Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.

BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79­1·02] during years 5­9 and 0·75 [0·62­0·90] in later years; breast cancer mortality RR 0·97 [0·79­1·18] during years 5­9 and 0·71 [0·58­0·88] in later years). The cumulative risk of recurrence during years 5­14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5­14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·89­1·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·13­3·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·83­1·36), ischaemic heart disease 0·76 (0·60­0·95, p=0·02), and endometrial cancer 1·74 (1·30­2·34, p=0·0002). The cumulative risk of endometrial cancer during years 5­14 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is a clinically well-defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life (QOL). Drug therapy focuses on reducing key symptoms and improving quality of life. OBJECTIVES: To assess the benefits and harms of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo for treating FMS symptoms in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2012, Issue 9), MEDLINE (1966 to September 2012), EMBASE (1980 to September 2012), www.clinicalstudyresults.org (U.S.-marketed pharmaceuticals) (to September 2012) and www.clinicaltrials.gov (to September 2012) for published and ongoing trials and examined the reference lists of reviewed articles. SELECTION CRITERIA: We selected randomized, controlled trials of any formulation of SNRIs against placebo for the treatment of FMS in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data from the included studies, and assessed the risks of bias of the studies. Discrepancies were resolved by discussion. MAIN RESULTS: Ten studies were included with a total of 6038 participants. Five studies investigated duloxetine against placebo, and five investigated milnacipran against placebo. A total of 3611 participants were included into duloxetine or milnacipran groups and 2427 participants into placebo groups. The studies had a low risk of bias in general. Duloxetine and milnacipran had a small incremental effect over placebo in reducing pain (standardized mean difference (SMD) -0.23; 95% confidence interval (CI) -0.29 to -0.18; 6.1% relative improvement). One-hundred and ninety-two participants per 1000 on placebo reported an at least 50% pain reduction compared to 280 per 1000 on SNRIs (Risk ratio (RR) 1.49, 95% CI 1.35 to 1.64; number needed to treat to benefit (NNTB) 11, 95% CI 9 to 15). Duloxetine and milnacipran did not reduce fatigue substantially (SMD -0.14; 95% CI -0.19 to -0.08; 2.5% relative improvement; NNTB 17, 95% CI 12 to 29), and did not improve QOL substantially (SMD -0.20; 95% CI -0.25 to -0.14; 4.6% relative improvement; NNTB 12, 95% CI 9 to 17) compared to placebo. There were no statistically significant differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95% CI -0.16 to 0.03; 2.5% relative improvement). One-hundred and seven participants per 1000 on placebo dropped out due to adverse events compared to 196 per 1000 on SNRIs. The dropout rate due to adverse events in the duloxetine and milnacipran groups was statistically significantly higher than in placebo groups (RR 1.83, 95% CI 1.53 to 2.18; number needed to treat to harm (NNTH) 11, 95% CI 9 to 13). There was no statistically significant difference in serious adverse events between either duloxetine or milnacipran and placebo (RR 0.78, 95% CI 0.55 to 1.12). AUTHORS' CONCLUSIONS: The SNRIs duloxetine and milnacipran provided a small incremental benefit over placebo in reducing pain. The superiority of duloxetine and milnacipran over placebo in reducing fatigue and limitations of QOL was not substantial. Duloxetine and milnacipran were not superior to placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. The most frequently reported symptoms leading to stopping medication were nausea, dry mouth, constipation, headache, somnolence/dizziness and insomnia. Rare complications of both drugs may include suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation.

Monoamine oxidase inhibitors (MAOIs) for fibromyalgia syndrome.

