WITHDRAWN: Iodine supplementation for preventing iodine deficiency disorders in children.

BACKGROUND: Iodine deficiency is the main cause of potentially preventable mental retardation in childhood, as well as causing goitre and hypothyroidism in people of all ages. It is still prevalent in large parts of the world. OBJECTIVES: To assess the effects of iodine supplementation overall, and of different forms and dosages of iodine supplementation separately, in the prevention of iodine deficiency disorders in children. SEARCH METHODS: The Cochrane Library, MEDLINE, EMBASE and reference lists, databases of ongoing trials and the Internet were searched. SELECTION CRITERIA: We included randomised controlled trials and prospective controlled trials not using randomisation of iodine supplementation in children living in areas of iodine deficiency. DATA COLLECTION AND ANALYSIS: Two reviewers did the initial data selection and quality assessment of trials independently. As the studies identified were not sufficiently similar and not of sufficient quality, we did not do a meta-analysis but summarised the data in a narrative format. MAIN RESULTS: Twenty-six prospective controlled trials were related to our question, assessing a total of 29613 children. Twenty of them were classified as being of low quality, six of moderate quality. Most studies used iodised oil as a supplement, but other supplements were also used. The intervention groups were compared to a non-supplemented control group, different doses or different forms of iodine supplementation.There was a clear tendency towards goitre reduction with iodine supplementation; this was significant in several studies. Significant differences in physical development were not seen, except in one study. Results for differences in cognitive and psychomotor measures were mixed, with only few studies showing a positive intervention effect. One study suggested that infant mortality was lowered after iodine supplementation.Most studies showed a significant increase in urinary iodine excretion and levels recommended by the WHO were reached in most cases after supplementation. Thyroid-stimulating hormone (TSH) levels were significantly reduced in one study. In 1.8% of the children investigated, adverse effects were found, most of them were minor and transient. AUTHORS' CONCLUSIONS: Despite most of the included studies being of low quality, the results suggest that iodine supplementation, especially iodised oil, is an effective means of decreasing goitre rates and improving iodine status in children. Indications of positive effects on physical and mental development and mortality were seen, although results were not always significant. Adverse effects were generally minor and transient. Insufficient evidence was available on non-oil supplements. High quality controlled studies investigating relevant long term outcome measures are needed to address the question of the best form of iodine supplementation in different population groups and settings.

Whole grain cereals for the primary or secondary prevention of cardiovascular disease.

BACKGROUND: There is evidence from observational studies that whole grains can have a beneficial effect on risk for cardiovascular disease (CVD). Earlier versions of this review found mainly short-term intervention studies. There are now longer-term randomised controlled trials (RCTs) available. This is an update and expansion of the original review conducted in 2007. OBJECTIVES: The aim of this systematic review was to assess the effect of whole grain foods or diets on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible RCTs. SEARCH METHODS: We searched CENTRAL (Issue 8, 2016) in the Cochrane Library, MEDLINE (1946 to 31 August 2016), Embase (1980 to week 35 2016), and CINAHL Plus (1937 to 31 August 2016) on 31 August 2016. We also searched ClinicalTrials.gov on 5 July 2017 and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 6 July 2017. We checked reference lists of relevant articles and applied no language restrictions. SELECTION CRITERIA: We selected RCTs assessing the effects of whole grain foods or diets containing whole grains compared to foods or diets with a similar composition, over a minimum of 12 weeks, on cardiovascular disease and related risk factors. Eligible for inclusion were healthy adults, those at increased risk of CVD, or those previously diagnosed with CVD. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies. Data were extracted and quality-checked by one review author and checked by a second review author. A second review author checked the analyses. We assessed treatment effect using mean difference in a fixed-effect model and heterogeneity using the I2 statistic and the Chi2 test of heterogeneity. We assessed the overall quality of evidence using GRADE with GRADEpro software. MAIN RESULTS: We included nine RCTs randomising a total of 1414 participants (age range 24 to 70; mean age 45 to 59, where reported) to whole grain versus lower whole grain or refined grain control groups. We found no studies that reported the effect of whole grain diets on total cardiovascular mortality or cardiovascular events (total myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, total stroke). All included studies reported the effect of whole grain diets on risk factors for cardiovascular disease including blood lipids and blood pressure. All studies were in primary prevention populations and had an unclear or high risk of bias, and no studies had an intervention duration greater than 16 weeks.Overall, we found no difference between whole grain and control groups for total cholesterol (mean difference 0.07, 95% confidence interval -0.07 to 0.21; 6 studies (7 comparisons); 722 participants; low-quality evidence).Using GRADE, we assessed the overall quality of the available evidence on cholesterol as low. Four studies were funded by independent national and government funding bodies, while the remaining studies reported funding or partial funding by organisations with commercial interests in cereals. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs of an effect of whole grain diets on cardiovascular outcomes or on major CVD risk factors such as blood lipids and blood pressure. Trials were at unclear or high risk of bias with small sample sizes and relatively short-term interventions, and the overall quality of the evidence was low. There is a need for well-designed, adequately powered RCTs with longer durations assessing cardiovascular events as well as cardiovascular risk factors.

