Wolbachia-carrying Aedes mosquitoes for preventing dengue infection.

BACKGROUND: Dengue is a global health problem of high significance, with 3.9 billion people at risk of infection. The geographic expansion of dengue virus (DENV) infection has resulted in increased frequency and severity of the disease, and the number of deaths has increased in recent years. Wolbachia,an intracellular bacterial endosymbiont, has been under investigation for several years as a novel dengue-control strategy. Some dengue vectors (Aedes mosquitoes) can be transinfected with specific strains of Wolbachia, which decreases their fitness (ability to survive and mate) and their ability to reproduce, inhibiting the replication of dengue. Both laboratory and field studies have demonstrated the potential effect of Wolbachia deployments on reducing dengue transmission, and modelling studies have suggested that this may be a self-sustaining strategy for dengue prevention, although long-term effects are yet to be elucidated. OBJECTIVES: To assess the efficacy of Wolbachia-carrying Aedes speciesdeployments (specifically wMel-, wMelPop-, and wAlbB- strains of Wolbachia) for preventing dengue virus infection. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registries up to 24 January 2024. SELECTION CRITERIA: Randomized controlled trials (RCTs), including cluster-randomized controlled trials (cRCTs), conducted in dengue endemic or epidemic-prone settings were eligible. We sought studies that investigated the impact of Wolbachia-carrying Aedes deployments on epidemiological or entomological dengue-related outcomes, utilizing either the population replacement or population suppression strategy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias using the Cochrane RoB 2 tool. We used odds ratios (OR) with the corresponding 95% confidence intervals (CI) as the effect measure for dichotomous outcomes. For count/rate outcomes, we planned to use the rate ratio with 95% CI as the effect measure. We used adjusted measures of effect for cRCTs. We assessed the certainty of evidence using GRADE. MAIN RESULTS: One completed cRCT met our inclusion criteria, and we identified two further ongoing cRCTs. The included trial was conducted in an urban setting in Yogyakarta, Indonesia. It utilized a nested test-negative study design, whereby all participants aged three to 45 years who presented at healthcare centres with a fever were enrolled in the study provided they had resided in the study area for the previous 10 nights. The trial showed that wMel-Wolbachia infected Ae aegypti deployments probably reduce the odds of contracting virologically confirmed dengue by 77% (OR 0.23, 95% CI 0.15 to 0.35; 1 trial, 6306 participants; moderate-certainty evidence). The cluster-level prevalence of wMel Wolbachia-carrying mosquitoes remained high over two years in the intervention arm of the trial, reported as 95.8% (interquartile range 91.5 to 97.8) across 27 months in clusters receiving wMel-Wolbachia Ae aegypti deployments, but there were no reliable comparative data for this outcome. Other primary outcomes were the incidence of virologically confirmed dengue, the prevalence of dengue ribonucleic acid in the mosquito population, and mosquito density, but there were no data for these outcomes. Additionally, there were no data on adverse events. AUTHORS' CONCLUSIONS: The included trial demonstrates the potential significant impact of wMel-Wolbachia-carrying Ae aegypti mosquitoes on preventing dengue infection in an endemic setting, and supports evidence reported in non-randomized and uncontrolled studies. Further trials across a greater diversity of settings are required to confirm whether these findings apply to other locations and country settings, and greater reporting of acceptability and cost are important.

A Reporting Tool for Adapted Guidelines in Health Care: The RIGHT-Ad@pt Checklist.

