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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    SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal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. Sasongko TH, Kademane K, Chai Soon Hou S, Jocelyn TXY, Zabidi-Hussin Z
    Cochrane Database Syst Rev, 2023 Jul 11;7(7):CD011272.
    PMID: 37432030 DOI: 10.1002/14651858.CD011272.pub3
    BACKGROUND: Potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex (TSC) have been shown. Currently everolimus (a rapalog) is only approved for TSC-associated renal angiomyolipoma and subependymal giant cell astrocytoma (SEGA), but not other manifestations of TSC. A systematic review needs to establish evidence for rapamycin or rapalogs for various manifestations in TSC. This is an updated review.

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

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

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

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

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

    AUTHORS' CONCLUSIONS: Oral everolimus reduces the size of SEGA and renal angiomyolipoma by 50%, reduces seizure frequency by 25% and 50% and implements beneficial effects on skin lesions with no difference in the total number of AEs compared to placebo; however, more participants in the treatment group required a dose reduction, interruption or withdrawal and marginally more experienced serious AEs compared to placebo. Topical rapamycin increases the response to skin lesions and facial angiofibroma, an improvement score, satisfaction and the risk of any AE, but not severe adverse events. With caution regarding the risk of severe AEs, this review supports oral everolimus for renal angiomyolipoma, SEGA, seizure, and skin lesions, and topical rapamycin for facial angiofibroma.

  4. 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.

  5. 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.

  6. Aye SZ, Ni H, Sein HH, Mon ST, Zheng Q, Wong YKY
    Cochrane Database Syst Rev, 2021 02 14;2:CD013457.
    PMID: 33583058 DOI: 10.1002/14651858.CD013457.pub2
    BACKGROUND: Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted.

    OBJECTIVES: To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD.

    SEARCH METHODS: In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events.  SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD.

    DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review.

    MAIN RESULTS: We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted at two sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out 1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment. The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reported low certainty evidence of little to no difference between the two groups for all outcomes measured at one week post-treatment: social interaction impairment (mean difference (MD) 3.61 (assessed with the Social Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment (MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD (RR 0.97 (measured by the Clinical Global Impression-Improvement scale), 95% CI 0.49 to 1.93); and tolerability of D-cycloserine (RR 0.32 (assessed by the number of dropouts), 95% CI 0.01 to 7.68).  AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.

  7. Moy FM, Ray A, Buckley BS, West HM
    Cochrane Database Syst Rev, 2017 Jun 11;6(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.

  8. McGee RG, Webster AC, Lewis SR, Welsford M
    Cochrane Database Syst Rev, 2023 Jun 05;6(6):CD009688.
    PMID: 37272501 DOI: 10.1002/14651858.CD009688.pub3
    BACKGROUND: Jellyfish envenomation is common in many coastal regions and varies in severity depending upon the species. Stings cause a variety of symptoms and signs including pain, dermatological reactions, and, in some species, Irukandji syndrome (which may include abdominal/back/chest pain, tachycardia, hypertension, cardiac phenomena, and, rarely, death). Many treatments have been suggested for these symptoms, but their effectiveness is unclear. This is an update of a Cochrane Review last published in 2013.

    OBJECTIVES: To determine the benefits and harms associated with the use of any intervention, in both adults and children, for the treatment of jellyfish stings, as assessed by randomised and quasi-randomised trials.

    SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and Web of Science up to 27 October 2022. We searched clinical trials registers and the grey literature, and conducted forward-citation searching of relevant articles.  SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of any intervention given to treat stings from any species of jellyfish stings. Interventions were compared to another active intervention, placebo, or no treatment. If co-interventions were used, we included the study only if the co-intervention was used in each group.  DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.  MAIN RESULTS: We included nine studies (six RCTs and three quasi-RCTs) involving a total of 574 participants. We found one ongoing study. Participants were either stung accidentally, or were healthy volunteers exposed to stings in a laboratory setting. Type of jellyfish could not be confirmed in beach settings and was determined by investigators using participant and local information. We categorised interventions into comparison groups: hot versus cold applications; topical applications. A third comparison of parenteral administration included no relevant outcome data: a single study (39 participants) evaluated intravenous magnesium sulfate after stings from jellyfish that cause Irukandji syndrome (Carukia). No studies assessed a fourth comparison group of pressure immobilisation bandages.  We downgraded the certainty of the evidence due to very serious risk of bias, serious and very serious imprecision, and serious inconsistency in some results.  Application of heat versus application of cold Four studies involved accidental stings treated on the beach or in hospital. Jellyfish were described as bluebottles (Physalia; location: Australia), and box jellyfish that do not cause Irukandji syndrome (Hawaiian box jellyfish (Carybdea alata) and major box jellyfish (Chironex fleckeri, location: Australia)). Treatments were applied with hot packs or hot water (showers, baths, buckets, or hoses), or ice packs or cold packs.  The evidence for all outcomes was of very low certainty, thus we are unsure whether heat compared to cold leads to at least a clinically significant reduction in pain within six hours of stings from Physalia (risk ratio (RR) 2.25, 95% confidence interval (CI) 1.42 to 3.56; 2 studies, 142 participants) or Carybdea alata and Chironex fleckeri (RR 1.66, 95% CI 0.56 to 4.94; 2 studies, 71 participants). We are unsure whether there is a difference in adverse events due to treatment (RR 0.50, 95% CI 0.05 to 5.19; 2 studies, 142 participants); these were minor adverse events reported for Physalia stings. We are also unsure whether either treatment leads to a clinically significant reduction in pain in the first hour (Physalia: RR 2.66, 95% CI 1.71 to 4.15; 1 study, 88 participants; Carybdea alata and Chironex fleckeri: RR 1.16, 95% CI 0.71 to 1.89; 1 study, 42 participants) or cessation of pain at the end of treatment (Physalia: RR 1.63, 95% CI 0.81 to 3.27; 1 study, 54 participants; Carybdea alata and Chironex fleckeri: RR 3.54, 95% CI 0.82 to 15.31; 1 study, 29 participants). Evidence for retreatment with the same intervention was only available for Physalia, with similar uncertain findings (RR 0.19, 95% CI 0.01 to 3.90; 1 study, 96 participants), as was the case for retreatment with the alternative hot or cold application after Physalia (RR 1.00, 95% CI 0.55 to 1.82; 1 study, 54 participants) and Chironex fleckeri stings (RR 0.48, 95% CI 0.02 to 11.17; 1 study, 42 participants). Evidence for dermatological signs (itchiness or rash) was available only at 24 hours for Physalia stings (RR 1.02, 95% CI 0.63 to 1.65; 2 studies, 98 participants).  Topical applications One study (62 participants) included accidental stings from Hawaiian box jellyfish (Carybdea alata) treated on the beach with fresh water, seawater, Sting Aid (a commercial product), or Adolph's (papain) meat tenderiser. In another study, healthy volunteers (97 participants) were stung with an Indonesian sea nettle (Chrysaora chinensis from Malaysia) in a laboratory setting and treated with isopropyl alcohol, ammonia, heated water, acetic acid, or sodium bicarbonate. Two other eligible studies (Carybdea alata and Physalia stings) did not measure the outcomes of this review.  The evidence for all outcomes was of very low certainty, thus we could not be certain whether or not topical applications provided at least a clinically significant reduction in pain (1 study, 62 participants with Carybdea alata stings, reported only as cessation of pain). For adverse events due to treatment, one study (Chrysaora chinensis stings) withdrew ammonia as a treatment following a first-degree burn in one participant. No studies evaluated clinically significant reduction in pain, retreatment with the same or the alternative treatment, or dermatological signs.

    AUTHORS' CONCLUSIONS: Few studies contributed data to this review, and those that did contribute varied in types of treatment, settings, and range of jellyfish species. We are unsure of the effectiveness of any of the treatments evaluated in this review given the very low certainty of all the evidence. This updated review includes two new studies (with 139 additional participants). The findings are consistent with the previous review.

