeSH) to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE (via PubMed), EMBASE (hosted by EBSCOHOST), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and references cited in our short-listed articles, up to February 29, 2016.

    SELECTION CRITERIA: We included randomized controlled trials with randomization by twin pair and/or by neonatal unit. We excluded cross-over studies.

    DATA COLLECTION AND ANALYSIS: We extracted data using standard methods of the CNRG. Two review authors independently assessed the relevance and risk of bias of retrieved records. We contacted the authors of included studies to request important information missing from their published papers. We expressed our results using risk ratios (RRs) and mean differences (MDs) when appropriate, along with 95% confidence intervals (95% CIs). We adjusted the unit of analysis from individual infants to twin pairs by averaging measurements for each twin pair (continuous outcomes) or by counting outcomes as positive if developed by either twin (dichotomous outcomes).

    MAIN RESULTS: Six studies met the inclusion criteria; however, only five studies provided data for analysis. Four of the six included studies were small and had significant limitations in design. As each study reported outcomes differently, data for most outcomes were effectively contributed by a single study. Study authors reported no differences between co-bedded twins and twins receiving separate care in terms of rate of weight gain (MD 0.20 grams/kg/d, 95% CI -1.60 to 2.00; one study; 18 pairs of twins; evidence of low quality); apnea, bradycardia, and desaturation (A/B/D) episodes (RR 0.85, 95% CI 0.18 to 4.05; one study; 62 pairs of twins; evidence of low quality); episodes in co-regulated states (MD 0.96, 95% CI -3.44 to 5.36; one study; three pairs of twins; evidence of very low quality); suspected or proven infection (RR 0.84, 95% CI 0.30 to 2.31; three studies; 65 pairs of twins; evidence of very low quality); length of hospital stay (MD -4.90 days, 95% CI -35.23 to 25.43; one study; three pairs of twins; evidence of very low quality); and parental satisfaction measured on a scale of 0 to 55 (MD -0.38, 95% CI -4.49 to 3.73; one study; nine pairs of twins; evidence of moderate quality). Although co-bedded twins appeared to have lower pain scores 30 seconds after heel lance on a scale of 0 to 21 (MD -0.96, 95% CI -1.68 to -0.23; two studies; 117 pairs of twins; I(2) = 75%; evidence of low quality), they had higher pain scores 90 seconds after the procedure (MD 1.00, 95% CI 0.14 to 1.86; one study; 62 pairs of twins). Substantial heterogeneity in the outcome of infant pain response after heel prick at 30 seconds post procedure and conflicting results at 30 and 90 seconds post procedure precluded clear conclusions.

    AUTHORS' CONCLUSIONS: Evidence on the benefits and harms of co-bedding for stable preterm twins was insufficient to permit recommendations for practice. Future studies must be adequately powered to detect clinically important differences in growth and neurodevelopment. Researchers should assess harms such as infection, along with medication errors and caregiver satisfaction.

  17. Lai NM, Lai NA, O'Riordan E, Chaiyakunapruk N, Taylor JE, Tan K
    Cochrane Database Syst Rev, 2016 Jul 13;7:CD010140.
    PMID: 27410189 DOI: 10.1002/14651858.CD010140.pub2
    BACKGROUND: The central venous catheter (CVC) is a device used for many functions, including monitoring haemodynamic indicators and administering intravenous medications, fluids, blood products and parenteral nutrition. However, as a foreign object, it is susceptible to colonisation by micro-organisms, which may lead to catheter-related blood stream infection (BSI) and in turn, increased mortality, morbidities and health care costs.

    OBJECTIVES: To assess the effects of skin antisepsis as part of CVC care for reducing catheter-related BSIs, catheter colonisation, and patient mortality and morbidities.

    SEARCH METHODS: In May 2016 we searched: The Cochrane Wounds Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations and Epub Ahead of Print); Ovid EMBASE and EBSCO CINAHL Plus. We also searched clinical trial registries for ongoing and unpublished studies. There were no restrictions with respect to language, date of publication or study setting.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed any type of skin antiseptic agent used either alone or in combination, compared with one or more other skin antiseptic agent(s), placebo or no skin antisepsis in patients with a CVC in place.