BACKGROUND: Fibromyalgia (FM) syndrome is a chronic condition of unknown aetiology characterised by musculoskeletal pain that often co-exists with sleep disturbance, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of FM, drug therapy focuses on pain reduction and improvement of other bothersome symptoms. OBJECTIVES: The objective of this review was to assess the effectiveness and safety of monoamine oxidase inhibitors (MAOIs) in the treatment of FM syndrome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE (1966 to November 2010), EMBASE (1980 to November 2010) and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomised, double-blind trials of MAOIs used for the treatment of FM pain in adult participants. DATA COLLECTION AND ANALYSIS: Two authors assessed risk of bias and extracted data independently onto a specially designed pro forma and a third review author cross-checked them. MAIN RESULTS: We included two studies of inconsistent risk of bias with a total of 230 patients diagnosed with FM. We evaluated two MAOIs: pirlindole and moclobemide. Pirlindole showed statistically significant results compared with placebo for several outcomes (pain, tender points and overall assessment by the patient and the physician), whereas moclobemide did not show statistically significant differences between groups. Pooled results of the two studies displayed a modest effect size in pain (mean difference (MD) -1.45 (121 patients; 95% confidence interval (CI) -2.71 to -0.20; number needed to treat (NNT) 2 (95% CI 1 to 12); I(2) = 59%)), implying a minimal clinically important difference (MCID) and a small effect on tender points (standardised mean difference (SMD) -0.36 (121 patients; 95% CI -0.72 to -0.00; I(2) = 31%)). No effect was seen on global assessment by patient. Physical function and sleep disturbance were not measured. The most frequent adverse events were nausea and vomiting, with statistically significant differences between groups (risk ratio (RR) 7.82 (89 patients; 95% CI 1.02 to 59.97; NNT 7 (95% CI 4 to 33)). AUTHORS' CONCLUSIONS: Data suggest that the effectiveness of MAOIs for the treatment of FM symptoms is limited. Although we observed a moderate effect size on pain and a small one on tender points, these results should be taken with caution as they are only based on two studies with a small number of patients and inconsistent risk of bias among them.

Primary school interventions to promote fruit and vegetable consumption: a systematic review and meta-analysis.

OBJECTIVE: The consumption of fruits and vegetables (FV) may contribute to the prevention of many diseases. However, children at school age do not eat an enough amount of those foods. We have systematically reviewed the literature to assess the effectiveness of school interventions for promoting the consumption of FV. METHODS: We performed a search in MEDLINE, EMBASE, CINAHL and CENTRAL. We pooled results and stratified the analysis according to type of intervention and study design. RESULTS: Nineteen cluster studies were included. Most studies did not describe randomization method and did not take the cluster's effect into account. Pooled results of two randomized controlled trials (RCTs) of computer-based interventions showed effectiveness in improving consumption of FV [Standardized Mean Difference (SMD) 0.33 (95% CI 0.16, 0.50)]. No significant differences were found in pooled analysis of seven RCTs of multicomponent interventions or pooling results of two RCTs evaluating free/subsidized FV interventions. CONCLUSIONS: Meta-analysis shows that computer-based interventions were effective in increasing FV consumption. Multicomponent interventions and free/subsidized FV interventions were not effective. Improvements in methodology are needed in future cluster studies. Although these results are preliminary, computer-based interventions could be considered in schools, given that they are effective and cheaper than other alternatives.

Quality assessment of clinical practice guidelines for the prevention and treatment of childhood overweight and obesity.

BACKGROUND: The prevalence of childhood overweight and obesity is increasing at dramatic rates in children and adolescents worldwide. Clinical practice guidelines (CPGs) are "systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances." Their objective is to provide explicit recommendations for clinical practice based on current evidence for best practice in the management of diseases. MATERIALS AND METHODS: The aim of this study was to identify and assess the quality of CPGs for the prevention and treatment of obesity and overweight in childhood. We developed a search to identify CPGs published between January 1998 and August 2007. We considered for inclusion documents that provided recommendations for clinical practice referring to children and adolescents. Three independent appraisers assessed the quality of the1 CPGs using the AGREE (Appraisal of Guidelines Research and Evaluation) instrument. We identified 376 references and selected 22 for further assessment. RESULTS: The overall agreement among reviewers using the intraclass correlation coefficient was 0.856 (95% confidence interval [CI] 0.731-0.932). Six of the 22 initial guidelines were recommended and a further eight were recommended with conditions or provisos. We concluded that the number of documents with recommendations on the prevention and treatment of childhood obesity published during the 10-year study period was considerable, but only a few of them could be considered as high quality. CPGs were deficient in areas such as applicability, editorial independence and rigor in development. CONCLUSION: Due to the increasing burden of obesity among children and the potential for long-term comorbidities, clinicians need to be critical in assessing the rigor of how these are developed and their appropriateness for use in the clinician's own practice. There is a need to improve the methodology and the quality of CPGs on childhood obesity to help clinicians and other decision-makers to tackle this disease.

[Sex and gender equity in research: rationale for the SAGER guidelines and recommended use]. / Equidad según sexo y de género en la investigación: justificación de las guías SAGER y recomendaciones para su uso.