Low glycaemic index diets for the prevention of cardiovascular disease.

BACKGROUND: The glycaemic index (GI) is a physiological measure of the ability of a carbohydrate to affect blood glucose. Interest is growing in this area for the clinical management of people at risk of, or with, established cardiovascular disease. There is a need to review the current evidence from randomised controlled trials (RCTs) in this area. This is an update of the original review published in 2008. OBJECTIVES: To assess the effect of the dietary GI on total mortality, cardiovascular events, and cardiovascular risk factors (blood lipids, blood pressure) in healthy people or people who have established cardiovascular disease or related risk factors, using all eligible randomised controlled trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and CINAHL in July 2016. We also checked reference lists of relevant articles. No language restrictions were applied. SELECTION CRITERIA: We selected RCTs that assessed the effects of low GI diets compared to diets with a similar composition but a higher GI on cardiovascular disease and related risk factors. Minimum trial duration was 12 weeks. Participants included were healthy adults or those at increased risk of cardiovascular disease, or previously diagnosed with cardiovascular disease. Studies in people with diabetes mellitus were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened and selected studies. Two review authors independently assessed risk of bias, evaluated the overall quality of the evidence using GRADE, and extracted data following the Cochrane Handbook for Systematic Reviews of Interventions. We contacted trial authors for additional information. Analyses were checked by a second reviewer. Continuous outcomes were synthesized using mean differences and adverse events were synthesized narratively. MAIN RESULTS: Twenty-one RCTs were included, with a total of 2538 participants randomised to low GI intervention (1288) or high GI (1250). All 21 included studies reported the effect of low GI diets on risk factors for cardiovascular disease, including blood lipids and blood pressure.Twenty RCTs (18 of which were newly included in this version of the review) included primary prevention populations (healthy individuals or those at high risk of CVD, with mean age range from 19 to 69 years) and one RCT was in those diagnosed with pre-existing CVD (a secondary prevention population, with mean age 26.9 years). Most of the studies did not have an intervention duration of longer than six months. Difference in GI intake between comparison groups varied widely from 0.6 to 42.None of the included studies reported the effect of low GI dietary intake on cardiovascular mortality and cardiovascular events such as fatal and nonfatal myocardial infarction, unstable angina, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, and stroke. The unclear risk of bias of most of the included studies makes overall interpretation of the data difficult. Only two of the included studies (38 participants) reported on adverse effects and did not observe any harms (low-quality evidence). AUTHORS' CONCLUSIONS: There is currently no evidence available regarding the effect of low GI diets on cardiovascular disease events. Moreover, there is currently no convincing evidence that low GI diets have a clear beneficial effect on blood lipids or blood pressure parameters.

Vitamin K for the primary prevention of cardiovascular disease.