    DATA COLLECTION AND ANALYSIS: Two authors independently assessed the studies for their eligibility, extracted data and assessed risk of bias. We expressed our results in terms of risk ratio (RR), absolute risk reduction (ARR) and number need to treat for an additional beneficial outcome (NNTB) for dichotomous data, and mean difference (MD) for continuous data, with 95% confidence intervals (CIs).

    MAIN RESULTS: Thirteen studies were eligible for inclusion, but only 12 studies contributed data, with a total of 3446 CVCs assessed. The total number of participants enrolled was unclear as some studies did not provide such information. The participants were mainly adults admitted to intensive care units, haematology oncology units or general wards. Most studies assessed skin antisepsis prior to insertion and regularly thereafter during the in-dwelling period of the CVC, ranging from every 24 h to every 72 h. The methodological quality of the included studies was mixed due to wide variation in their risk of bias. Most trials did not adequately blind the participants or personnel, and four of the 12 studies had a high risk of bias for incomplete outcome data.Three studies compared different antisepsis regimens with no antisepsis. There was no clear evidence of a difference in all outcomes examined, including catheter-related BSI, septicaemia, catheter colonisation and number of patients who required systemic antibiotics for any of the three comparisons involving three different antisepsis regimens (aqueous povidone-iodine, aqueous chlorhexidine and alcohol compared with no skin antisepsis). However, there were great uncertainties in all estimates due to underpowered analyses and the overall very low quality of evidence presented.There were multiple head-to-head comparisons between different skin antiseptic agents, with different combinations of active substance and base solutions. The most frequent comparison was chlorhexidine solution versus povidone-iodine solution (any base). There was very low quality evidence (downgraded for risk of bias and imprecision) that chlorhexidine may reduce catheter-related BSI compared with povidone-iodine (RR of 0.64, 95% CI 0.41 to 0.99; ARR 2.30%, 95% CI 0.06 to 3.70%). This evidence came from four studies involving 1436 catheters. None of the individual subgroup comparisons of aqueous chlorhexidine versus aqueous povidone-iodine, alcoholic chlorhexidine versus aqueous povidone-iodine and alcoholic chlorhexidine versus alcoholic povidone-iodine showed clear differences for catheter-related BSI or mortality (and were generally underpowered). Mortality was only reported in a single study.There was very low quality evidence that skin antisepsis with chlorhexidine may also reduce catheter colonisation relative to povidone-iodine (RR of 0.68, 95% CI 0.56 to 0.84; ARR 8%, 95% CI 3% to 12%; ; five studies, 1533 catheters, downgraded for risk of bias, indirectness and inconsistency).Evaluations of other skin antiseptic agents were generally in single, small studies, many of which did not report the primary outcome of catheter-related BSI. Trials also poorly reported other outcomes, such as skin infections and adverse events.

    AUTHORS' CONCLUSIONS: It is not clear whether cleaning the skin around CVC insertion sites with antiseptic reduces catheter related blood stream infection compared with no skin cleansing. Skin cleansing with chlorhexidine solution may reduce rates of CRBSI and catheter colonisation compared with cleaning with povidone iodine. These results are based on very low quality evidence, which means the true effects may be very different. Moreover these results may be influenced by the nature of the antiseptic solution (i.e. aqueous or alcohol-based). Further RCTs are needed to assess the effectiveness and safety of different skin antisepsis regimens in CVC care; these should measure and report critical clinical outcomes such as sepsis, catheter-related BSI and mortality.

  18. Dixit R, Nettem S, Madan SS, Soe HHK, Abas AB, Vance LD, et al.
    Cochrane Database Syst Rev, 2018 03 16;3:CD011130.
    PMID: 29546732 DOI: 10.1002/14651858.CD011130.pub3
    BACKGROUND: Sickle cell disease (SCD) is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with SCD, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with SCD, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating SCD.