BACKGROUND: Adaptation of existing guidelines can be an efficient way to develop contextualized recommendations. Transparent reporting of the adaptation approach can support the transparency and usability of the adapted guidelines. OBJECTIVE: To develop an extension of the RIGHT (Reporting Items for practice Guidelines in HealThcare) statement for the reporting of adapted guidelines (including recommendations that have been adopted, adapted, or developed de novo), the RIGHT-Ad@pt checklist. DESIGN: A multistep process was followed to develop the checklist: establishing a working group, generating an initial checklist, optimizing the checklist (through an initial assessment of adapted guidelines, semistructured interviews, a Delphi consensus survey, an external review, and a final assessment of adapted guidelines), and approval of the final checklist by the working group. SETTING: International collaboration. PARTICIPANTS: A total of 119 professionals participated in the development process. MEASUREMENTS: Participants' consensus on items in the checklist. RESULTS: The RIGHT-Ad@pt checklist contains 34 items grouped in 7 sections: basic information (7 items); scope (6 items); rigor of development (10 items); recommendations (4 items); external review and quality assurance (2 items); funding, declaration, and management of interest (2 items); and other information (3 items). A user guide with explanations and real-world examples for each item was developed to provide a better user experience. LIMITATION: The RIGHT-Ad@pt checklist requires further validation in real-life use. CONCLUSION: The RIGHT-Ad@pt checklist has been developed to improve the reporting of adapted guidelines, focusing on the standardization, rigor, and transparency of the process and the clarity and explicitness of adapted recommendations. PRIMARY FUNDING SOURCE: None.

Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: Update of a living systematic review and meta-analysis.

BACKGROUND: Debate about the level of asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection continues. The amount of evidence is increasing and study designs have changed over time. We updated a living systematic review to address 3 questions: (1) Among people who become infected with SARS-CoV-2, what proportion does not experience symptoms at all during their infection? (2) What is the infectiousness of asymptomatic and presymptomatic, compared with symptomatic, SARS-CoV-2 infection? (3) What proportion of SARS-CoV-2 transmission in a population is accounted for by people who are asymptomatic or presymptomatic? METHODS AND FINDINGS: The protocol was first published on 1 April 2020 and last updated on 18 June 2021. We searched PubMed, Embase, bioRxiv, and medRxiv, aggregated in a database of SARS-CoV-2 literature, most recently on 6 July 2021. Studies of people with PCR-diagnosed SARS-CoV-2, which documented symptom status at the beginning and end of follow-up, or mathematical modelling studies were included. Studies restricted to people already diagnosed, of single individuals or families, or without sufficient follow-up were excluded. One reviewer extracted data and a second verified the extraction, with disagreement resolved by discussion or a third reviewer. Risk of bias in empirical studies was assessed with a bespoke checklist and modelling studies with a published checklist. All data syntheses were done using random effects models. Review question (1): We included 130 studies. Heterogeneity was high so we did not estimate a mean proportion of asymptomatic infections overall (interquartile range (IQR) 14% to 50%, prediction interval 2% to 90%), or in 84 studies based on screening of defined populations (IQR 20% to 65%, prediction interval 4% to 94%). In 46 studies based on contact or outbreak investigations, the summary proportion asymptomatic was 19% (95% confidence interval (CI) 15% to 25%, prediction interval 2% to 70%). (2) The secondary attack rate in contacts of people with asymptomatic infection compared with symptomatic infection was 0.32 (95% CI 0.16 to 0.64, prediction interval 0.11 to 0.95, 8 studies). (3) In 13 modelling studies fit to data, the proportion of all SARS-CoV-2 transmission from presymptomatic individuals was higher than from asymptomatic individuals. Limitations of the evidence include high heterogeneity and high risks of selection and information bias in studies that were not designed to measure persistently asymptomatic infection, and limited information about variants of concern or in people who have been vaccinated. CONCLUSIONS: Based on studies published up to July 2021, most SARS-CoV-2 infections were not persistently asymptomatic, and asymptomatic infections were less infectious than symptomatic infections. Summary estimates from meta-analysis may be misleading when variability between studies is extreme and prediction intervals should be presented. Future studies should determine the asymptomatic proportion of SARS-CoV-2 infections caused by variants of concern and in people with immunity following vaccination or previous infection. Without prospective longitudinal studies with methods that minimise selection and measurement biases, further updates with the study types included in this living systematic review are unlikely to be able to provide a reliable summary estimate of the proportion of asymptomatic infections caused by SARS-CoV-2. REVIEW PROTOCOL: Open Science Framework (https://osf.io/9ewys/).