BACKGROUND: A deficiency in vitamin K has been associated with increased calcium deposition and coronary artery calcification, which may lead to cardiovascular disease. OBJECTIVES: To determine the effectiveness of vitamin K supplementation as a single nutrient supplement for the primary prevention of cardiovascular disease. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 8 of 12, 2014); MEDLINE (Ovid, 1946 to September week 2 2014); EMBASE Classic + EMBASE (Ovid, 1947 to September 18 2014); Science Citation Index Expanded (SCI-EXPANDED) and Conference Proceedings Citation Index, Science (CPCI-S) (both 1990 to 17 September 2014) on Web of Science (Thomson Reuters); Database of Abstracts of Reviews of Effects (DARE); Health Technology Assessment Database and Health Economics Evaluations Database (Issue 3 of 4, 2014). We searched trial registers and reference lists of reviews for further studies. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials of vitamin K supplementation as a single nutrient supplement, lasting at least three months, and involving healthy adults or adults at high risk of cardiovascular disease. The comparison group was no intervention or placebo. The outcomes of interest were cardiovascular disease clinical events and cardiovascular disease risk factors. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, abstracted the data and assessed the risk of bias. MAIN RESULTS: We included only one small trial (60 participants randomised) which overall was judged to be at low risk of bias. The study examined two doses of menaquinone (vitamin K2) over 3 months in healthy participants aged 40 to 65 years. The primary focus of the trial was to examine the effects of menaquinone (subtype MK7) on different matrix Gla proteins (MGP - vitamin K dependent proteins in the vessel wall) at different doses, but the authors also reported blood pressure and lipid levels. The trial did not report on our primary outcomes (cardiovascular disease clinical events) as it was small, short term and conducted in healthy participants.In terms of cardiovascular disease risk factors, no effects were seen for vitamin K2 on blood pressure or lipid levels, although the trial was small and findings are limited. The trial did not report any of our other secondary outcomes. AUTHORS' CONCLUSIONS: The very limited results of this review highlight the lack of evidence currently available to determine the effectiveness of vitamin K supplementation for the primary prevention of cardiovascular disease, and demonstrate the need for further high quality trials in this area.

Influenza vaccines for preventing cardiovascular disease.

BACKGROUND: This is an update of the original review published in 2008. The risk of adverse cardiovascular outcomes is increased with influenza-like infection, and vaccination against influenza may improve cardiovascular outcomes. OBJECTIVES: To assess the potential benefits of influenza vaccination for primary and secondary prevention of cardiovascular disease. SEARCH METHODS: We searched the following electronic databases on 18 October 2013: The Cochrane Library (including Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Economic Evaluation Database (EED) and Health Technology Assessment database (HTA)), MEDLINE, EMBASE, Science Citation Index Expanded, Conference Proceedings Citation Index - Science and ongoing trials registers (www.controlled-trials.com/ and www.clinicaltrials.gov). We examined reference lists of relevant primary studies and systematic reviews. We performed a limited PubMed search on 20 February 2015, just before publication. SELECTION CRITERIA: Randomised controlled trials (RCTs) of influenza vaccination compared with placebo or no treatment in participants with or without cardiovascular disease, assessing cardiovascular death or non-fatal cardiovascular events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. We carried out meta-analyses only for cardiovascular death, as other outcomes were reported too infrequently. We expressed effect sizes as risk ratios (RRs), and we used random-effects models. MAIN RESULTS: We included eight trials of influenza vaccination compared with placebo or no vaccination, with 12,029 participants receiving at least one vaccination or control treatment. We included six new studies (n = 11,251), in addition to the two included in the previous version of the review. Four of these trials (n = 10,347) focused on prevention of influenza in the general or elderly population and reported cardiovascular outcomes among their safety analyses; four trials (n = 1682) focused on prevention of cardiovascular events in patients with established coronary heart disease. These populations were analysed separately. Follow-up continued between 42 days and one year. Five RCTs showed deficits in at least three of the risk of bias criteria assessed. When reported (seven studies), vaccination provided adequate immunogenicity or protection against influenza. Cardiovascular mortality was reported by four secondary prevention trials and was significantly reduced by influenza vaccination overall (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.26 to 0.76; P value 0.003) with no significant heterogeneity between studies, and by three trials reporting cardiovascular mortality as part of their safety analyses when the numbers of events were too small to permit conclusions. In studies of patients with coronary heart disease, composite outcomes of cardiovascular events tended to be decreased with influenza vaccination compared with placebo. Generally no significant difference was found between comparison groups regarding individual outcomes such as myocardial infarction. AUTHORS' CONCLUSIONS: In patients with cardiovascular disease, influenza vaccination may reduce cardiovascular mortality and combined cardiovascular events. However, studies had some risk of bias, and results were not always consistent, so additional higher-quality evidence is necessary to confirm these findings. Not enough evidence was available to establish whether influenza vaccination has a role to play in the primary prevention of cardiovascular disease.

Omega 6 fatty acids for the primary prevention of cardiovascular disease.

