Evidence-informed guidelines in oral health: insights from a systematic survey.

BACKGROUND: Oral diseases are a major global public health problem, impacting the quality of life of those affected. While consensus exists on the importance of high-quality, evidence-informed guidelines to inform practice and public health decisions in medicine, appropriate methodologies and standards are not commonly adhered to among producers of oral health guidelines. This study aimed to systematically identify organizations that develop evidence-informed guidelines in oral health globally and survey the methodological process followed to formulate recommendations. METHODS: We searched numerous electronic databases, guideline repositories, and websites of guideline developers, scientific societies, and international organizations (January 2012-October 2023) to identify organizations that develop guidelines addressing any oral health topic and that explicitly declare the inclusion of research evidence in their development. Pairs of reviewers independently evaluated potentially eligible organizations according to predefined selection criteria and extracted data about the organization's characteristics, key features of their guidelines, and the process followed when formulating formal recommendations. Descriptive statistics were used to analyze and summarize data. RESULTS: We included 46 organizations that developed evidence-informed guidelines in oral health. The organizations were mainly professional associations and scientific societies (67%), followed by governmental organizations (28%). In total, organizations produced 55 different guideline document types, most of them containing recommendations for clinical practice (77%). Panels were primarily composed of healthcare professionals (87%), followed by research methodologists (40%), policymakers (24%), and patient partners (18%). Most (60%) of the guidelines reported their funding source, but only one out of three (33%) included a conflict of interest (COI) policy management. The methodology used in the 55 guideline document types varied across the organizations, but only 19 (35%) contained formal recommendations. Half (51%) of the guideline documents referred to a methodology handbook, 46% suggested a structured approach or system for rating the certainty of the evidence and the strength of recommendations, and 37% mentioned using a framework to move from evidence to decisions, with the GRADE-EtD being the most widely used (27%). CONCLUSION: Our findings underscore the need for alignment and standardization of both terminology and methodologies used in oral health guidelines with current international standards to formulate trustworthy recommendations.

Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI).

BACKGROUND: Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini-Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. OBJECTIVES: To determine the accuracy of the Mini Mental State Examination for the early detection of dementia in people with mild cognitive impairment SEARCH METHODS: We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data. SELECTION CRITERIA: We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia. DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve. MAIN RESULTS: In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis. AUTHORS' CONCLUSIONS: Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.

Drugs for preventing lung cancer in healthy people.

BACKGROUND: This is the second update of this Cochrane Review. Some studies have suggested a protective effect of antioxidant nutrients and higher dietary levels of fruits and vegetables on lung cancer. OBJECTIVES: To determine whether vitamins and minerals and other potential agents, alone or in combination, reduce lung cancer incidence and lung cancer mortality in healthy populations. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase from 1974 to May 2019 and screened references included in published studies and reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing vitamins or mineral supplements with placebo, administered to healthy people with the aim of preventing lung cancer. DATA COLLECTION AND ANALYSIS: Four review authors independently selected the trials to be included in the review, assessed their methodological quality and extracted data. For dichotomous outcomes we calculated risk ratios (RRs) and 95% confidence intervals (CIs) and pooled results using the random-effects model. We assessed the risk of bias using Cochrane's 'Risk of bias' assessment tool and certainty of evidence using the GRADE approach. MAIN RESULTS: In this update, we identified three new trials for a total of 12 studies. Six analysed vitamin A, three vitamin C, three combined vitamin D3 + calcium, four vitamin E combined with other products, one selenium supplements and nine studied combinations of two or more products. Four studies included only men and five only women. Vitamin A results in little to no difference in lung cancer incidence (RR 1.09, 95% CI 1.00 to 1.19; 5 RCTs, 212314 participants; high-certainty evidence) and lung cancer mortality (RR 1.06, 95% CI 0.81 to 1.38; 3 RCTs, 190118 participants; high-certainty evidence). But in smokers or asbestos workers vitamin A increases the risk of lung cancer incidence (RR 1.10, 95% CI 1.01 to 1.20; 3 RCTs, 43995 participants; high-certainty evidence), lung cancer mortality (RR 1.18, 95% CI 1.01 to 1.38; 2 RCTs, 29426 participants; high-certainty evidence) and all-cause mortality (RR 1.09, 95% CI 1.05 to 1.13; 2 RCTs, 32883 participants; high-certainty evidence). Vitamin A increases the risk of minor side effects, such as yellowing of the skin and minor gastrointestinal symptoms (high-certainty evidence). Vitamin C likely results in little to no difference in lung cancer incidence (RR 1.29, 95% CI 0.67 to 2.49; 2 RCTs, 14953 participants; moderate-certainty evidence). In women, vitamin C increases the risk of lung cancer incidence (RR 1.84, 95% CI 1.14 to 2.95; 1 RCT, 7627 participants; high-certainty evidence). In men, vitamin C results in little to no difference in mortality for lung cancer (RR 0.81, 95% CI 0.53 to 1.23; 1 RCT, 7326 participants; high-certainty evidence). Vitamin D + calcium may result in little to no difference in lung cancer incidence in postmenopausal women (RR 0.90, 95% CI 0.39 to 2.08; 3 RCTs, 37601 women; low-certainty evidence). Vitamin E results in little to no difference in lung cancer incidence (RR 1.01, 95% CI 0.90 to 1.14; 3 RCTs, 36841 participants; high-certainty evidence) or to lung cancer mortality (RR 0.96, 95% CI 0.77 to 1.18; 2 RCTs, 29214 participants; high-certainty evidence), but increases the risk of haemorrhagic strokes (hazard ratio (HR), 1.74, 95% CI 1.04 to 2.91; 1 RCT, 14641 participants; high-certainty evidence). Calcium results in little to no difference in lung cancer incidence in postmenopausal women (RR 0.65, 95% CI 0.13 to 3.18; 1 RCT, 733 participants) or in risk of renal calculi (RR 1.94, 95% CI 0.20 to 18.57; 1 RCT, 733 participants; low-certainty evidence). Selenium in men results in little to no difference in lung cancer incidence (RR 1.11, 95% CI 0.80 to 1.54; 1 RCT, 17448 participants; high-certainty evidence) and lung cancer mortality (RR 1.09, 95% CI 0.72 to 1.66; 1 RCT, 17448 participants; high-certainty evidence) and increases the risk for grade 1 to 2 dermatitis (RR 1.16, 95% CI 1.04 to 1.31; 1 RCT, 17448 participants; high-certainty evidence) and for alopecia (RR 1.28, 95% CI 1.07 to 1.53; 1 RCT, 17448 participants; high-certainty evidence). The combination of vitamins A, C, E + selenium + zinc results in little to no difference in lung cancer incidence (RR 0.64, 95% CI 0.28 to 1.48; 1 RCT, 12741 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: Well-designed RCTs have shown no beneficial effect of supplements for the prevention of lung cancer and lung cancer mortality in healthy people. Vitamin A supplements increase lung cancer incidence and mortality in smokers or persons exposed to asbestos. Vitamin C increases lung cancer incidence in women. Vitamin E increases the risk of haemorrhagic strokes.

Citicoline for treating people with acute ischemic stroke.