Meta-DiSc 2.0: a web application for meta-analysis of diagnostic test accuracy data.

BACKGROUND: Diagnostic evidence of the accuracy of a test for identifying a target condition of interest can be estimated using systematic approaches following standardized methodologies. Statistical methods for the meta-analysis of diagnostic test accuracy (DTA) studies are relatively complex, presenting a challenge for reviewers without extensive statistical expertise. In 2006, we developed Meta-DiSc, a free user-friendly software to perform test accuracy meta-analysis. This statistical program is now widely used for performing DTA meta-analyses. We aimed to build a new version of the Meta-DiSc software to include statistical methods based on hierarchical models and an enhanced web-based interface to improve user experience. RESULTS: In this article, we present the updated version, Meta-DiSc 2.0, a web-based application developed using the R Shiny package. This new version implements recommended state-of-the-art statistical models to overcome the limitations of the statistical approaches included in the previous version. Meta-DiSc 2.0 performs statistical analyses of DTA reviews using a bivariate random effects model. The application offers a thorough analysis of heterogeneity, calculating logit variance estimates of sensitivity and specificity, the bivariate I-squared, the area of the 95% prediction ellipse, and the median odds ratios for sensitivity and specificity, and facilitating subgroup and meta-regression analyses. Furthermore, univariate random effects models can be applied to meta-analyses with few studies or with non-convergent bivariate models. The application interface has an intuitive design set out in four main menus: file upload; graphical description (forest and ROC plane plots); meta-analysis (pooling of sensitivity and specificity, estimation of likelihood ratios and diagnostic odds ratio, sROC curve); and summary of findings (impact of test through downstream consequences in a hypothetical population with a given prevalence). All computational algorithms have been validated in several real datasets by comparing results obtained with STATA/SAS and MetaDTA packages. CONCLUSION: We have developed and validated an updated version of the Meta-DiSc software that is more accessible and statistically sound. The web application is freely available at www.metadisc.es .

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.

Current methods for development of rapid reviews about diagnostic tests: an international survey.

BACKGROUND: Rapid reviews (RRs) have emerged as an efficient alternative to time-consuming systematic reviews-they can help meet the demand for accelerated evidence synthesis to inform decision-making in healthcare. The synthesis of diagnostic evidence has important methodological challenges. Here, we performed an international survey to identify the current practice of producing RRs for diagnostic tests. METHODS: We developed and administered an online survey inviting institutions that perform RRs of diagnostic tests from all over the world. RESULTS: All participants (N = 25) reported the implementation of one or more methods to define the scope of the RR; however, only one strategy (defining a structured question) was used by ≥90% of participants. All participants used at least one methodological shortcut including the use of a previous review as a starting point (92%) and the use of limits on the search (96%). Parallelization and automation of review tasks were not extensively used (48 and 20%, respectively). CONCLUSION: Our survey indicates a greater use of shortcuts and limits for conducting diagnostic test RRs versus the results of a recent scoping review analyzing published RRs. Several shortcuts are used without knowing how their implementation affects the results of the evidence synthesis in the setting of diagnostic test reviews. Thus, a structured evaluation of the challenges and implications of the adoption of these RR methods is warranted.

Acetyl-L-carnitine for patients with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. OBJECTIVES: To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites. SELECTION CRITERIA: We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms. DATA COLLECTION AND ANALYSIS: We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach. MAIN RESULTS: We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.