BACKGROUND: Sex and gender differences are often overlooked in research design, study implementation and scientific reporting, as well as in general science communication. This oversight limits the generalizability of research findings and their applicability to clinical practice, in particular for women but also for men. This article describes the rationale for an international set of guidelines to encourage a more systematic approach to the reporting of sex and gender in research across disciplines. METHODS: A panel of 13 experts representing nine countries developed the guidelines through a series of teleconferences, conference presentations and a 2-day workshop. An internet survey of 716 journal editors, scientists and other members of the international publishing community was conducted as well as a literatura search on sex and gender policies in scientific publishing. RESULTS: The Sex and Gender Equity in Research (SAGER) guidelines are a comprehensive procedure for reporting of sex and gender information in study design, data analyses, results and interpretation of findings. CONCLUSIONS: The SAGER guidelines are designed primarily to guide authors in preparing their manuscripts, but they are also useful for editors, as gatekeepers of science, to integrate assessment of sex and gender into all manuscripts as an integral part of the editorial process.

[Sex and Gender Equity in Research: rationale for the SAGER guidelines and recommended use]. / Equidade de sexo e gênero na pesquisa: fundamentação das diretrizes SAGER e uso recomendado.

BACKGROUND: Sex and gender differences are often overlooked in research design, study implementation and scientific reporting, as well as in general science communication. This oversight limits the generalizability of research findings and their applicability to clinical practice, in particular for women but also for men. This article describes the rationale for an international set of guidelines to encourage a more systematic approach to the reporting of sex and gender in research across disciplines. METHODS: A panel of 13 experts representing nine countries developed the guidelines through a series of teleconferences, conference presentations and a 2-day workshop. An internet survey of 716 journal editors, scientists and other members of the international publishing community was conducted as well as a literature search on sex and gender policies in scientific publishing. RESULTS: The Sex and Gender Equity in Research (SAGER) guidelines are a comprehensive procedure for reporting of sex and gender information in study design, data analyses, results and interpretation of findings. CONCLUSIONS: The SAGER guidelines are designed primarily to guide authors in preparing their manuscripts, but they are also useful for editors, as gatekeepers of science, to integrate assessment of sex and gender into all manuscripts as an integral part of the editorial process.

CONTEXTO: Diferenças de sexo e gênero são muitas vezes negligenciadas no desenho da pesquisa, na implementação do estudo e no relato científico, bem como na comunicação científica em geral. Este descuido limita a capacidade de generalização dos achados das pesquisas e a sua aplicabilidade à prática clínica, em particular para as mulheres, mas também para os homens. Este artigo descreve a fundamentação lógica para um conjunto internacional de diretrizes, com o intuito de encorajar uma abordagem mais sistemática para o relato de sexo e gênero na pesquisa entre disciplinas. MÉTODOS: Um painel de 13 peritos, representando nove países, desenvolveu as diretrizes por meio de uma série de teleconferências, apresentações em conferências e uma oficina de dois dias. Realizou-se uma pesquisa na internet com 716 editores de revistas, cientistas e outros membros da comunidade editorial internacional, bem como uma busca bibliográfica sobre políticas de gênero e sexo na publicação científica. RESULTADOS: As diretrizes sobre Equidade de Sexo e Gênero em Pesquisa (Sex and Gender Equity in Research - SAGER) são um procedimento abrangente para relatar informações sobre sexo e gênero no desenho do estudo, na análise de dados, nos resultados e na interpretação dos achados. CONCLUSÕES: As diretrizes da SAGER destinam-se principalmente a orientar os autores na preparação de seus manuscritos, mas também são úteis para os editores, como guardiões da ciência, para integrar a avaliação de sexo e gênero em todos os manuscritos como parte integrante do processo editorial.

Sex and Gender Equity in Research: rationale for the SAGER guidelines and recommended use.

BACKGROUND: Sex and gender differences are often overlooked in research design, study implementation and scientific reporting, as well as in general science communication. This oversight limits the generalizability of research findings and their applicability to clinical practice, in particular for women but also for men. This article describes the rationale for an international set of guidelines to encourage a more systematic approach to the reporting of sex and gender in research across disciplines. METHODS: A panel of 13 experts representing nine countries developed the guidelines through a series of teleconferences, conference presentations and a 2-day workshop. An internet survey of 716 journal editors, scientists and other members of the international publishing community was conducted as well as a literature search on sex and gender policies in scientific publishing. RESULTS: The Sex and Gender Equity in Research (SAGER) guidelines are a comprehensive procedure for reporting of sex and gender information in study design, data analyses, results and interpretation of findings. CONCLUSIONS: The SAGER guidelines are designed primarily to guide authors in preparing their manuscripts, but they are also useful for editors, as gatekeepers of science, to integrate assessment of sex and gender into all manuscripts as an integral part of the editorial process.