BACKGROUND: Stroke is one of the leading causes of long-lasting disability and mortality and its global burden has increased in the past two decades. Several therapies have been proposed for the recovery from, and treatment of, ischemic stroke. One of them is citicoline. This review assessed the benefits and harms of citicoline for treating patients with acute ischemic stroke. OBJECTIVES: To assess the clinical benefits and harms of citicoline compared with placebo or any other control for treating people with acute ischemic stroke. SEARCH METHODS: We searched in the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS until 29 January 2020. We searched the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. Additionally, we also reviewed reference lists of the retrieved publications and review articles, and searched the websites of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). SELECTION CRITERIA: We included randomized controlled trials (RCTs) in any setting including participants with acute ischemic stroke. Trials were eligible for inclusion if they compared citicoline versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: We selected RCTs, assessed the risk of bias in seven domains, and extracted data by duplicate. Our primary outcomes of interest were all-cause mortality and the degree of disability or dependence in daily activities at 90 days. We estimated risk ratios (RRs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed-effect and random-effects model meta-analyses. We assessed the overall quality of evidence for six pre-specified outcomes using the GRADE approach. MAIN RESULTS: We identified 10 RCTs including 4281 participants. In all these trials, citicoline was given either orally, intravenously, or a combination of both compared with placebo or standard care therapy. Citicoline doses ranged between 500 mg and 2000 mg per day. We assessed all the included trials as having high risk of bias. Drug companies sponsored six trials. A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias). Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias). Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias). Overall, either serious or non-serious adverse events - central nervous system, gastrointestinal, musculoskeletal, etc. - were poorly reported and harms may have been underestimated. Four trials assessing functional recovery with the Barthel Index at a cut-off point of 95 points or more did not find differences comparing citicoline with placebo (32.78% versus 30.70%; RR 1.03, 95% CI 0.94 to 1.13; I² = 24%; low-quality evidence due to risk of bias). There were no differences in neurological function (National Institutes of Health Stroke Scale at a cut-off point of ≤ 1 points) comparing citicoline with placebo according to five trials (24.31% versus 22.44%; RR 1.08, 95% CI 0.96 to 1.21; I² = 27%, low-quality evidence due to risk of bias). A pre-planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes but no trial provided information on quality of life. AUTHORS' CONCLUSIONS: This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke. The findings of the review suggest there may be little to no difference between citicoline and its controls regarding all-cause mortality, disability or dependence in daily activities, severe adverse events, functional recovery and the assessment of the neurological function, based on low-certainty evidence. None of the included trials assessed quality of life and the safety profile of citicoline remains unknown. The available evidence is of low quality due to either limitations in the design or execution of the trials.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.

Early enteral nutrition (within 48 hours) versus delayed enteral nutrition (after 48 hours) with or without supplemental parenteral nutrition in critically ill adults.

BACKGROUND: Early enteral nutrition support (within 48 hours of admission or injury) is frequently recommended for the management of patients in intensive care units (ICU). Early enteral nutrition is recommended in many clinical practice guidelines, although there appears to be a lack of evidence for its use and benefit. OBJECTIVES: To evaluate the efficacy and safety of early enteral nutrition (initiated within 48 hours of initial injury or ICU admission) versus delayed enteral nutrition (initiated later than 48 hours after initial injury or ICU admission), with or without supplemental parenteral nutrition, in critically ill adults. SEARCH METHODS: We searched CENTRAL (2019, Issue 4), MEDLINE Ovid (1946 to April 2019), Embase Ovid SP (1974 to April 2019), CINAHL EBSCO (1982 to April 2019), and ISI Web of Science (1945 to April 2019). We also searched Turning Research Into Practice (TRIP), trial registers (ClinicalTrials.gov, ISRCTN registry), and scientific conference reports, including the American Society for Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism. We applied no restrictions by language or publication status. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) that compared early versus delayed enteral nutrition, with or without supplemental parenteral nutrition, in adults who were in the ICU for longer than 72 hours. This included individuals admitted for medical, surgical, and trauma diagnoses, and who required any type of enteral nutrition. DATA COLLECTION AND ANALYSIS: Two review authors extracted study data and assessed the risk of bias in the included studies. We expressed results as risk ratios (RR) for dichotomous data, and as mean differences (MD) for continuous data, both with 95% confidence intervals (CI). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included seven RCTs with a total of 345 participants. Outcome data were limited, and we judged many trials to have an unclear risk of bias in several domains. Early versus delayed enteral nutrition Six trials (318 participants) assessed early versus delayed enteral nutrition in general, medical, and trauma ICUs in the USA, Australia, Greece, India, and Russia. Primary outcomes Five studies (259 participants) measured mortality. It is uncertain whether early enteral nutrition affects the risk of mortality within 30 days (RR 1.00, 95% CI 0.16 to 6.38; 1 study, 38 participants; very low-quality evidence). Four studies (221 participants) reported mortality without describing the timeframe; we did not pool these results. None of the studies reported a clear difference in mortality between groups. Three studies (156 participants) reported infectious complications. We were unable to pool the results due to unreported data and substantial clinical heterogeneity. The results were inconsistent across studies. One trial measured feed intolerance or gastrointestinal complications; it is uncertain whether early enteral nutrition affects this outcome (RR 0.84, 95% CI 0.35 to 2.01; 59 participants; very low-quality evidence). Secondary outcomes One trial assessed hospital length of stay and reported a longer stay in the early enteral group (median 15 days (interquartile range (IQR) 9.5 to 20) versus 12 days (IQR 7.5 to15); P = 0.05; 59 participants; very low-quality evidence). Three studies (125 participants) reported the duration of mechanical ventilation. We did not pool the results due to clinical and statistical heterogeneity. The results were inconsistent across studies. It is uncertain whether early enteral nutrition affects the risk of pneumonia (RR 0.77, 95% CI 0.55 to 1.06; 4 studies, 192 participants; very low-quality evidence). Early enteral nutrition with supplemental parenteral nutrition versus delayed enteral nutrition with supplemental parenteral nutrition We identified one trial in a burn ICU in the USA (27 participants). Primary outcomes It is uncertain whether early enteral nutrition with supplemental parenteral nutrition affects the risk of mortality (RR 0.74, 95% CI 0.25 to 2.18; very low-quality evidence), or infectious complications (MD 0.00, 95% CI -1.94 to 1.94; very low-quality evidence). There were no data available for feed intolerance or gastrointestinal complications. Secondary outcomes It is uncertain whether early enteral nutrition with supplemental parenteral nutrition reduces the duration of mechanical ventilation (MD 9.00, 95% CI -10.99 to 28.99; very low-quality evidence). There were no data available for hospital length of stay or pneumonia. AUTHORS' CONCLUSIONS: Due to very low-quality evidence, we are uncertain whether early enteral nutrition, compared with delayed enteral nutrition, affects the risk of mortality within 30 days, feed intolerance or gastrointestinal complications, or pneumonia. Due to very low-quality evidence, we are uncertain if early enteral nutrition with supplemental parenteral nutrition compared with delayed enteral nutrition with supplemental parenteral nutrition reduces mortality, infectious complications, or duration of mechanical ventilation. There is currently insufficient evidence; there is a need for large, multicentred studies with rigorous methodology, which measure important clinical outcomes.

Consideration of sex and gender in Cochrane reviews of interventions for preventing healthcare-associated infections: a methodology study.