Interventions for preventing high altitude illness: Part 3. Miscellaneous and non-pharmacological interventions.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE), and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this, the third of a series of three reviews about preventive strategies for HAI, we assessed the effectiveness of miscellaneous and non-pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of miscellaneous and non-pharmacological interventions for preventing acute HAI in people who are at risk of developing high altitude illness in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in January 2019. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA: We included randomized controlled trials conducted in any setting where non-pharmacological and miscellaneous interventions were employed to prevent acute HAI, including preacclimatization measures and the administration of non-pharmacological supplements. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with, and without, a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant intervention was administered before the beginning of ascent. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures employed by Cochrane. MAIN RESULTS: We included 20 studies (1406 participants, 21 references) in this review. Thirty studies (14 ongoing, and 16 pending classification (awaiting)) will be considered in future versions of this suite of three reviews as appropriate. We report the results for the primary outcome of this review (risk of AMS) by each group of assessed interventions.Group 1. Preacclimatization and other measures based on pressureUse of simulated altitude or remote ischaemic preconditioning (RIPC) might not improve the risk of AMS on subsequent exposure to altitude, but this effect is uncertain (simulated altitude: risk ratio (RR) 1.18, 95% confidence interval (CI) 0.82 to 1.71; I² = 0%; 3 trials, 140 participants; low-quality evidence. RIPC: RR 3.0, 95% CI 0.69 to 13.12; 1 trial, 40 participants; low-quality evidence). We found evidence of improvement of this risk using positive end-expiratory pressure (PEEP), but this information was derived from a cross-over trial with a limited number of participants (OR 3.67, 95% CI 1.38 to 9.76; 1 trial, 8 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions.Group 2. Supplements and vitaminsSupplementation of antioxidants, medroxyprogesterone, iron or Rhodiola crenulata might not improve the risk of AMS on exposure to high altitude, but this effect is uncertain (antioxidants: RR 0.58, 95% CI 0.32 to 1.03; 1 trial, 18 participants; low-quality evidence. Medroxyprogesterone: RR 0.71, 95% CI 0.48 to 1.05; I² = 0%; 2 trials, 32 participants; low-quality evidence. Iron: RR 0.65, 95% CI 0.38 to 1.11; I² = 0%; 2 trials, 65 participants; low-quality evidence. R crenulata: RR 1.00, 95% CI 0.78 to 1.29; 1 trial, 125 participants; low-quality evidence). We found evidence of improvement of this risk with the administration of erythropoietin, but this information was extracted from a trial with issues related to risk of bias and imprecision (RR 0.41, 95% CI 0.20 to 0.84; 1 trial, 39 participants; very low-quality evidence). Regarding administration of ginkgo biloba, we did not perform a pooled estimation of RR for AMS due to considerable heterogeneity between the included studies (I² = 65%). RR estimates from the individual studies were conflicting (from 0.05 to 1.03; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions.Group 3. Other comparisonsWe found heterogeneous evidence regarding the risk of AMS when ginkgo biloba was compared with acetazolamide (I² = 63%). RR estimates from the individual studies were conflicting (estimations from 0.11 (95% CI 0.01 to 1.86) to 2.97 (95% CI 1.70 to 5.21); low-quality evidence). We found evidence of improvement when ginkgo biloba was administered along with acetazolamide, but this information was derived from a single trial with issues associated to risk of bias (compared to ginkgo biloba alone: RR 0.43, 95% CI 0.26 to 0.71; 1 trial, 311 participants; low-quality evidence). Administration of medroxyprogesterone plus acetazolamide did not improve the risk of AMS when compared to administration of medroxyprogesterone or acetazolamide alone (RR 1.33, 95% CI 0.50 to 3.55; 1 trial, 12 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions. AUTHORS' CONCLUSIONS: This Cochrane Review is the final in a series of three providing relevant information to clinicians, and other interested parties, on how to prevent high altitude illness. The assessment of non-pharmacological and miscellaneous interventions suggests that there is heterogeneous and even contradictory evidence related to the effectiveness of these prophylactic strategies. Safety of these interventions remains as an unclear issue due to lack of assessment. Overall, the evidence is limited due to its quality (low to very low), the relative paucity of that evidence and the number of studies pending classification for the three reviews belonging to this series (30 studies either awaiting classification or ongoing). Additional studies, especially those comparing with pharmacological alternatives (such as acetazolamide) are required, in order to establish or refute the strategies evaluated in this review.

Plasma interleukin-6 concentration for the diagnosis of sepsis in critically ill adults.