BACKGROUND: Omega 6 plays a vital role in many physiological functions but there is controversy concerning its effect on cardiovascular disease (CVD) risk. There is conflicting evidence whether increasing or decreasing omega 6 intake results in beneficial effects. OBJECTIVES: The two primary objectives of this Cochrane review were to determine the effectiveness of:1. Increasing omega 6 (Linoleic acid (LA), Gamma-linolenic acid (GLA), Dihomo-gamma-linolenic acid (DGLA), Arachidonic acid (AA), or any combination) intake in place of saturated or monounsaturated fats or carbohydrates for the primary prevention of CVD.2. Decreasing omega 6 (LA, GLA, DGLA, AA, or any combination) intake in place of carbohydrates or protein (or both) for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases up to 23 September 2014: the Cochrane Central Register of Controlled Trials (CENTRAL) on the Cochrane Library (Issue 8 of 12, 2014); MEDLINE (Ovid) (1946 to September week 2, 2014); EMBASE Classic and EMBASE (Ovid) (1947 to September 2014); Web of Science Core Collection (Thomson Reuters) (1990 to September 2014); Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment Database, and Health Economics Evaluations Database on the Cochrane Library (Issue 3 of 4, 2014). We searched trial registers and reference lists of reviews for further studies. We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions stating an intention to increase or decrease omega 6 fatty acids, lasting at least six months, and including healthy adults or adults at high risk of CVD. The comparison group was given no advice, no supplementation, a placebo, a control diet, or continued with their usual diet. The outcomes of interest were CVD clinical events (all-cause mortality, cardiovascular mortality, non-fatal end points) and CVD risk factors (changes in blood pressure, changes in blood lipids, occurrence of type 2 diabetes). We excluded trials involving exercise or multifactorial interventions to avoid confounding. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted the data, and assessed the risk of bias in the included trials. MAIN RESULTS: We included four RCTs (five papers) that randomised 660 participants. No ongoing trials were identified. All included trials had at least one domain with an unclear risk of bias. There were no RCTs of omega 6 intake reporting CVD clinical events. Three trials investigated the effect of increased omega 6 intake on lipid levels (total cholesterol, low density lipoprotein (LDL-cholesterol), and high density lipoprotein (HDL-cholesterol)), two trials reported triglycerides, and two trials reported blood pressure (diastolic and systolic blood pressure). Two trials, one with two relevant intervention arms, investigated the effect of decreased omega 6 intake on blood pressure parameters and lipid levels (total cholesterol, LDL-cholesterol, and HDL-cholesterol) and one trial reported triglycerides. Our analyses found no statistically significant effects of either increased or decreased omega 6 intake on CVD risk factors.Two studies were supported by funding from the UK Food Standards Agency and Medical Research Council. One study was supported by Lipid Nutrition, a commercial company in the Netherlands and the Dutch Ministry of Economic Affairs. The final study was supported by grants from the Finnish Food Research Foundation, Finnish Heart Research Foundation, Aarne and Aili Turnen Foundation, and the Research Council for Health, Academy of Finland. AUTHORS' CONCLUSIONS: We found no studies examining the effects of either increased or decreased omega 6 on our primary outcome CVD clinical endpoints and insufficient evidence to show an effect of increased or decreased omega 6 intake on CVD risk factors such as blood lipids and blood pressure. Very few trials were identified with a relatively small number of participants randomised. There is a need for larger well conducted RCTs assessing cardiovascular events as well as cardiovascular risk factors.

Cost-effectiveness of manual therapy for the management of musculoskeletal conditions: a systematic review and narrative synthesis of evidence from randomized controlled trials.

OBJECTIVES: The purpose of this study was to systematically review trial-based economic evaluations of manual therapy relative to other alternative interventions used for the management of musculoskeletal conditions. METHODS: A comprehensive literature search was undertaken in major medical, health-related, science and health economic electronic databases. RESULTS: Twenty-five publications were included (11 trial-based economic evaluations). The studies compared cost-effectiveness and/or cost-utility of manual therapy interventions to other treatment alternatives in reducing pain (spinal, shoulder, ankle). Manual therapy techniques (e.g., osteopathic spinal manipulation, physiotherapy manipulation and mobilization techniques, and chiropractic manipulation with or without other treatments) were more cost-effective than usual general practitioner (GP) care alone or with exercise, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. Chiropractic manipulation was found to be less costly and more effective than alternative treatment compared with either physiotherapy or GP care in improving neck pain. CONCLUSIONS: Preliminary evidence from this review shows some economic advantage of manual therapy relative to other interventions used for the management of musculoskeletal conditions, indicating that some manual therapy techniques may be more cost-effective than usual GP care, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. However, at present, there is a paucity of evidence on the cost-effectiveness and/or cost-utility evaluations for manual therapy interventions. Further improvements in the methodological conduct and reporting quality of economic evaluations of manual therapy are warranted in order to facilitate adequate evidence-based decisions among policy makers, health care practitioners, and patients.