Enhancing nutritional environments through access to fruit and vegetables in schools and homes among children and youth: a systematic review.

BACKGROUND: Low fruit and vegetable (FV) consumption is one of the top 10 global risk factors for mortality, and is related to increased risk for cancer, cardiovascular disease and diabetes. Many environmental, sociodemographic and personal factors affect FV consumption. The purpose of this review is to examine the effects of interventions delivered in the home, school and other nutritional environments designed to increase FV availability for five to 18-year olds. METHODS: The search included: 19 electronic bibliographic databases; grey literature databases; reference lists of key articles; targeted Internet searching of key organization websites; hand searching of key journals and conference proceedings; and consultation with experts for additional references. Articles were included if: in English, French and Spanish; from high-, middle-, and low-income countries; delivered to anyone who could bring about change in FV environment for 5 to 18 year olds; with randomized and non-randomized study designs that provided before-after comparisons, with or without a control group. Primary outcomes of interest were measures of FV availability. RESULTS: The search strategy retrieved nearly 23,000 citations and resulted in 23 unique studies. Interventions were primarily policy interventions at the regional or state level, a number of curriculum type interventions in schools and community groups and a garden intervention. The majority of studies were done in high-income countries.The diversity of interventions, populations, outcomes and outcome measurements precluded meta-analysis. The most promising strategies for improving the FV environment for children are through local school food service policies. Access to FV was successfully improved in four of the six studies that evaluated school-based policies, with the other two studies finding no effect. Broader state or federally mandated policies or educational programs for food service providers and decision makers had mixed or small impact. Similarly family interventions had no or small impact on home accessibility, with smaller impact on consumption. CONCLUSIONS: The studies have high risk of bias but more rigorous studies are difficult to impossible to conduct in naturalistic settings and in policy implementation and evaluation. However, there are promising strategies to improve the FV environment, particularly through school food service policies.

The quality of clinical practice guidelines over the last two decades: a systematic review of guideline appraisal studies.

BACKGROUND: Despite the increasing number of manuals on how to develop clinical practice guidelines (CPGs) there remain concerns about their quality. The aim of this study was to review the quality of CPGs across a wide range of healthcare topics published since 1980. METHODS: The authors conducted a literature search in MEDLINE to identify publications assessing the quality of CPGs with the Appraisal of Guidelines, Research and Evaluation (AGREE) instrument. For the included guidelines in each study, the authors gathered data about the year of publication, institution, country, healthcare topic, AGREE score per domain and overall assessment. RESULTS: In total, 42 reviews were selected, including a total of 626 guidelines, published between 1980 and 2007, with a median of 25 CPGs. The mean scores were acceptable for the domain 'Scope and purpose' (64%; 95% CI 61.9 to 66.4) and 'Clarity and presentation' (60%; 95% CI 57.9 to 61.9), moderate for domain 'Rigour of development' (43%; 95% CI 41.0 to 45.2), and low for the other domains ('Stakeholder involvement' 35%; 95% CI 33.9 to 37.5, 'Editorial independence' 30%; 95% CI 27.9 to 32.3, and 'Applicability' 22%; 95% CI 20.4 to 23.9). From those guidelines that included an overall assessment, 62% (168/270) were recommended or recommended with provisos. There was a significant improvement over time for all domains, except for 'Editorial independence.' CONCLUSIONS: This review shows that despite some increase in quality of CPGs over time, the quality scores as measured with the AGREE Instrument have remained moderate to low over the last two decades. This finding urges guideline developers to continue improving the quality of their products. International collaboration could help increasing the efficiency of the process.

[Meta-analyses (QUOROM)]. / Metaanálisis (QUOROM).

The increase in the number of published systematic reviews and meta-analyses over the last few years has highlighted the need to establish guidelines for their publication, in order to facilitate their interpretation and use. The Quality of Reporting of Meta-analyses Conference, which took place in 1996, resulted in the QUOROM statement, consisting of a checklist and flow diagram. The checklist is composed of 18 items to encourage authors to provide essential information to readers about the methods and results of the meta-analysis. The flow diagram of randomized clinical trials (RCT) helps to provide information about the number of RCTs identified, included and excluded in the meta-analysis and the reasons for excluding them. Both tools provide standards for improving the quality of reporting of meta-analyses to make them rigorous, useful and reliable.