BACKGROUND: The definition of sepsis has evolved over time, along with the clinical and scientific knowledge behind it. For years, sepsis was defined as a systemic inflammatory response syndrome (SIRS) in the presence of a documented or suspected infection. At present, sepsis is defined as a life-threatening organ dysfunction resulting from a dysregulated host response to infection. Even though sepsis is one of the leading causes of mortality in critically ill patients, and the World Health Organization (WHO) recognizes it as a healthcare priority, it still lacks an accurate diagnostic test. Determining the accuracy of interleukin-6 (IL-6) concentrations in plasma, which is proposed as a new biomarker for the diagnosis of sepsis, might be helpful to provide adequate and timely management of critically ill patients, and thus reduce the morbidity and mortality associated with this condition. OBJECTIVES: To determine the diagnostic accuracy of plasma interleukin-6 (IL-6) concentration for the diagnosis of bacterial sepsis in critically ill adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and Web of Science on 25 January 2019. We screened references in the included studies to identify additional studies. We did not apply any language restriction to the electronic searches. SELECTION CRITERIA: We included diagnostic accuracy studies enrolling critically ill adults aged 18 years or older under suspicion of sepsis during their hospitalization, where IL-6 concentrations were evaluated by serological measurement. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the references to identify relevant studies and extracted data. We assessed the methodological quality of studies using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We estimated a summary receiver operating characteristic (SROC) curve by fitting a hierarchical summary ROC (HSROC) non-linear mixed model. We explored sources of heterogeneity using the HSROC model parameters. We conducted all analyses in the SAS statistical software package and R software. MAIN RESULTS: We included 23 studies (n = 4192) assessing the accuracy of IL-6 for the diagnosis of sepsis in critically ill adults. Twenty studies that were available as conference proceedings only are awaiting classification. The included participants were heterogeneous in terms of their distribution of age, gender, main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and origin of infection, among other factors. Prevalence of sepsis greatly varied across studies, ranging from 12% to 78%. We considered all studies to be at high risk of bias due to issues related to the index test domain in QUADAS-2. The SROC curve showed a great dispersion in individual studies accuracy estimates (21 studies, 3650 adult patients), therefore the considerable heterogeneity in the collected data prevented us from calculating formal accuracy estimates. Using a fixed prevalence of sepsis of 50% and a fixed specificity of 74%, we found a sensitivity of 66% (95% confidence interval 60 to 72). If we test a cohort 1000 adult patients under suspicion of sepsis with IL-6, we will find that 330 patients would receive appropriate and timely antibiotic therapy, while 130 patients would be wrongly considered to have sepsis. In addition, 370 out of 1000 patients would avoid unnecessary antibiotic therapy, and 170 patients would have been undiagnosed of sepsis. This numerical approach should be interpreted with caution due to the limitations described above. AUTHORS' CONCLUSIONS: Our evidence assessment of plasma interleukin-6 concentrations for the diagnosis of sepsis in critically ill adults reveals several limitations. High heterogeneity of collected evidence regarding the main diagnosis, setting, country, positivity threshold, sepsis criteria, year of publication, and the origin of infection, among other factors, along with the potential number of misclassifications, remain significant constraints for its implementation. The 20 conference proceedings assessed as studies awaiting classification may alter the conclusions of the review once they are fully published and evaluated. Further studies about the accuracy of interleukin-6 for the diagnosis of sepsis in adults that apply rigorous methodology for conducting diagnostic test accuracy studies are needed. The conclusions of the review will likely change once the 20 studies pending publication are fully published and included.

Interventions for preventing high altitude illness: Part 2. Less commonly-used drugs.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants who are at risk of developing high altitude illness in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in May 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA: We included randomized controlled trials conducted in any setting where one of five classes of drugs was employed to prevent acute HAI: selective 5-hydroxytryptamine(1) receptor agonists; N-methyl-D-aspartate (NMDA) antagonist; endothelin-1 antagonist; anticonvulsant drugs; and spironolactone. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with and without a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures employed by Cochrane. MAIN RESULTS: We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.We report results for the following four main comparisons.Sumatriptan versus placebo (1 parallel study; 102 participants)Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.Magnesium citrate versus placebo (1 parallel study; 70 participants)The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.Spironolactone versus placebo (2 parallel studies; 205 participants)Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.Acetazolamide versus spironolactone (1 parallel study; 232 participants)Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. AUTHORS' CONCLUSIONS: This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.