Glucagon-like peptide analogues for type 2 diabetes mellitus.

BACKGROUND: Glucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety. OBJECTIVES: To assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus. SEARCH STRATEGY: Studies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials. SELECTION CRITERIA: Studies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes. DATA COLLECTION AND ANALYSIS: Data extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model). MAIN RESULTS: Seventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 µg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 µg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.None of the studies was long enough to assess long-term positive or negative effects. AUTHORS' CONCLUSIONS: GLP-1 agonists are effective in improving glycaemic control.

[Climate protection in practices - current status, motivation and challenges in outpatient care]. / Klimaschutz in der Praxis ­ Status quo, Bereitschaft und Herausforderungen in der ambulanten Versorgung.

INTRODUCTION: The impact of climate change on health and the necessity to reduce emissions in the health sector is becoming an increasingly discussed topic. Little is known about medical doctors' (MDs) attitude towards climate protection measures in outpatient practices. METHODS: Between October 2020 and February 2021, a survey was conducted among MDs in German practices. 1,683 participants answered 39 questions on energy use, transportation, disposable materials, budget and patient counselling. Data were collected on status, motivation, obstacles and needs regarding climate protection in practices. RESULTS: 83% considered climate change an urgent problem requiring immediate action. A majority reported climate effects on their patients' health. Most MDs felt responsible for climate protection in their practices, showing a high degree of willingness to implement climate-friendly measures. Obstacles reported include lack of information and institutional support as well as the expected financial burden. A majority of MDs called on professional associations and politics to develop climate-friendly strategies. CONCLUSION: In view of national climate targets and the willingness of outpatient MDs to contribute to climate protection, support from medical associations is required, e. g. through practical recommendations and financial help, in order to transform the health sector in accordance with the idea of Planetary Health. Accompanying studies should provide further evidence on effective measures to reduce greenhouse gas emissions in practices.

Glucagon-like peptide analogues for type 2 diabetes mellitus: systematic review and meta-analysis.

BACKGROUND: Glucagon-like peptide (GLP-1) analogues are a new class of drugs used in the treatment of type 2 diabetes. They are given by injection, and regulate glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, suppressing glucagon secretion, and delaying gastric emptying and promoting satiety. This systematic review aims to provide evidence on the clinical effectiveness of the GLP-1 agonists in patients not achieving satisfactory glycaemic control with one or more oral glucose lowering drugs. METHODS: MEDLINE, EMBASE, the Cochrane Library and Web of Science were searched to find the relevant papers. We identified 28 randomised controlled trials comparing GLP-1 analogues with placebo, other glucose-lowering agents, or another GLP-1 analogue, in patients with type 2 diabetes with inadequate control on a single oral agent, or on dual therapy. Primary outcomes included HbA1c, weight change and adverse events. RESULTS: Studies were mostly of short duration, usually 26 weeks. All GLP-1 agonists reduced HbA1c by about 1% compared to placebo. Exenatide twice daily and insulin gave similar reductions in HbA1c, but exenatide 2 mg once weekly and liraglutide 1.8 mg daily reduced it by 0.20% and 0.30% respectively more than glargine. Liraglutide 1.2 mg daily reduced HbA1c by 0.34% more than sitagliptin 100 mg daily. Exenatide and liraglutide gave similar improvements in HbA1c to sulphonylureas. Exenatide 2 mg weekly and liraglutide 1.8 mg daily reduced HbA1c by more than exenatide 10 µg twice daily and sitagliptin 100 mg daily. Exenatide 2 mg weekly reduced HbA1c by 0.3% more than pioglitazone 45 mg daily.Exenatide and liraglutide resulted in greater weight loss (from 2.3 to 5.5 kg) than active comparators. This was not due simply to nausea. Hypoglycaemia was uncommon, except when combined with a sulphonylurea. The commonest adverse events with all GLP-1 agonists were initial nausea and vomiting. The GLP-1 agonists have some effect on beta-cell function, but this is not sustained after the drug is stopped. CONCLUSIONS: GLP-1 agonists are effective in improving glycaemic control and promoting weight loss.

Autologous chondrocyte implantation in the knee: systematic review and economic evaluation.