    OBJECTIVES: To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with SCD.

    SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 17 November 2017.

    SELECTION CRITERIA: Randomised, placebo-controlled trials of folate supplementation for SCD.

    DATA COLLECTION AND ANALYSIS: Four review authors assessed We used the standard Cochrane-defined methodological procedures.Four review authors independently assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. The quality of the evidence was assessed using GRADE.

    MAIN RESULTS: One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with SCD. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children).Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/L and values below 5 µg/L (low-quality evidence). In the folic acid group, values above 18 µg/L were observed in 33 of 41 (81%) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/L, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year (low-quality evidence). It is important to note that none of the raw data for the outcomes listed above were available for analysis.The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio (RR) 0.99 (95% confidence interval (CI) 0.85 to 1.15) (low-quality evidence); major infections, RR 0.89 (95% CI 0.47 to 1.66) (low-quality evidence); dactylitis, RR 0.67 (95% CI 0.35 to 1.27) (low-quality evidence); acute splenic sequestration, RR 1.07 (95% CI 0.44 to 2.57) (low-quality evidence); or episodes of pain, RR 1.16 (95% CI 0.70 to 1.92) (low-quality evidence). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05).Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups.The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low.There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet).

    AUTHORS' CONCLUSIONS: One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with SCD was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear.If further trials were conducted, these may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to SCD-related morbidity. Such trials should include people with SCD of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow-up, than the trial currently included in this review. However, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

  19. Dixit R, Nettem S, Madan SS, Soe HH, Abas AB, Vance LD, et al.
    Cochrane Database Syst Rev, 2016 Feb 16;2:CD011130.
    PMID: 26880182 DOI: 10.1002/14651858.CD011130.pub2
    BACKGROUND: Sickle cell disease is a group of disorders that affects haemoglobin, which causes distorted sickle- or crescent-shaped red blood cells. It is characterized by anaemia, increased susceptibility to infections and episodes of pain. The disease is acquired by inheriting abnormal genes from both parents, the combination giving rise to different forms of the disease. Due to increased erythropoiesis in people with sickle cell disease, it is hypothesized that they are at an increased risk for folate deficiency. For this reason, children and adults with sickle cell disease, particularly those with sickle cell anaemia, commonly take 1 mg of folic acid orally every day on the premise that this will replace depleted folate stores and reduce the symptoms of anaemia. It is thus important to evaluate the role of folate supplementation in treating sickle cell disease.

    OBJECTIVES: To analyse the efficacy and possible adverse effects of folate supplementation (folate occurring naturally in foods, provided as fortified foods or additional supplements such as tablets) in people with sickle cell disease.

    SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also conducted additional searches in both electronic databases and clinical trial registries.Date of last search: 07 December 2015.

    SELECTION CRITERIA: Randomised, placebo-controlled trials of folate supplementation for sickle cell disease.

    DATA COLLECTION AND ANALYSIS: Four review authors assessed the eligibility and risk of bias of the included trials and extracted and analysed the data included in the review. We used the standard Cochrane-defined methodological procedures.