Interventions for infantile haemangiomas of the skin.

BACKGROUND: Infantile haemangiomas (previously known as strawberry birthmarks) are soft, raised swellings of the skin that occur in 3% to 10% of infants. These benign vascular tumours are usually uncomplicated and tend to regress spontaneously. However, when haemangiomas occur in high-risk areas, such as near the eyes, throat, or nose, impairing their function, or when complications develop, intervention may be necessary. This is an update of a Cochrane Review first published in 2011. OBJECTIVES: To assess the effects of interventions for the management of infantile haemangiomas in children. SEARCH METHODS: We updated our searches of the following databases to February 2017: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, AMED, LILACS, and CINAHL. We also searched five trials registries and checked the reference lists of included studies for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of all types of interventions, versus placebo, active monitoring, or other interventions, in any child with single or multiple infantile haemangiomas (IHs) located on the skin. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcome measures were clearance, a subjective measure of improvement, and adverse events. Secondary outcomes were other measures of resolution; proportion of parents or children who consider there is still a problem; aesthetic appearance; and requirement for surgical correction. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included 28 RCTs, with a total of 1728 participants, assessing 12 different interventions, including lasers, beta blockers (e.g. propranolol, timolol maleate), radiation therapy, and steroids. Comparators included placebo, an active monitoring approach, sham radiation, and interventions given alone or in combination.Studies were conducted in a number of countries, including China, Egypt, France, and Australia. Participant age ranged from 12 weeks to 13.4 years. Most studies (23/28) included a majority of females and different types of IHs. Duration of follow-up ranged from 7 days to 72 months.We considered most of the trials as at low risk of random sequence generation, attrition bias, and selective reporting bias. Domains such as allocation concealment and blinding were not clearly reported in general. We downgraded evidence for issues related to risk of bias and imprecision.We report results for the three most important comparisons, which we chose on the basis of current use. Outcome measurement of these comparisons was at 24 weeks' follow-up.Oral propranolol versus placeboCompared with placebo, oral propranolol 3 mg/kg/day probably improves clinician-assessed clearance (risk ratio (RR) 16.61, 95% confidence interval (CI) 4.22 to 65.34; 1 study; 156 children; moderate-quality evidence) and probably leads to a clinician-assessed reduction in mean haemangioma volume of 45.9% (95% CI 11.60 to 80.20; 1 study; 40 children; moderate-quality evidence). We found no evidence of a difference in terms of short- or long-term serious adverse events (RR 1.05, 95% CI 0.33 to 3.39; 3 studies; 509 children; low-quality evidence), nor in terms of bronchospasm, hypoglycaemia, or serious cardiovascular adverse events. The results relating to clearance and resolution for this comparison were based on one industry-sponsored study.Topical timolol maleate versus placeboThe chance of reduction of redness, as a measure of clinician-assessed resolution, may be improved with topical timolol maleate 0.5% gel applied twice daily when compared with placebo (RR 8.11, 95% CI 1.09 to 60.09; 1 study; 41 children;low-quality evidence). Regarding short- or long-term serious cardiovascular events, we found no instances of bradycardia (slower than normal heart rate) or hypotension in either group (1 study; 41 children; low-quality evidence). No other safety data were assessed, and clearance was not measured.Oral propranolol versus topical timolol maleateWhen topical timolol maleate (0.5% eye drops applied twice daily) was compared with oral propranolol (via a tablet taken once per day, at a 1.0 mg/kg dose), there was no evidence of a difference in haemangioma size (as a measure of resolution) when measured by the proportion of patients with a clinician-assessed reduction of 50% or greater (RR 1.13, 95% CI 0.64 to 1.97; 1 study; 26 participants; low-quality evidence). Although there were more short- or long-term general adverse effects (such as severe diarrhoea, lethargy, and loss of appetite) in the oral propranolol group, there was no evidence of a difference between groups (RR 7.00, 95% CI 0.40 to 123.35; 1 study; 26 participants; very low-quality evidence). This comparison did not measure clearance.None of our key comparisons evaluated, at any follow-up, a subjective measure of improvement assessed by the parent or child; proportion of parents or children who consider there is still a problem; or physician-, child-, or parent-assessed aesthetic appearance. AUTHORS' CONCLUSIONS: We found there to be a limited evidence base for the treatment of infantile haemangiomas: a large number of interventions and outcomes have not been assessed in RCTs.Our key results indicate that in the management of IH in children, oral propranolol and topical timolol maleate are more beneficial than placebo in terms of clearance or other measures of resolution, or both, without an increase in harms. We found no evidence of a difference between oral propranolol and topical timolol maleate with regard to reducing haemangioma size, but we are uncertain if there is a difference in safety. Oral propranolol is currently the standard treatment for this condition, and our review has not found evidence to challenge this. However, these results are based on moderate- to very low-quality evidence.The included studies were limited by small sample sizes and risk of bias in some domains. Future trials should blind personnel and participants; describe trials thoroughly in publications; and recruit a sufficient number of children to deduce meaningful results. Future trials should assess patient-reported outcomes, as well as objective outcomes of benefit, and should report adverse events comprehensively. Propranolol and timolol maleate require further assessment in RCTs of all types of IH, including those considered problematic, as do other lesser-used interventions and new interventions. All treatments should be compared against propranolol and timolol maleate, as beta blockers are approved as standard care.