BACKGROUND: The surfaces of the bones in the knee are covered with articular cartilage, a rubber-like substance that is very smooth, allowing frictionless movement in the joint and acting as a shock absorber. The cells that form the cartilage are called chondrocytes. Natural cartilage is called hyaline cartilage. Articular cartilage has very little capacity for self-repair, so damage may be permanent. Various methods have been used to try to repair cartilage. Autologous chondrocyte implantation (ACI) involves laboratory culture of cartilage-producing cells from the knee and then implanting them into the chondral defect. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of ACI in chondral defects in the knee, compared with microfracture (MF). DATA SOURCES: A broad search was done in MEDLINE, EMBASE, The Cochrane Library, NHS Economic Evaluation Database and Web of Science, for studies published since the last Health Technology Assessment review. REVIEW METHODS: Systematic review of recent reviews, trials, long-term observational studies and economic evaluations of the use of ACI and MF for repairing symptomatic articular cartilage defects of the knee. A new economic model was constructed. Submissions from two manufacturers and the ACTIVE (Autologous Chondrocyte Transplantation/Implantation Versus Existing Treatment) trial group were reviewed. Survival analysis was based on long-term observational studies. RESULTS: Four randomised controlled trials (RCTs) published since the last appraisal provided evidence on the efficacy of ACI. The SUMMIT (Superiority of Matrix-induced autologous chondrocyte implant versus Microfracture for Treatment of symptomatic articular cartilage defects) trial compared matrix-applied chondrocyte implantation (MACI®) against MF. The TIG/ACT/01/2000 (TIG/ACT) trial compared ACI with characterised chondrocytes against MF. The ACTIVE trial compared several forms of ACI against standard treatments, mainly MF. In the SUMMIT trial, improvements in knee injury and osteoarthritis outcome scores (KOOSs), and the proportion of responders, were greater in the MACI group than in the MF group. In the TIG/ACT trial there was improvement in the KOOS at 60 months, but no difference between ACI and MF overall. Patients with onset of symptoms < 3 years' duration did better with ACI. Results from ACTIVE have not yet been published. Survival analysis suggests that long-term results are better with ACI than with MF. Economic modelling suggested that ACI was cost-effective compared with MF across a range of scenarios. LIMITATIONS: The main limitation is the lack of RCT data beyond 5 years of follow-up. A second is that the techniques of ACI are evolving, so long-term data come from trials using forms of ACI that are now superseded. In the modelling, we therefore assumed that durability of cartilage repair as seen in studies of older forms of ACI could be applied in modelling of newer forms. A third is that the high list prices of chondrocytes are reduced by confidential discounting. The main research needs are for longer-term follow-up and for trials of the next generation of ACI. CONCLUSIONS: The evidence base for ACI has improved since the last appraisal by the National Institute for Health and Care Excellence. In most analyses, the incremental cost-effectiveness ratios for ACI compared with MF appear to be within a range usually considered acceptable. Research is needed into long-term results of new forms of ACI. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013083. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation.

BACKGROUND: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. OBJECTIVE: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. SOURCES: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. METHODS: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. RESULTS: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). LIMITATIONS: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. CONCLUSIONS: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic reviews in endocrinology. The Cochrane Metabolism and Endocrine Disorders Review Group.

The Cochrane Collaboration is an international nonprofit organization that aims to make up-to-date accurate information about the effects of health care readily available worldwide by preparing, maintaining, and disseminating systematic reviews of the effects of health care. The Cochrane Metabolism, Endocrinology, and Diabetes Review Group's primary concern is the evaluation of randomized controlled trials and other controlled comparisons of health care interventions relevant to the prevention, treatment or management, and rehabilitation of metabolic, nutritional, and endocrine disorders. This article discusses the role of systematic reviews and metaanalyses and invites interested parties to get involved and contribute.

Pharmacotherapy for thyroid nodules. A systematic review and meta-analysis.

The review highlights the uncertainty in the management of nodular thyroid disease. Thyroxine suppressive treatment is given in the hope that nodules might decrease in size, sometimes assuming that dependency on TSH is different in benign and malignant nodular disease. Follow-up of benign nodules over 10 years suggested that most remain the same, shrink, or disappear [14]. TSH suppression may lead to hyperthyroidism, reduced bone density [37.39], and atrial fibrilation; however, apart from reduction of nodule size or arrest in nodule growth, thyroxine therapy may benefit patients by reducing perinodular volume. Consequently, both pressure symptoms and cosmetic complaints could improve. Unfortunately, no information concerning symptoms or well-being is available from published randomized trials. In conclusion, more high quality studies of sufficient duration with adequate power estimation are needed. Uncertainty about predictors of response or the impact on outcomes that are important to patients leaves considerable doubt about the wisdom of applying suppressive therapy. Future studies shoudl include patient-important outcomes including thyroid cancer incidence, health-related quality of life and costs.