BACKGROUND: Healthcare-associated infections (HAIs) are common and increase morbidity, mortality, and healthcare costs. Their control continues to be an unresolved issue worldwide. HAIs epidemiology shows sex/gender differences. Thus the lack of consideration of sex/gender in Cochrane reviews will limit their applicability and capacity to support informed decisions. This study aims to describe the extent to which Cochrane reviews of interventions for preventing HAIs consider sex and gender. METHODS: Methodology study appraising Cochrane reviews of interventions to prevent HAIs. SEARCH METHODS: Cochrane Database of Systematic Reviews from 1995 (launch of the journal) to 31 December 2016. Two authors independently extracted data with EPPI-Reviewer 4 software, and independently appraised the sex/gender content of the reviews with the Sex and Gender Appraisal Tool for Systematic Reviews (SGAT-SR). RESULTS: This study included 113 reviews assessing the effects of interventions for preventing HAIs. 100 reviews (88%) used at least one sex or gender-related term. The terminology used was heterogeneous, being "sex" the term used in more reviews (51%). No review defined neither sex nor gender. Thus we could not assess the definitions provided. Consideration of sex and gender was practically absent in the included reviews; in fact, no review met all the applicable items of the SGAT-SR, and 51 reviews (50%) fulfilled no item. No review provided a complete description of the sex and the gender of the samples of the included studies. Only ten reviews (10%) planned to perform sex- and gender-based analysis and only three (3%) could complete the analysis. The method chosen was always the subgroup analysis based on sex (one review) or gender (two reviews). Three reviews (3%) considered sex or gender-related findings in the conclusions. CONCLUSION: Consideration of sex and gender in Cochrane reviews of interventions for preventing HAIs was practically absent. This lack of attention to sex and gender reduces the quality of Cochrane reviews, and their applicability for all people: women and men, boys and girls, and people of diverse gender identities. Cochrane should attempt to address the shortfalls detected.

Surgery versus stereotactic radiotherapy for people with single or solitary brain metastasis.

BACKGROUND: Brain metastases occur when cancer cells spread from their original site to the brain and are a frequent cause of morbidity and death in people with cancer. They occur in 20% to 40% of people during the course of their disease. Brain metastases are also the most frequent type of brain malignancy. Single and solitary brain metastasis is infrequent and choosing the most appropriate treatment is a clinical challenge. Surgery and stereotactic radiotherapy are two options. For surgery, tumour resection is performed using microsurgical techniques, while in stereotactic radiotherapy, external ionising radiation beams are precisely focused on the brain metastasis. Stereotactic radiotherapy may be given as a single dose, also known as single dose radiosurgery, or in a number of fractions, also known as fractionated stereotactic radiotherapy. There is uncertainty regarding which treatment (surgery or stereotactic radiotherapy) is more effective for people with single or solitary brain metastasis. OBJECTIVES: To assess the effectiveness and safety of surgery versus stereotactic radiotherapy for people with single or solitary brain metastasis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, March 2018), MEDLINE and Embase up to 25 March 2018 for relevant studies. We also searched trials databases, grey literature and handsearched relevant literature. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing surgery versus stereotactic radiotherapy, either a single fraction (stereotactic radiosurgery) or multiple fractions (fractionated stereotactic radiotherapy) for treatment of single or solitary brain metastasis. DATA COLLECTION AND ANALYSIS: Two review authors screened all references, evaluated the quality of the included studies using the Cochrane tool for assessing risk of bias, and performed data extraction. The primary outcomes were overall survival and adverse events. Secondary outcomes included progression-free survival and quality of life . We analysed overall survival and progression-free survival as hazard ratios (HRs) with 95% confidence intervals (CIs), and analysed adverse events as risk ratios (RRs). For quality of life we used mean difference (MD). MAIN RESULTS: Two RCTs including 85 participants met our inclusion criteria. One study included people with single untreated brain metastasis (n = 64), and the other included people with solitary brain metastasis (22 consented to randomisation and 21 were analysed). We identified a third trial reported as completed and pending results this may be included in future updates of this review. The two included studies were prematurely closed due to poor participant accrual. One study compared surgery plus whole brain radiotherapy (WBRT) versus stereotactic radiosurgery alone, and the second study compared surgery plus WBRT versus stereotactic radiosurgery plus WBRT. Meta-analysis was not possible due to clinical heterogeneity between trial interventions. The overall certainty of evidence was low or very low for all outcomes due to high risk of bias and imprecision.We found no difference in overall survival in either of the two comparisons. For the comparison of surgery plus WBRT versus stereotactic radiosurgery alone: HR 0.92, 95% CI 0.48 to 1.77; 64 participants, very low-certainty evidence. We downgraded the certainty of the evidence to very low due to risk of bias and imprecision. For the comparison of surgery plus WBRT versus stereotactic radiosurgery plus WBRT: HR 0.53, 95% CI 0.20 to 1.42; 21 participants, low-certainty evidence. We downgraded the certainty of the evidence to low due to imprecision. Adverse events were reported in both trial groups in the two studies, showing no differences for surgery plus WBRT versus stereotactic radiosurgery alone (RR 0.31, 95% CI 0.07 to 1.44; 64 participants) and for surgery plus WBRT versus stereotactic radiosurgery plus WBRT (RR 0.37, 95% CI 0.05 to 2.98; 21 participants). Most of the adverse events were related to radiation toxicities. We considered the certainty of the evidence from the two comparisons to be very low due to risk of bias and imprecision.There was no difference in progression-free survival in the study comparing surgery plus WBRT versus stereotactic radiosurgery plus WBRT (HR 0.55, 95% CI 0.22 to 1.38; 21 participants, low-certainty evidence). We downgraded the evidence to low certainty due to imprecision. This outcome was not clearly reported for the other comparison. In general, there were no differences in quality of life between the two studies. The study comparing surgery plus WBRT versus stereotactic radiosurgery plus WBRT found no differences after two months using the QLQ-C30 global scale (MD -10.80, 95% CI -44.67 to 23.07; 14 participants, very low-certainty evidence). We downgraded the certainty of evidence to very low due to risk of bias and imprecision. AUTHORS' CONCLUSIONS: Currently, there is no definitive evidence regarding the effectiveness and safety of surgery versus stereotactic radiotherapy on overall survival, adverse events, progression-free survival and quality of life in people with single or solitary brain metastasis, and benefits must be decided on a case-by-case basis until well powered and designed trials are available. Given the difficulties in participant accrual, an international multicentred approach should be considered for future studies.

Vasodilators for women undergoing fertility treatment.