  9. Ramamurthy P, Rath A, Sidhu P, Fernandes B, Nettem S, Fee PA, et al.
    Cochrane Database Syst Rev, 2022 Feb 11;2(2):CD012981.
    PMID: 35146744 DOI: 10.1002/14651858.CD012981.pub2
    BACKGROUND: Pit and fissure sealants are plastic materials that are used to seal deep pits and fissures on the occlusal surfaces of teeth, where decay occurs most often in children and adolescents. Deep pits and fissures can retain food debris and bacteria, making them difficult to clean, thereby causing them to be more susceptible to dental caries. The application of a pit and fissure sealant, a non-invasive preventive approach, can prevent dental caries by forming a protective barrier that reduces food entrapment and bacterial growth. Though moderate-certainty evidence shows that sealants are effective in preventing caries in permanent teeth, the effectiveness of applying pit and fissure sealants to primary teeth has yet to be established.

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

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

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

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

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

    AUTHORS' CONCLUSIONS: The certainty of the evidence for the comparisons and outcomes in this review was low or very low, reflecting the fragility and uncertainty of the evidence base. The volume of evidence for this review was limited, which typically included small studies where the number of events was low. The majority of studies in this review were of split-mouth design, an efficient study design for this research question; however, there were often shortcomings in the analysis and reporting of results that made synthesising the evidence difficult. An important omission from the included studies was the reporting of adverse events. Given the importance of prevention for maintaining good oral health, there exists an important evidence gap pertaining to the caries-preventive effect and retention of sealants in the primary dentition, which should be addressed through robust RCTs.

  10. 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.

  11. 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.

  12. 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.

  13. Kumbargere Nagraj S, Eachempati P, Paisi M, Nasser M, Sivaramakrishnan G, Francis T, et al.
    Cochrane Database Syst Rev, 2022 Aug 22;8(8):CD013826.
    PMID: 35994295 DOI: 10.1002/14651858.CD013826.pub2
    BACKGROUND: Aerosols and spatter are generated in a dental clinic during aerosol-generating procedures (AGPs) that use high-speed hand pieces. Dental healthcare providers can be at increased risk of transmission of diseases such as tuberculosis, measles and severe acute respiratory syndrome (SARS) through droplets on mucosae, inhalation of aerosols or through fomites on mucosae, which harbour micro-organisms. There are ways to mitigate and contain spatter and aerosols that may, in turn, reduce any risk of disease transmission. In addition to personal protective equipment (PPE) and aerosol-reducing devices such as high-volume suction, it has been hypothesised that the use of mouth rinse by patients before dental procedures could reduce the microbial load of aerosols that are generated during dental AGPs.

    OBJECTIVES: To assess the effects of preprocedural mouth rinses used in dental clinics to minimise incidence of infection in dental healthcare providers and reduce or neutralise contamination in aerosols.

    SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 4 February 2022.

    SELECTION CRITERIA: We included randomised controlled trials and excluded laboratory-based studies. Study participants were dental patients undergoing AGPs. Studies compared any preprocedural mouth rinse used to reduce contaminated aerosols versus placebo, no mouth rinse or another mouth rinse. Our primary outcome was incidence of infection of dental healthcare providers and secondary outcomes were reduction in the level of contamination of the dental operatory environment, cost, change in mouth microbiota, adverse events, and acceptability and feasibility of the intervention.