Glucocorticoid withdrawal schemes in chronic medical disorders. A systematic review.

This systematic review highlights the uncertainty about the safety and efficacy of glucocorticoid withdrawal in many chronic diseases, elucidating the need for further research in this area. The problem of glucocorticoid withdrawal seems to be good example for wide variation in physicians' approaches to weaning patients off glucocorticoids. This practice variation appears justified, given the well known extraordinary array of individual reactions to systemic glucocorticoid therapy [44], the obligation to individualize treatment, and scientific uncertainty. Moreover, only sparse information concerning health-related quality of life, well-being and symptoms, and socioeconomic sequelae after glucocorticoid withdrawal is available from published randomized trials. In conclusion, clinicians and patients need many more--and in a number of conditions, initial--high quality studies to assess the safety and efficacy of systemic glucocorticoid withdrawal schedules in chronic diseases.

Aspirin in diabetic retinopathy. A systematic review.

Diabetes mellitus is a risk factor for eye disease that can lead to blindness. There have been both concerns that aspirin use might worsen diabetic retinopathy, as well as hopes that aspirin might be beneficial in treating it. We investigated whether there are beneficial effects of aspirin alone and in combination with other antiplatelet agents in the treatment of diabetic retinopathy, and the relative hazards for the development of high-risk proliferative retinopathy following aspirin treatment. We conducted a sensitive search for randomized controlled trials combined with index terms for identifying studies on aspirin treatment in diabetic retinopathy in the Cochrane Library (issue 4, 2001) and Medline (1966 to October, 2001). We examined randomized controlled clinical trials in diabetic patients with (non) proliferative diabetic retinopathy and aspirin treatment alone or in combination with dipyramidole versus placebo administration. Two independent reviewers judged trial eligibility, collected details of study population, interventions, and outcomes using a standard data extraction form. One reviewer assessed the quality of trial reporting. We identified six publications pertinent to our objective. Aspirin dosages ranged from 650 mg to 990 mg daily, the dose of dipyridamole, used in only one trial, was 225 mg per day. Studies lasted 8 weeks to 5 years. All trials showed that aspirin alone or in combination with dipyridamole neither lowered nor increased the risk of the development of diabetic retinopathy. The results suggest that there are no ocular contraindications to taking aspirin if required as part of a treatment for cardiovascular diseases or other medical indications.

Iodized salt for iodine deficiency disorders. A systematic review.

The results suggest that iodized salt is an effective means of improving iodine status, and support the current endeavors to achieve universal salt iodization. Variations in the iodine levels in the salt suggest that particular care must be taken to ensure the quality of the production and storage of iodized salt. It appears that in small children salt intake may not be high enough to guarantee adequate iodine levels through the use of iodized salt. While the studies provided no information about unwanted side effects with the use of iodized salt, most studies did not specifically consider adverse effects. so inferences about side effects remain weak. In conclusion, health policymakers and other decision makers require high-quality studies to measure the effect of iodized salt in comparison with other forms of iodine supplementation. These should be large studies lasting at least two years. Investigators should not retstrict their outcomes to goiter rates and urinary iodine excretion, but should include the other outcome measures specified above, such as mental and physical development in children, mortality, and others. Investigators should pay special attention to adverse effects and their report in primary studies, and should assess children (including very young children who may have a relatively low salt consumption) separately from adults.

Clinical effectiveness of manual therapy for the management of musculoskeletal and non-musculoskeletal conditions: systematic review and update of UK evidence report.