BACKGROUND: The rate of successful pregnancies brought to term has barely increased since the first assisted reproductive technology (ART) technique became available. Vasodilators have been proposed to increase endometrial receptivity, thicken the endometrium, and favour uterine relaxation, all of which could improve uterine receptivity and enhance the chances for successful assisted pregnancy. OBJECTIVES: To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment. SEARCH METHODS: We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of controlled trials, the Cochrane Central Register of of Controlled Trials, via the Cochrane Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, the Open System for Information on Grey Literature in Europe (OpenSIGLE), the Latin American and Caribbean Health Science Information Database (LILACS), clinical trial registries, and the reference lists of relevant articles. We conducted the search in October 2017 and applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing vasodilators alone or in combination with other treatments versus placebo or no treatment or versus other agents in women undergoing fertility treatment. DATA COLLECTION AND ANALYSIS: Four review authors independently selected studies, assessed risk of bias, extracted data, and calculated risk ratios (RRs). We combined study data using a fixed-effect model and assessed evidence quality using Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) methods. Our primary outcomes were live birth or ongoing pregnancy and vasodilator side effects. Secondary outcomes included clinical pregnancy, endometrial thickness, multiple pregnancy, miscarriage, and ectopic pregnancy. MAIN RESULTS: We included 15 studies with a total of 1326 women. All included studies compared a vasodilator versus placebo or no treatment. We judged most of these studies as having unclear risk of bias. Overall, the quality of evidence was low to moderate for most outcomes. The main limitations were imprecision due to low numbers of events and participants and risk of bias due to unclear methods of randomisation.Vasodilators probably make little or no difference in rates of live birth compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.83 to 1.69; three RCTs; N = 350; I² = 0%; moderate-quality evidence) but probably increase overall rates of side effects including headache and tachycardia (RR 2.35, 95% CI 1.51 to 3.66; four RCTs; N = 418; I² = 0%; moderate-quality evidence). Evidence suggests that if 236 per 1000 women achieve live birth with placebo or no treatment, then between 196 and 398 per 1000 will do so with the use of vasodilators.Compared with placebo or no treatment, vasodilators may slightly improve clinical pregnancy rates (RR 1.45, 95% CI 1.19 to 1.77; 11 RCTs; N = 1054; I² = 6%; low-quality evidence). Vasodilators probably make little or no difference in rates of multiple gestation (RR 1.15, 95% CI 0.55 to 2.42; three RCTs; N = 370; I² = 0%; low-quality evidence), miscarriage (RR 0.83, 95% CI 0.37 to 1.86; three RCTs; N = 350; I² = 0%; low-quality evidence), or ectopic pregnancy (RR 1.48, 95% CI 0.25 to 8.69; two RCTs; N = 250; I² = 5%; low-quality evidence). All studies found benefit for endometrial thickening, but reported effects varied (I² = 92%) and ranged from a mean difference of 0.80 higher (95% CI 0.18 to 1.42) to 3.57 higher (95% CI 3.01 to 4.13) with very low-quality evidence, so we are uncertain how to interpret these results. AUTHORS' CONCLUSIONS: Evidence was insufficient to show whether vasodilators increase the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may slightly increase clinical pregnancy rates. Moderate-quality evidence shows that vasodilators increase overall side effects in comparison with placebo or no treatment. Adequately powered studies are needed so that each treatment can be evaluated more accurately.

Second-line systemic therapy for metastatic colorectal cancer.

BACKGROUND: The therapeutic management of people with metastatic colorectal cancer (CRC) who did not respond to first-line treatment represents a formidable challenge. OBJECTIVES: To determine the efficacy and toxicity of second-line systemic therapy in people with metastatic CRC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2016, Issue 4), Ovid MEDLINE (1950 to May 2016), Ovid MEDLINE In-process & Other Non-Indexed Citations (1946 to May 2016) and Ovid Embase (1974 to May 2016). There were no language or date of publication restrictions. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the efficacy (survival, tumour response) and toxicity (incidence of severe adverse effects (SAEs)) of second-line systemic therapy (single or combined treatment with any anticancer drug, at any dose and number of cycles) in people with metastatic CRC that progressed, recurred or did not respond to first-line systemic therapy. DATA COLLECTION AND ANALYSIS: Authors performed a descriptive analysis of each included RCT in terms of primary (survival) and secondary (tumour response, toxicity) endpoints. In the light of the variety of drug regimens tested in the included trials, we could carry out meta-analysis considering classes of (rather than single) anticancer regimens; to this aim, we applied the random-effects model to pool the data. We used hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and SAE rate) data, respectively, with 95% confidence intervals (CI). MAIN RESULTS: Thirty-four RCTs (enrolling 13,787 participants) fulfilled the eligibility criteria. Available evidence enabled us to address multiple clinical issues regarding the survival effects of second-line systemic therapy of people with metastatic CRC.1. Chemotherapy (irinotecan) was more effective than best supportive care (HR for OS: 0.58, 95% CI 0.43 to 0.80; 1 RCT; moderate-quality evidence); 2. modern chemotherapy (FOLFOX (5-fluorouracil plus leucovorin plus oxaliplatin), irinotecan) is more effective than outdated chemotherapy (5-fluorouracil) (HR for PFS: 0.59, 95% CI 0.49 to 0.73; 2 RCTs; high-quality evidence) (HR for OS: 0.69, 95% CI 0.51 to 0.94; 1 RCT; moderate-quality evidence); 3. irinotecan-based combinations were more effective than irinotecan alone (HR for PFS: 0.68, 95% CI 0.60 to 0.76; 6 RCTs; moderate-quality evidence); 4. targeted agents improved the efficacy of conventional chemotherapy both when considered together (HR for OS: 0.84, 95% CI 0.77 to 0.91; 6 RCTs; high-quality evidence) and when bevacizumab was used alone (HR for PFS: 0.67, 95% CI 0.60 to 0.75; 4 RCTs; high-quality evidence).With regard to secondary endpoints, tumour response rates generally paralleled the survival results; moreover, higher anticancer efficacy was generally associated with worse treatment-related toxicity, with the important exception of bevacizumab-containing regimens, where the addition of the targeted agent to chemotherapy did not result in a significant increase in the rate of SAE. Finally, we found that oral (instead of intravenous) fluoropyrimidines significantly reduced the incidence of adverse effects (without compromising efficacy) in people treated with oxaliplatin-based regimens.We could not draw any conclusions on other debated aspects in this field of oncology, such as ranking of treatments (not all possible comparisons have been tested and many comparisons were based on single trials enrolling a small number of participants) and quality of life (virtually no data available). AUTHORS' CONCLUSIONS: Systemic therapy offers a survival benefit to people with metastatic CRC who did not respond to first-line treatment, especially when targeted agents are combined with conventional chemotherapeutic drugs. Further research is needed to define the optimal regimen and to identify people who most benefit from each treatment.

18F PET with florbetaben for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

BACKGROUND: 18F-florbetaben uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-florbetaben. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-florbetaben to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-florbetaben PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD), or any form of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F-florbetaben scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: Progression from MCI to ADD, any other form of dementia, and any form of dementia was evaluated in one study (Ong 2015). It reported data on 45 participants at four years of follow-up; 21 participants met NINCDS-ADRDA criteria for Alzheimer's disease dementia at four years of follow-up, the proportion converting to ADD was 47% of the 45 participants, and 11% of the 45 participants met criteria for other types of dementias (three cases of FrontoTemporal Dementia (FTD), one of Dementia with Lewy body (DLB), and one of Progressive Supranuclear Palsy (PSP)). We considered the study to be at high risk of bias in the domains of the reference standard, flow, and timing (QUADAS-2). MCI to ADD; 18F-florbetaben PET scan analysed visually: the sensitivity was 100% (95% confidence interval (CI) 84% to 100%) and the specificity was 83% (95% CI 63% to 98%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 100% (95% CI 84% to 100%) and the specificity was 88% (95% CI 68% to 97%) for the diagnosis of ADD at follow-up (n = 45, 1 study). MCI to any other form of dementia (non-ADD); 18F-florbetaben PET scan analysed visually: the sensitivity was 0% (95% CI 0% to 52%) and the specificity was 38% (95% CI 23% to 54%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 0% (95% CI 0% to 52%) and the specificity was 40% (95% CI 25% to 57%) for the diagnosis of any other form of dementia at follow-up (n = 45, 1 study). MCI to any form of dementia;18F-florbetaben PET scan analysed visually: the sensitivity was 81% (95% CI 61% to 93%) and the specificity was 79% (95% CI 54% to 94%) (n = 45, 1 study). Analysed quantitatively: the sensitivity was 81% (95% CI 61% to 93%) and the specificity was 84% (95% CI 60% to 97%) for the diagnosis of any form of dementia at follow-up (n = 45, 1 study). AUTHORS' CONCLUSIONS: Although we were able to calculate one estimation of DTA in, especially, the prediction of progression from MCI to ADD at four years follow-up, the small number of participants implies imprecision of sensitivity and specificity estimates. We cannot make any recommendation regarding the routine use of 18F-florbetaben in clinical practice based on one single study with 45 participants. 18F-florbetaben has high financial costs, therefore, clearly demonstrating its DTA and standardising the process of the 18F-florbetaben modality are important prior to its wider use.