    DATA COLLECTION AND ANALYSIS: Two review authors screened search results, extracted data from included studies, assessed the risk of bias in the studies and judged the certainty of the available evidence. We used mean differences (MDs) and 95% confidence intervals (CIs) as the effect estimate for continuous outcomes, and random-effects meta-analysis to combine data  MAIN RESULTS:  We included 17 studies with 830 participants aged 18 to 70 years. We judged three trials at high risk of bias, two at low risk and 12 at unclear risk of bias.  None of the studies measured our primary outcome of the incidence of infection in dental healthcare providers.  The primary outcome in the studies was reduction in the level of bacterial contamination measured in colony-forming units (CFUs) at distances of less than 2 m (intended to capture larger droplets) and 2 m or more (to capture droplet nuclei from aerosols arising from the participant's oral cavity). It is unclear what size of CFU reduction represents a clinically significant amount. There is low- to very low-certainty evidence that chlorhexidine (CHX) may reduce bacterial contamination, as measured by CFUs, compared with no rinsing or rinsing with water. There were similar results when comparing cetylpyridinium chloride (CPC) with no rinsing and when comparing CPC, essential oils/herbal mouthwashes or boric acid with water. There is very low-certainty evidence that tempered mouth rinses may provide a greater reduction in CFUs than cold mouth rinses. There is low-certainty evidence that CHX may reduce CFUs more than essential oils/herbal mouthwashes. The evidence for other head-to-head comparisons was limited and inconsistent.  The studies did not provide any information on costs, change in micro-organisms in the patient's mouth or adverse events such as temporary discolouration, altered taste, allergic reaction or hypersensitivity. The studies did not assess acceptability of the intervention to patients or feasibility of implementation for dentists.  AUTHORS' CONCLUSIONS: None of the included studies measured the incidence of infection among dental healthcare providers. The studies measured only reduction in level of bacterial contamination in aerosols. None of the studies evaluated viral or fungal contamination. We have only low to very low certainty for all findings. We are unable to draw conclusions regarding whether there is a role for preprocedural mouth rinses in reducing infection risk or the possible superiority of one preprocedural rinse over another. Studies are needed that measure the effect of rinses on infectious disease risk among dental healthcare providers and on contaminated aerosols at larger distances with standardised outcome measurement.

  14. Kumbargere Nagraj S, Eachempati P, Paisi M, Nasser M, Sivaramakrishnan G, Verbeek JH
    Cochrane Database Syst Rev, 2020 Oct 12;10(10):CD013686.
    PMID: 33047816 DOI: 10.1002/14651858.CD013686.pub2
    BACKGROUND: Many dental procedures produce aerosols (droplets, droplet nuclei and splatter) that harbour various pathogenic micro-organisms and may pose a risk for the spread of infections between dentist and patient. The COVID-19 pandemic has led to greater concern about this risk.

    OBJECTIVES: To assess the effectiveness of methods used during dental treatment procedures to minimize aerosol production and reduce or neutralize contamination in aerosols.

    SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases on 17 September 2020: Cochrane Oral Health's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (in the Cochrane Library, 2020, Issue 8), MEDLINE Ovid (from 1946); Embase Ovid (from 1980); the WHO COVID-19 Global literature on coronavirus disease; the US National Institutes of Health Trials Registry (ClinicalTrials.gov); and the Cochrane COVID-19 Study Register. We placed no restrictions on the language or date of publication.

    SELECTION CRITERIA: We included randomized controlled trials (RCTs) and controlled clinical trials (CCTs) on aerosol-generating procedures (AGPs) performed by dental healthcare providers that evaluated methods to reduce contaminated aerosols in dental clinics (excluding preprocedural mouthrinses). The primary outcomes were incidence of infection in dental staff or patients, and reduction in volume and level of contaminated aerosols in the operative environment. The secondary outcomes were cost, accessibility and feasibility.

    DATA COLLECTION AND ANALYSIS: Two review authors screened search results, extracted data from the included studies, assessed the risk of bias in the studies, and judged the certainty of the available evidence. We used mean differences (MDs) and 95% confidence intervals (CIs) as the effect estimate for continuous outcomes, and random-effects meta-analysis to combine data. We assessed heterogeneity.