BACKGROUND: This systematic review updated and extended the "UK evidence report" by Bronfort et al. (Chiropr Osteopath 18:3, 2010) with respect to conditions/interventions that received an 'inconclusive' or 'negative' evidence rating or were not covered in the report. METHODS: A literature search of more than 10 general medical and specialised databases was conducted in August 2011 and updated in March 2013. Systematic reviews, primary comparative studies and qualitative studies of patients with musculoskeletal or non-musculoskeletal conditions treated with manual therapy and reporting clinical outcomes were included. Study quality was assessed using standardised instruments, studies were summarised, and the results were compared against the evidence ratings of Bronfort. These were either confirmed, updated, or new categories not assessed by Bronfort were added. RESULTS: 25,539 records were found; 178 new and additional studies were identified, of which 72 were systematic reviews, 96 were randomised controlled trials, and 10 were non-randomised primary studies. Most 'inconclusive' or 'moderate' evidence ratings of the UK evidence report were confirmed. Evidence ratings changed in a positive direction from inconclusive to moderate evidence ratings in only three cases (manipulation/mobilisation [with exercise] for rotator cuff disorder; spinal mobilisation for cervicogenic headache; and mobilisation for miscellaneous headache). In addition, evidence was identified on a large number of non-musculoskeletal conditions not previously considered; most of this evidence was rated as inconclusive. CONCLUSIONS: Overall, there was limited high quality evidence for the effectiveness of manual therapy. Most reviewed evidence was of low to moderate quality and inconsistent due to substantial methodological and clinical diversity. Areas requiring further research are highlighted.

Treatments for macular oedema following central retinal vein occlusion: systematic review.

OBJECTIVES: To review systematically the randomised controlled trial (RCT) evidence for treatment of macular oedema due to central retinal vein occlusion (CRVO). DATA SOURCES: MEDLINE, EMBASE, CDSR, DARE, HTA, NHSEED, CENTRAL and meeting abstracts (January 2005 to March 2013). STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: RCTs with at least 12 months of follow-up assessing pharmacological treatments for CRVO were included with no language restrictions. STUDY APPRAISAL AND SYNTHESIS METHODS: 2 authors screened titles and abstracts and conducted data extracted and Cochrane risk of bias assessment. Meta-analysis was not possible due to lack of comparable studies. RESULTS: 8 studies (35 articles, 1714 eyes) were included, assessing aflibercept (n=2), triamcinolone (n=2), bevacizumab (n=1), pegaptanib (n=1), dexamethasone (n=1) and ranibizumab (n=1). In general, bevacizumab, ranibizumab, aflibercept and triamcinolone resulted in clinically significant increases in the proportion of participants with an improvement in visual acuity of ≥15 letters, with 40-60% gaining ≥15 letters on active drugs, compared to 12-28% with sham. Results for pegaptanib and dexamethasone were mixed. Steroids were associated with cataract formation and increased intraocular pressure. No overall increase in adverse events was found with bevacizumab, ranibizumab, aflibercept or pegaptanib compared with control. Quality of life was poorly reported. All studies had a low or unclear risk of bias. LIMITATIONS: All studies evaluated a relatively short primary follow-up (1 year or less). Most had an unmasked extension phase. There was no head-to-head evidence. The majority of participants included had non-ischaemic CRVO. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Bevacizumab, ranibizumab, aflibercept and triamcinolone appear to be effective in treating macular oedema secondary to CRVO. Long-term data on effectiveness and safety are needed. Head-to-head trials and research to identify 'responders' is needed to help clinicians make the right choices for their patients. Research aimed to improve sight in people with ischaemic CRVO is required.

Current treatments in diabetic macular oedema: systematic review and meta-analysis.

OBJECTIVES: The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events DATA SOURCE: MEDLINE, EMBASE, Web of Science with Conference Proceedings and the Cochrane Library (inception to July 2012). Certain conference abstracts and drug regulatory web sites were also searched. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Randomised controlled trials were used to assess clinical effectiveness and observational trials were used for safety. Trials which assessed triamcinolone, dexamethasone, fluocinolone, bevacizumab, ranibizumab, pegaptanib or aflibercept in patients with DMO were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias was assessed using the Cochrane risk of bias tool. Study results are narratively described and, where appropriate, data were pooled using random effects meta-analysis. RESULTS: Anti-VEGF drugs are effective compared to both laser and placebo and seem to be more effective than steroids in improving BCVA. They have been shown to be safe in the short term but require frequent injections. Studies assessing steroids (triamcinolone, dexamethasone and fluocinolone) have reported mixed results when compared with laser or placebo. Steroids have been associated with increased incidence of cataracts and intraocular pressure rise but require fewer injections, especially when steroid implants are used. LIMITATIONS: The quality of included studies varied considerably. Five of 14 meta-analyses had moderate or high statistical heterogeneity. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The anti-VEGFs ranibizumab and bevacizumab have consistently shown good clinical effectiveness without major unwanted side effects. Steroid results have been mixed and are usually associated with cataract formation and  intraocular pressure increase. Despite the current wider spectrum of treatments for DMO, only a small proportion of patients recover good vision (≥20/40), and thus the search for new therapies needs to continue.