18F PET with flutemetamol for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

BACKGROUND: 18F-flutemetamol uptake by brain tissue, measured by positron emission tomography (PET), is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and the confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using some amyloid biomarkers tests like 18F-flutemetamol. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-flutemetamol to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-flutemetamol PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD) or any form of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F-flutemetamol scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: Progression from MCI to ADD was evaluated in 243 participants from two studies. The studies reported data on 19 participants with two years of follow-up and on 224 participants with three years of follow-up. Nine (47.4%) participants converted at two years follow-up and 81 (36.2%) converted at three years of follow-up.There were concerns about participant selection and sampling in both studies. The index test domain in one study was considered unclear and in the second study it was considered at low risk of bias. For the reference standard domain, one study was considered at low risk and the second study was considered to have an unclear risk of bias. Regarding the domains of flow and timing, both studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD at two years of follow-up had a sensitivity of 89% (95% CI 52 to 100) and a specificity of 80% (95% CI 44 to 97) by quantitative assessment by SUVR (n = 19, 1 study).Progression from MCI to ADD at three years of follow-up had a sensitivity of 64% (95% CI 53 to 75) and a specificity of 69% (95% CI 60 to 76) by visual assessment (n = 224, 1 study).There was no information regarding the other two objectives in this systematic review (SR): progression from MCI to other forms of dementia and progression to any form of dementia at follow-up. AUTHORS' CONCLUSIONS: Due to the varying sensitivity and specificity for predicting the progression from MCI to ADD and the limited data available, we cannot recommend routine use of 18F-flutemetamol in clinical practice. 18F-flutemetamol has high financial costs; therefore, clearly demonstrating its DTA and standardising the process of the 18F-flutemetamol modality is important prior to its wider use.

18F PET with florbetapir for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

BACKGROUND: 18F-florbetapir uptake by brain tissue measured by positron emission tomography (PET) is accepted by regulatory agencies like the Food and Drug Administration (FDA) and the European Medicine Agencies (EMA) for assessing amyloid load in people with dementia. Its added value is mainly demonstrated by excluding Alzheimer's pathology in an established dementia diagnosis. However, the National Institute on Aging and Alzheimer's Association (NIA-AA) revised the diagnostic criteria for Alzheimer's disease and confidence in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease may be increased when using amyloid biomarkers tests like 18F-florbetapir. These tests, added to the MCI core clinical criteria, might increase the diagnostic test accuracy (DTA) of a testing strategy. However, the DTA of 18F-florbetapir to predict the progression from MCI to Alzheimer's disease dementia (ADD) or other dementias has not yet been systematically evaluated. OBJECTIVES: To determine the DTA of the 18F-florbetapir PET scan for detecting people with MCI at time of performing the test who will clinically progress to ADD, other forms of dementia (non-ADD), or any form of dementia at follow-up. SEARCH METHODS: This review is current to May 2017. We searched MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), BIOSIS Citation Index (Thomson Reuters Web of Science), Web of Science Core Collection, including the Science Citation Index (Thomson Reuters Web of Science) and the Conference Proceedings Citation Index (Thomson Reuters Web of Science), LILACS (BIREME), CINAHL (EBSCOhost), ClinicalTrials.gov (https://clinicaltrials.gov), and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://www.who.int/ictrp/search/en/). We also searched ALOIS, the Cochrane Dementia & Cognitive Improvement Group's specialised register of dementia studies (http://www.medicine.ox.ac.uk/alois/). We checked the reference lists of any relevant studies and systematic reviews, and performed citation tracking using the Science Citation Index to identify any additional relevant studies. No language or date restrictions were applied to the electronic searches. SELECTION CRITERIA: We included studies that had prospectively defined cohorts with any accepted definition of MCI at time of performing the test and the use of 18F-florbetapir scan to evaluate the DTA of the progression from MCI to ADD or other forms of dementia. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis, for example, National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles and abstracts identified in electronic-database searches. Two review authors independently selected studies for inclusion and extracted data to create two-by-two tables, showing the binary test results cross-classified with the binary reference standard. We used these data to calculate sensitivities, specificities, and their 95% confidence intervals. Two independent assessors performed quality assessment using the QUADAS-2 tool plus some additional items to assess the methodological quality of the included studies. MAIN RESULTS: We included three studies, two of which evaluated the progression from MCI to ADD, and one evaluated the progression from MCI to any form of dementia.Progression from MCI to ADD was evaluated in 448 participants. The studies reported data on 401 participants with 1.6 years of follow-up and in 47 participants with three years of follow-up. Sixty-one (15.2%) participants converted at 1.6 years follow-up; nine (19.1%) participants converted at three years of follow-up.Progression from MCI to any form of dementia was evaluated in five participants with 1.5 years of follow-up, with three (60%) participants converting to any form of dementia.There were concerns regarding applicability in the reference standard in all three studies. Regarding the domain of flow and timing, two studies were considered at high risk of bias. MCI to ADD;Progression from MCI to ADD in those with a follow-up between two to less than four years had a sensitivity of 67% (95% CI 30 to 93) and a specificity of 71% (95% CI 54 to 85) by visual assessment (n = 47, 1 study).Progression from MCI to ADD in those with a follow-up between one to less than two years had a sensitivity of 89% (95% CI 78 to 95) and a specificity of 58% (95% CI 53 to 64) by visual assessment, and a sensitivity of 87% (95% CI 76 to 94) and a specificity of 51% (95% CI 45 to 56) by quantitative assessment by the standardised uptake value ratio (SUVR)(n = 401, 1 study). MCI to any form of dementia;Progression from MCI to any form of dementia in those with a follow-up between one to less than two years had a sensitivity of 67% (95% CI 9 to 99) and a specificity of 50% (95% CI 1 to 99) by visual assessment (n = 5, 1 study). MCI to any other forms of dementia (non-ADD);There was no information regarding the progression from MCI to any other form of dementia (non-ADD). AUTHORS' CONCLUSIONS: Although sensitivity was good in one included study, considering the poor specificity and the limited data available in the literature, we cannot recommend routine use of 18F-florbetapir PET in clinical practice to predict the progression from MCI to ADD.Because of the poor sensitivity and specificity, limited number of included participants, and the limited data available in the literature, we cannot recommend its routine use in clinical practice to predict the progression from MCI to any form of dementia.Because of the high financial costs of 18F-florbetapir, clearly demonstrating the DTA and standardising the process of this modality are important prior to its wider use.