    MAIN RESULTS: We included 16 studies with 425 participants aged 5 to 69 years. Eight studies had high risk of bias; eight had unclear risk of bias. No studies measured infection. All studies measured bacterial contamination using the surrogate outcome of colony-forming units (CFU). Two studies measured contamination per volume of air sampled at different distances from the patient's mouth, and 14 studies sampled particles on agar plates at specific distances from the patient's mouth. The results presented below should be interpreted with caution as the evidence is very low certainty due to heterogeneity, risk of bias, small sample sizes and wide confidence intervals. Moreover, we do not know the 'minimal clinically important difference' in CFU. High-volume evacuator Use of a high-volume evacuator (HVE) may reduce bacterial contamination in aerosols less than one foot (~ 30 cm) from a patient's mouth (MD -47.41, 95% CI -92.76 to -2.06; 3 RCTs, 122 participants (two studies had split-mouth design); very high heterogeneity I² = 95%), but not at longer distances (MD -1.00, -2.56 to 0.56; 1 RCT, 80 participants). One split-mouth RCT (six participants) found that HVE may not be more effective than conventional dental suction (saliva ejector or low-volume evacuator) at 40 cm (MD CFU -2.30, 95% CI -5.32 to 0.72) or 150 cm (MD -2.20, 95% CI -14.01 to 9.61). Dental isolation combination system One RCT (50 participants) found that there may be no difference in CFU between a combination system (Isolite) and a saliva ejector (low-volume evacuator) during AGPs (MD -0.31, 95% CI -0.82 to 0.20) or after AGPs (MD -0.35, -0.99 to 0.29). However, an 'n of 1' design study showed that the combination system may reduce CFU compared with rubber dam plus HVE (MD -125.20, 95% CI -174.02 to -76.38) or HVE (MD -109.30, 95% CI -153.01 to -65.59). Rubber dam One split-mouth RCT (10 participants) receiving dental treatment, found that there may be a reduction in CFU with rubber dam at one-metre (MD -16.20, 95% CI -19.36 to -13.04) and two-metre distance (MD -11.70, 95% CI -15.82 to -7.58). One RCT of 47 dental students found use of rubber dam may make no difference in CFU at the forehead (MD 0.98, 95% CI -0.73 to 2.70) and occipital region of the operator (MD 0.77, 95% CI -0.46 to 2.00). One split-mouth RCT (21 participants) found that rubber dam plus HVE may reduce CFU more than cotton roll plus HVE on the patient's chest (MD -251.00, 95% CI -267.95 to -234.05) and dental unit light (MD -12.70, 95% CI -12.85 to -12.55). Air cleaning systems One split-mouth CCT (two participants) used a local stand-alone air cleaning system (ACS), which may reduce aerosol contamination during cavity preparation (MD -66.70 CFU, 95% CI -120.15 to -13.25 per cubic metre) or ultrasonic scaling (MD -32.40, 95% CI - 51.55 to -13.25). Another CCT (50 participants) found that laminar flow in the dental clinic combined with a HEPA filter may reduce contamination approximately 76 cm from the floor (MD -483.56 CFU, 95% CI -550.02 to -417.10 per cubic feet per minute per patient) and 20 cm to 30 cm from the patient's mouth (MD -319.14 CFU, 95% CI - 385.60 to -252.68). Disinfectants ‒ antimicrobial coolants Two RCTs evaluated use of antimicrobial coolants during ultrasonic scaling. Compared with distilled water, coolant containing chlorhexidine (CHX), cinnamon extract coolant or povidone iodine may reduce CFU: CHX (MD -124.00, 95% CI -135.78 to -112.22; 20 participants), povidone iodine (MD -656.45, 95% CI -672.74 to -640.16; 40 participants), cinnamon (MD -644.55, 95% CI -668.70 to -620.40; 40 participants). CHX coolant may reduce CFU more than povidone iodine (MD -59.30, 95% CI -64.16 to -54.44; 20 participants), but not more than cinnamon extract (MD -11.90, 95% CI -35.88 to 12.08; 40 participants).

    AUTHORS' CONCLUSIONS: We found no studies that evaluated disease transmission via aerosols in a dental setting; and no evidence about viral contamination in aerosols. All of the included studies measured bacterial contamination using colony-forming units. There appeared to be some benefit from the interventions evaluated but the available evidence is very low certainty so we are unable to draw reliable conclusions. We did not find any studies on methods such as ventilation, ionization, ozonisation, UV light and fogging. Studies are needed that measure contamination in aerosols, size distribution of aerosols and infection transmission risk for respiratory diseases such as COVID-19 in dental patients and staff.

  15. Kumbargere Nagraj S, Eachempati P, Uma E, Singh VP, Ismail NM, Varghese E
    Cochrane Database Syst Rev, 2019 Dec 11;12(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.

  16. 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.

  17. 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.

  18. 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.
  19. 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.

  20. 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.
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