    MAIN RESULTS: One trial, undertaken in 1983, was eligible for inclusion in the review. This was a double-blind placebo-controlled quasi-randomised triaI of supplementation of folic acid in people with sickle cell disease. A total of 117 children with homozygous sickle cell (SS) disease aged six months to four years of age participated over a one-year period (analysis was restricted to 115 children).Serum folate measures, obtained after trial entry at six and 12 months, were available in 80 of 115 (70%) participants. There were significant differences between the folic acid and placebo groups with regards to serum folate values above 18 µg/l and values below 5 µg/l. In the folic acid group, values above 18 µg/l were observed in 33 of 41 (81 %) compared to six of 39 (15%) participants in the placebo (calcium lactate) group. Additionally, there were no participants in the folic acid group with serum folate levels below 5 µg/l, whereas in the placebo group, 15 of 39 (39%) participants had levels below this threshold. Haematological indices were measured in 100 of 115 (87%) participants at baseline and at one year. After adjusting for sex and age group, the investigators reported no significant differences between the trial groups with regards to total haemoglobin concentrations, either at baseline or at one year. It is important to note that none of the raw data for the outcomes listed above were available for analysis.The proportions of participants who experienced certain clinical events were analysed in all 115 participants, for which raw data were available. There were no statistically significant differences noted; however, the trial was not powered to investigate differences between the folic acid and placebo groups with regards to: minor infections, risk ratio 0.99 (95% confidence interval 0.85 to 1.15); major infections, risk ratio 0.89 (95% confidence interval 0.47 to 1.66); dactylitis, risk ratio 0.67 (95% confidence interval 0.35 to 1.27); acute splenic sequestration, risk ratio 1.07 (95% confidence interval 0.44 to 2.57); or episodes of pain, risk ratio 1.16 (95% confidence interval 0.70 to 1.92). However, the investigators reported a higher proportion of repeat dactylitis episodes in the placebo group, with two or more attacks occurring in 10 of 56 participants compared to two of 59 in the folic acid group (P < 0.05).Growth, determined by height-for-age and weight-for-age, as well as height and growth velocity, was measured in 103 of the 115 participants (90%), for which raw data were not available. The investigators reported no significant differences in growth between the two groups.The trial had a high risk of bias with regards to random sequence generation and incomplete outcome data. There was an unclear risk of bias in relation to allocation concealment, outcome assessment, and selective reporting. Finally, There was a low risk of bias with regards to blinding of participants and personnel. Overall the quality of the evidence in the review was low.There were no trials identified for other eligible comparisons, namely: folate supplementation (fortified foods and physical supplementation with tablets) versus placebo; folate supplementation (naturally occurring in diet) versus placebo; folate supplementation (fortified foods and physical supplementation with tablets) versus folate supplementation (naturally occurring in diet).

    AUTHORS' CONCLUSIONS: One doubIe-blind, placebo-controlled triaI on folic acid supplementation in children with sickle cell disease was included in the review. Overall, the trial presented mixed evidence on the review's outcomes. No trials in adults were identified. With the limited evidence provided, we conclude that, while it is possible that folic acid supplementation may increase serum folate levels, the effect of supplementation on anaemia and any symptoms of anaemia remains unclear.Further trials may add evidence regarding the efficacy of folate supplementation. Future trials should assess clinical outcomes such as folate concentration, haemoglobin concentration, adverse effects and benefits of the intervention, especially with regards to sickle cell disease-related morbidity. Trials should include people with sickle cell disease of all ages and both sexes, in any setting. To investigate the effects of folate supplementation, trials should recruit more participants and be of longer duration, with long-term follow up, than the trial currently included in this review.

  20. Lai NM, Chang SMW, Ng SS, Tan SL, Chaiyakunapruk N, Stanaway F
    Cochrane Database Syst Rev, 2019 11 25;2019(11).
    PMID: 31763689 DOI: 10.1002/14651858.CD013243.pub2
    BACKGROUND: Dementia is a chronic condition which progressively affects memory and other cognitive functions, social behaviour, and ability to carry out daily activities. To date, no treatment is clearly effective in preventing progression of the disease, and most treatments are symptomatic, often aiming to improve people's psychological symptoms or behaviours which are challenging for carers. A range of new therapeutic strategies has been evaluated in research, and the use of trained animals in therapy sessions, termed animal-assisted therapy (AAT), is receiving increasing attention.

    OBJECTIVES: To evaluate the efficacy and safety of animal-assisted therapy for people with dementia.

    SEARCH METHODS: We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 5 September 2019. ALOIS contains records of clinical trials identified from monthly searches of major healthcare databases, trial registries, and grey literature sources. We also searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), ISI Web of Science, ClinicalTrials.gov, and the WHO's trial registry portal.

    SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-randomised trials, and randomised cross-over trials that compared AAT versus no AAT, AAT using live animals versus alternatives such as robots or toys, or AAT versus any other active intervention.

    DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of Cochrane Dementia. Two review authors independently assessed the eligibility and risk of bias of the retrieved records. We expressed our results using mean difference (MD), standardised mean difference (SMD), and risk ratio (RR) with their 95% confidence intervals (CIs) where appropriate.

    MAIN RESULTS: We included nine RCTs from 10 reports. All nine studies were conducted in Europe and the US. Six studies were parallel-group, individually randomised RCTs; one was a randomised cross-over trial; and two were cluster-RCTs that were possibly related where randomisation took place at the level of the day care and nursing home. We identified two ongoing trials from trial registries. There were three comparisons: AAT versus no AAT (standard care or various non-animal-related activities), AAT using live animals versus robotic animals, and AAT using live animals versus the use of a soft animal toy. The studies evaluated 305 participants with dementia. One study used horses and the remainder used dogs as the therapy animal. The duration of the intervention ranged from six weeks to six months, and the therapy sessions lasted between 10 and 90 minutes each, with a frequency ranging from one session every two weeks to two sessions per week. There was a wide variety of instruments used to measure the outcomes. All studies were at high risk of performance bias and unclear risk of selection bias. Our certainty about the results for all major outcomes was very low to moderate. Comparing AAT versus no AAT, participants who received AAT may be slightly less depressed after the intervention (MD -2.87, 95% CI -5.24 to -0.50; 2 studies, 83 participants; low-certainty evidence), but they did not appear to have improved quality of life (MD 0.45, 95% CI -1.28 to 2.18; 3 studies, 164 participants; moderate-certainty evidence). There were no clear differences in all other major outcomes, including social functioning (MD -0.40, 95% CI -3.41 to 2.61; 1 study, 58 participants; low-certainty evidence), problematic behaviour (SMD -0.34, 95% CI -0.98 to 0.30; 3 studies, 142 participants; very-low-certainty evidence), agitation (SMD -0.39, 95% CI -0.89 to 0.10; 3 studies, 143 participants; very-low-certainty evidence), activities of daily living (MD 4.65, 95% CI -16.05 to 25.35; 1 study, 37 participants; low-certainty evidence), and self-care ability (MD 2.20, 95% CI -1.23 to 5.63; 1 study, 58 participants; low-certainty evidence). There were no data on adverse events. Comparing AAT using live animals versus robotic animals, one study (68 participants) found mixed effects on social function, with longer duration of physical contact but shorter duration of talking in participants who received AAT using live animals versus robotic animals (median: 93 seconds with live versus 28 seconds with robotic for physical contact; 164 seconds with live versus 206 seconds with robotic for talk directed at a person; 263 seconds with live versus 307 seconds with robotic for talk in total). Another study showed no clear differences between groups in behaviour measured using the Neuropsychiatric Inventory (MD -6.96, 95% CI -14.58 to 0.66; 78 participants; low-certainty evidence) or quality of life (MD -2.42, 95% CI -5.71 to 0.87; 78 participants; low-certainty evidence). There were no data on the other outcomes. Comparing AAT using live animals versus a soft toy cat, one study (64 participants) evaluated only social functioning, in the form of duration of contact and talking. The data were expressed as median and interquartile ranges. Duration of contact was slightly longer in participants in the AAT group and duration of talking slightly longer in those exposed to the toy cat. This was low-certainty evidence.

    AUTHORS' CONCLUSIONS: We found low-certainty evidence that AAT may slightly reduce depressive symptoms in people with dementia. We found no clear evidence that AAT affects other outcomes in this population, with our certainty in the evidence ranging from very-low to moderate depending on the outcome. We found no evidence on safety or effects on the animals. Therefore, clear conclusions cannot yet be drawn about the overall benefits and risks of AAT in people with dementia. Further well-conducted RCTs are needed to improve the certainty of the evidence. In view of the difficulty in achieving blinding of participants and personnel in such trials, future RCTs should work on blinding outcome assessors, document allocation methods clearly, and include major patient-important outcomes such as affect, emotional and social functioning, quality of life, adverse events, and outcomes for animals.

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