Elevation of the head during intensive care management in people with severe traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major public health problem and a fundamental cause of morbidity and mortality worldwide. The burden of TBI disproportionately affects low- and middle-income countries. Intracranial hypertension is the most frequent cause of death and disability in brain-injured people. Special interventions in the intensive care unit are required to minimise factors contributing to secondary brain injury after trauma. Therapeutic positioning of the head (different degrees of head-of-bed elevation (HBE)) has been proposed as a low cost and simple way of preventing secondary brain injury in these people. The aim of this review is to evaluate the evidence related to the clinical effects of different backrest positions of the head on important clinical outcomes or, if unavailable, relevant surrogate outcomes. OBJECTIVES: To assess the clinical and physiological effects of HBE during intensive care management in people with severe TBI. SEARCH METHODS: We searched the following electronic databases from their inception up to March 2017: Cochrane Injuries' Specialised Register, CENTRAL, MEDLINE, Embase, three other databases and two clinical trials registers. The Cochrane Injuries' Information Specialist ran the searches. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) involving people with TBI who underwent different HBE or backrest positions. Studies may have had a parallel or cross-over design. We included adults and children over two years of age with severe TBI (Glasgow Coma Scale (GCS) less than 9). We excluded studies performed in children of less than two years of age because of their unfused skulls. We included any therapeutic HBE including supine (flat) or different degrees of head elevation with or without knee gatch or reverse Trendelenburg applied during the acute management of the TBI. DATA COLLECTION AND ANALYSIS: Two review authors independently checked all titles and abstracts, excluding references that clearly didn't meet all selection criteria, and extracted data from selected studies on to a data extraction form specifically designed for this review. There were no cases of multiple reporting. Each review author independently evaluated risk of bias through assessing sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. MAIN RESULTS: We included three small studies with a cross-over design, involving a total of 20 participants (11 adults and 9 children), in this review. Our primary outcome was mortality, and there was one death by the time of follow-up 28 days after hospital admission. The trials did not measure the clinical secondary outcomes of quality of life, GCS, and disability. The included studies provided information only for the secondary outcomes intracranial pressure (ICP), cerebral perfusion pressure (CPP), and adverse effects.We were unable to pool the results as the data were either presented in different formats or no numerical data were provided. We included narrative interpretations of the available data.The overall risk of bias of the studies was unclear due to poor reporting of the methods. There was marked inconsistency across studies for the outcome of ICP and small sample sizes or wide confidence intervals for all outcomes. We therefore rated the quality of the evidence as very low for all outcomes and have not included the results of individual studies here. We do not have enough evidence to draw conclusions about the effect of HBE during intensive care management of people with TBI. AUTHORS' CONCLUSIONS: The lack of consistency among studies, scarcity of data and the absence of evidence to show a correlation between physiological measurements such as ICP, CCP and clinical outcomes, mean that we are uncertain about the effects of HBE during intensive care management in people with severe TBI.Well-designed and larger trials that measure long-term clinical outcomes are needed to understand how and when different backrest positions can affect the management of severe TBI.

Posture and fluids for preventing post-dural puncture headache.

BACKGROUND: Post-dural puncture headache (PDPH) is a common complication of lumbar punctures. Several theories have identified the leakage of cerebrospinal fluid (CSF) through the hole in the dura as a cause of this side effect. It is therefore necessary to take preventive measures to avoid this complication. Prolonged bed rest has been used to treat PDPH once it has started, but it is unknown whether prolonged bed rest can also be used to prevent it. Similarly, the value of administering fluids additional to those of normal dietary intake to restore the loss of CSF produced by the puncture is unknown. This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (Issue 7, 2013) on "Posture and fluids for preventing post-dural puncture headache". OBJECTIVES: To assess whether prolonged bed rest combined with different body and head positions, as well as administration of supplementary fluids after lumbar puncture, prevent the onset of PDPH in people undergoing lumbar puncture for diagnostic or therapeutic purposes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and LILACS, as well as trial registries up to February 2015. SELECTION CRITERIA: We identified randomized controlled trials that compared the effects of bed rest versus immediate mobilization, head-down tilt versus horizontal position, prone versus supine positions during bed rest, and administration of supplementary fluids versus no/less supplementation, as prevention measures for PDPH in people who have undergone lumbar puncture. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for eligibility through the web-based software EROS (Early Review Organizing Software). Two different review authors independently assessed risk of bias using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We resolved any disagreements by consensus. We extracted data on cases of PDPH, severe PDPH, and any headache after lumbar puncture and performed intention-to-treat analyses and sensitivity analyses by risk of bias. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created a 'Summary of findings' table. MAIN RESULTS: We included 24 trials with 2996 participants in this updated review. The number of participants in each trial varied from 39 to 382. Most of the included studies compared bed rest versus immediate mobilization, and only two assessed the effects of supplementary fluids versus no supplementation. We judged the overall risk of bias of the included studies as low to unclear. The overall quality of evidence was low to moderate, downgraded because of the risk of bias assessment in most cases. The primary outcome in our review was the presence of PDPH.There was low quality evidence for an absence of benefits associated with bed rest compared with immediate mobilization on the incidence of severe PDPH (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.68 to 1.41; participants = 1568; studies = 9) and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 1.16; 95% CI 1.02 to 1.32; participants = 2477; studies = 18). Furthermore, bed rest probably increased PDPH (RR 1.24; 95% CI 1.04 to 1.48; participants = 1519; studies = 12) compared with immediate mobilization. An analysis restricted to the most methodologically rigorous trials (i.e. those with low risk of bias in allocation method, missing data and blinding of outcome assessment) gave similar results. There was low quality evidence for an absence of benefits associated with fluid supplementation on the incidence of severe PDPH (RR 0.67; 95% CI 0.26 to 1.73; participants = 100; studies = 1) and PDPH (RR 1; 95% CI 0.59 to 1.69; participants = 100; studies = 1), and moderate quality evidence on the incidence of any headache after lumbar puncture (RR 0.94; 95% CI 0.66 to 1.34; participants = 200; studies = 2). We did not expect other adverse events and did not assess them in this review. AUTHORS' CONCLUSIONS: Since the previous version of this review, we found one new study for inclusion, but the conclusion remains unchanged. We considered the quality of the evidence for most of the outcomes assessed in this review to be low to moderate. As identified studies had shortcomings on aspects related to randomization and blinding of outcome assessment, we therefore downgraded the quality of the evidence. In general, there was no evidence suggesting that routine bed rest after dural puncture is beneficial for the prevention of PDPH onset. The role of fluid supplementation in the prevention of PDPH remains unclear.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses. MAIN RESULTS: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.

Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis.

BACKGROUND: People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. OBJECTIVES: To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. SELECTION CRITERIA: Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a meta-analysis. We assessed the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 13 randomized controlled trials (RCTs) in the review, which enrolled 5824 participants. Trials were published between 1987 and 2015 and included participants in treatment with newly diagnosed pulmonary TB in countries with high TB prevalence. Only two trials reported the HIV status of included participants.Overall there is little or no difference detected between FDCs and single-drug formulations for most outcomes reported. We did not detect a difference in treatment failure between FDCs compared with single-drug formulations (RR 1.28, 95% CI 0.82 to 2.00; 3606 participants, seven trials, moderate quality evidence). Relapse may be more frequent in people treated with FDCs compared to single-drug formulations, although the confidence interval (CI) includes no difference (RR 1.28, 95% CI 1.00 to 1.64; 3621 participants, 10 trials, low quality evidence). We did not detect any difference in death between fixed-dose and single-drug formulation groups (RR 0.96, 95% CI 0.67 to 1.39; 4800 participants, 11 trials, moderate quality evidence).When we compared FDCs with single-drug formulations we found little or no difference for sputum smear or culture conversion at the end of treatment (RR 0.99, 95% CI 0.96 to 1.02; 2319 participants, seven trials, high quality evidence), for serious adverse events (RR 1.45, 95% CI 0.90 to 2.33; 3388 participants, six trials, moderate quality evidence), and for adverse events that led to discontinuation of therapy (RR 0.96, 95% CI 0.56 to 1.66; 5530 participants, 13 trials, low quality evidence).We conducted a sensitivity analysis excluding studies at high risk of bias and this did not alter the review findings. AUTHORS' CONCLUSIONS: Fixed-dose combinations and single-drug formulations probably have similar effects for treating people with newly diagnosed pulmonary TB.

Drug therapy for treating post-dural puncture headache.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 8, 2011, on 'Drug therapy for treating post-dural puncture headache'.Post-dural puncture headache (PDPH) is the most common complication of lumbar puncture, an invasive procedure frequently performed in the emergency room. Numerous pharmaceutical drugs have been proposed to treat PDPH but there are still some uncertainties about their clinical effectiveness. OBJECTIVES: To assess the effectiveness and safety of drugs for treating PDPH in adults and children. SEARCH METHODS: The searches included the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 6), MEDLINE and MEDLINE in Process (from 1950 to 29 July 2014), EMBASE (from 1980 to 29 July 2014) and CINAHL (from 1982 to July 2014). There were no language restrictions. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) assessing the effectiveness of any pharmacological drug used for treating PDPH. Outcome measures considered for this review were: PDPH persistence of any severity at follow-up (primary outcome), daily activity limited by headache, conservative supplementary therapeutic option offered, epidural blood patch performed, change in pain severity scores, improvements in pain severity scores, number of days participants stay in hospital, any possible adverse events and missing data. DATA COLLECTION AND ANALYSIS: Review authors independently selected studies, assessed risk of bias and extracted data. We estimated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous outcomes. We calculated a 95% confidence interval (CI) for each RR and MD. We did not undertake meta-analysis because the included studies assessed different sorts of drugs or different outcomes. We performed an intention-to-treat (ITT) analysis. MAIN RESULTS: We included 13 small RCTs (479 participants) in this review (at least 274 participants were women, with 118 parturients after a lumbar puncture for regional anaesthesia). In the original version of this Cochrane review, only seven small RCTs (200 participants) were included. Pharmacological drugs assessed were oral and intravenous caffeine, subcutaneous sumatriptan, oral gabapentin, oral pregabalin, oral theophylline, intravenous hydrocortisone, intravenous cosyntropin and intramuscular adrenocorticotropic hormone (ACTH).Two RCTs reported data for PDPH persistence of any severity at follow-up (primary outcome). Caffeine reduced the number of participants with PDPH at one to two hours when compared to placebo. Treatment with caffeine also decreased the need for a conservative supplementary therapeutic option.Treatment with gabapentin resulted in better visual analogue scale (VAS) scores after one, two, three and four days when compared with placebo and also when compared with ergotamine plus caffeine at two, three and four days. Treatment with hydrocortisone plus conventional treatment showed better VAS scores at six, 24 and 48 hours when compared with conventional treatment alone and also when compared with placebo. Treatment with theophylline showed better VAS scores compared with acetaminophen at two, six and 12 hours and also compared with conservative treatment at eight, 16 and 24 hours. Theophylline also showed a lower mean "sum of pain" when compared with placebo. Sumatriptan and ACTH did not show any relevant effect for this outcome.Theophylline resulted in a higher proportion of participants reporting an improvement in pain scores when compared with conservative treatment.There were no clinically significant drug adverse events.The rest of the outcomes were not reported by the included RCTs or did not show any relevant effect. AUTHORS' CONCLUSIONS: None of the new included studies have provided additional information to change the conclusions of the last published version of the original Cochrane review. Caffeine has shown effectiveness for treating PDPH, decreasing the proportion of participants with PDPH persistence and those requiring supplementary interventions, when compared with placebo. Gabapentin, hydrocortisone and theophylline have been shown to decrease pain severity scores. Theophylline has also been shown to increase the proportion of participants that report an improvement in pain scores when compared with conventional treatment.There is a lack of conclusive evidence for the other drugs assessed (sumatriptan, adrenocorticotropic hormone, pregabalin and cosyntropin).These conclusions should be interpreted with caution, due to the lack of information to allow correct appraisal of risk of bias, the small sample sizes of the studies and also their limited generalisability, as nearly half of the participants were postpartum women in their 30s.

Anti-TNF agents for paediatric psoriasis.

BACKGROUND: Psoriasis is a chronic skin disease that may develop at any age. Estimates for the United States and Europe suggest that psoriasis accounts for 4% of skin diseases in children. In most cases, the condition is mild and can be treated with creams. However, a small percentage of children have moderate to severe disease that requires drugs, such as ciclosporin or methotrexate, and some will require injections with newer biological agents, such as anti-TNF (tumour necrosis factor) drugs. Anti-TNF drugs (among them etanercept, infliximab, and adalimumab) are designed to reduce inflammation in the body caused by tumour necrosis factor. Evidence for the safety and efficacy of these biological agents in paediatric psoriasis is lacking. OBJECTIVES: To assess the efficacy and safety of anti-TNF agents for the treatment of paediatric psoriasis. SEARCH METHODS: We searched the following databases up to July 2015: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), and LILACS (from 1982). We also searched 13 trials registers and checked the reference lists of included studies and key review articles for further references to relevant randomised controlled trials (RCTs). We handsearched conference proceedings and attempted to contact trial authors and relevant pharmaceutical manufacturers. We searched the US Food and Drug Administration's and European Medicines Agency's adverse effects databases. SELECTION CRITERIA: All relevant RCTs that evaluated the efficacy and safety of anti-TNF agents for the treatment of chronic plaque psoriasis in individuals less than 18 years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently checked titles and abstracts and performed data extraction and 'Risk of bias' assessment of the included studies. One review author entered data into Review Manager (RevMan), and a second review author checked the data. We also attempted to obtain unclear data from the trial authors where possible.Our primary outcomes were investigator-assessed number of participants achieving a 75% improvement in Psoriasis Area and Severity Index-75 (PASI 75) compared to baseline, improvement in quality of life using an instrument such as Children's Dermatology Life Quality Index (CDLQI), and adverse effects. Our secondary outcomes included the proportion of participants achieving PASI 50 and the Physician's Global Assessment (PGA). MAIN RESULTS: We included one study with 211 participants (median age 13 years), in which etanercept (dosage ranged from 0.8 to 50 mg per kilogram of body weight) was compared to placebo. Follow-up was over a 48-week period.At week 12, 57% versus 11% who received etanercept or placebo, respectively, achieved the PASI 75 (risk ratio 4.95, 95% confidence interval (CI) 2.83 to 8.65; high-quality evidence). Absolute risk reduction and the number needed to treat to obtain a benefit with etanercept was 45% (95% CI 33.95 to 56.40) and 2 (95% CI 1.77 to 2.95), respectively.The percentage improvement from baseline of the CDLQI scores at week 12 was better in the etanercept group than the placebo group (52.3% versus 17.5%, respectively (P = 0.0001)). Analysis between the groups showed an effect size that was clinically important (mean difference 2.30, 95% CI 0.85 to 3.75; high-quality evidence). However, means, medians, and minimal important difference results and results of the Pediatric Quality of Life Inventory, Stein Impact on Family Scale, and Harter Self-Perception Profile for Children scores must be interpreted with caution, as they were not prespecified outcomes.Three serious adverse events were reported, but they were resolved without sequelae. Deaths or other events such as malignant tumours, opportunistic infections, tuberculosis, or demyelination were not reported in the included study.Also, 13% of participants in the placebo group and 53% in the etanercept group had a PGA of clear or almost clear (risk ratio 3.96, 95% CI 2.36 to 6.66; high-quality evidence) at week 12. AUTHORS' CONCLUSIONS: This review found only one RCT evaluating the use of this type of biological therapy. Although the risk of publication bias was high, as we included only one industry-sponsored RCT, the risk of allocation, selection, performance, attrition, and selective reporting biases for all outcomes (except for CDLQI) was low, and no short-term serious adverse events were found.We can conclude, based on this single included study, that etanercept seems to be efficacious and safe (at least in the short term) for the treatment of paediatric psoriasis. However, as the GRADE approach refers not to individual studies but to a body of evidence, we shall wait for the results of the ongoing studies in a future update of this review. In addition, future studies should evaluate quality-of-life endpoints established a priori and standardise primary outcome measures such as PASI 75, and should include the PGA as a secondary endpoint. Also, collating and reporting adverse events uniformly is required to better evaluate safety.

Endoscopic injection of cyanoacrylate glue versus other endoscopic procedures for acute bleeding gastric varices in people with portal hypertension.

BACKGROUND: In people with portal hypertension, gastric varices are less prevalent than oesophageal varices. The risk of bleeding from gastric varices seems to be lower than from oesophageal varices; however, when gastric varices bleed, it is often severe and associated with higher mortality. Endoscopic sclerotherapy of bleeding gastric varices with N-butyl-2-cyanoacrylate glue (cyanoacrylate) is considered the best haemostasis with a lower risk of re-bleeding compared with other endoscopic methods. However, there are some inconsistencies between trials regarding mortality, incidence of re-bleeding, and adverse effects. OBJECTIVES: To assess the benefits and harms of sclerotherapy using cyanoacrylate compared with other endoscopic sclerotherapy procedures or with variceal band ligation for treating acute gastric variceal bleeding with or without vasoactive drugs in people with portal hypertension and to assess the best dosage of cyanoacrylate. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded from inception to September 2014 and reference lists of articles. We included trials irrespective of trial setting, language, publication status, or date of publication. SELECTION CRITERIA: Randomised clinical trials comparing sclerotherapy using cyanoacrylate versus other endoscopic methods (sclerotherapy using alcohol-based compounds or endoscopy band ligation) for acute gastric variceal bleeding in people with portal hypertension. DATA COLLECTION AND ANALYSIS: We performed the review following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and the Cochrane Hepato-Biliary Module.We presented results as risk ratios (RR) with 95% confidence intervals (CI), with I(2) statistic values as a measure of intertrial heterogeneity. We analysed data with both fixed-effect and random-effects models, and reported the results with random-effects models. We performed subgroup, sensitivity, and trial sequential analyses to evaluate the robustness of the overall results, risk of bias, sources of intertrial heterogeneity, and risk of random errors. MAIN RESULTS: We included six randomised clinical trials with three different comparisons: one trial compared two different doses of cyanoacrylate in 91 adults, bleeding actively from all types of gastric varices; one trial compared cyanoacrylate versus alcohol-based compounds in 37 adults with active or acute bleeding from isolated gastric varices only; and four trials compared cyanoacrylate versus endoscopic band ligation in 365 adults, with active or acute bleeding from all types of gastric varices. Main outcomes in the included trials were bleeding-related mortality, failure of intervention, re-bleeding, adverse events, and control of bleeding. Follow-up varied from six to 26 months. The participants included in these trials had chronic liver disease of different severities, were predominantly men, and most were from Eastern countries. We judged all trials at high risk of bias. Application of quality criteria for all outcomes yielded very low quality grade of the evidence in the three analyses, except for the low quality evidence rated for the re-bleeding outcome in the cyanoacrylate versus endoscopic band ligation comparison. Two different doses of cyanoacrylate: we found very low quality evidence from one trial for the effect of 0.5 mL compared with 1.0 mL of cyanoacrylate on all-cause mortality (20/44 (45.5%) with 0.5 mL versus 21/47 (45%) with 1.0 mL; RR 1.02; 95% CI 0.65 to 1.60), 30-day mortality (RR 1.07; 95% CI 0.41 to 2.80), failure of intervention (RR 1.07; 95% CI 0.56 to 2.05), prevention of re-bleeding (RR 1.30; 95% CI 0.73 to 2.31), adverse events reported as fever (RR 0.56; 95% CI 0.32 to 0.98), and control of bleeding (RR 1.04; 95% CI 0.78 to 1.38). Cyanoacrylate versus alcohol-based compounds: we found very low quality evidence from one trial for the effect of cyanoacrylate versus alcohol-based compounds on 30-day mortality (2/20 (10%) with cyanoacrylate versus 4/17 (23.5%) with alcohol-based compound; RR 0.43; 95% CI 0.09 to 2.04), failure of intervention (RR 0.36; 95% CI 0.09 to 1.35), prevention of re-bleeding (RR 0.85; 95% CI 0.30 to 2.45), adverse events reported as fever (RR 0.43; 95% CI 0.22 to 0.80), and control of bleeding (RR 1.79; 95% CI 1.13 to 2.84). Cyanoacrylate versus endoscopic band ligation: we found very low quality evidence for the effect of cyanoacrylate versus endoscopic band ligation on bleeding-related mortality (44/185 (23.7%) with cyanoacrylate versus 50/181 (27.6%) with endoscopic band ligation; RR 0.83; 95% CI 0.52 to 1.31), failure of intervention (RR 1.13; 95% CI 0.23 to 5.69), complications (RR 2.81; 95% CI 0.69 to 11.49), and control of bleeding (RR 1.07; 95% CI 0.90 to 1.27). There was low quality evidence for the prevention of re-bleeding (RR 0.60; 95% CI 0.41 to 0.88). Trial sequential analysis showed that the analyses were underpowered (diversity-adjusted required information size was 5290 participants for bleeding-related mortality). AUTHORS' CONCLUSIONS: This review suggests that endoscopic sclerotherapy using cyanoacrylate may be more effective than endoscopic band ligation in terms of preventing re-bleeding from gastric varices. However, due to the very low quality of the evidence, we are very uncertain about our estimates on all-cause and bleeding-related mortality, failure of intervention, adverse events, and control of bleeding. The trials were at high risk of bias; the number of the included randomised clinical trials and number of participants included in each trial was small; and there was evidence of internal heterogeneity across trials, indirectness of evidence in terms of population, and possible publication bias.The effectiveness of different doses of cyanoacrylate and the comparison of cyanoacrylate versus alcohol compounds to treat variceal bleeding in people with portal hypertension is uncertain due to the very low quality of the evidence.The shortcomings mentioned call for more evidence from larger trials that need to be conducted according to the SPIRIT statement and reported according to CONSORT guidelines.