Interventions for treating acute high altitude illness.

BACKGROUND: Acute high altitude illness is defined as a group of cerebral and pulmonary syndromes that can occur during travel to high altitudes. It is more common above 2500 metres, but can be seen at lower elevations, especially in susceptible people. Acute high altitude illness includes a wide spectrum of syndromes defined under the terms 'acute mountain sickness' (AMS), 'high altitude cerebral oedema' and 'high altitude pulmonary oedema'. There are several interventions available to treat this condition, both pharmacological and non-pharmacological; however, there is a great uncertainty regarding their benefits and harms. OBJECTIVES: To assess the clinical effectiveness, and safety of interventions (non-pharmacological and pharmacological), as monotherapy or in any combination, for treating acute high altitude illness. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, ISI Web of Science, CINAHL, Wanfang database and the World Health Organization International Clinical Trials Registry Platform for ongoing studies on 10 August 2017. We did not apply any language restriction. SELECTION CRITERIA: We included randomized controlled trials evaluating the effects of pharmacological and non-pharmacological interventions for individuals suffering from acute high altitude illness: acute mountain sickness, high altitude pulmonary oedema or high altitude cerebral oedema. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of study reports, the risk of bias for each and performed the data extraction. We resolved disagreements through discussion with a third author. We assessed the quality of evidence with GRADE. MAIN RESULTS: We included 13 studies enrolling a total of 468 participants. We identified two ongoing studies. All studies included adults, and two studies included both teenagers and adults. The 13 studies took place in high altitude areas, mostly in the European Alps. Twelve studies included participants with acute mountain sickness, and one study included participants with high altitude pulmonary oedema. Follow-up was usually less than one day. We downgraded the quality of the evidence in most cases due to risk of bias and imprecision. We report results for the main comparisons as follows.Non-pharmacological interventions (3 studies, 124 participants)All-cause mortality and complete relief of AMS symptoms were not reported in the three included trials. One study in 64 participants found that a simulated descent of 193 millibars versus 20 millibars may reduce the average of symptoms to 2.5 vs 3.1 units after 12 hours of treatment (clinical score ranged from 0 to 11 ‒ worse; reduction of 0.6 points on average with the intervention; low quality of evidence). In addition, no complications were found with use of hyperbaric chambers versus supplementary oxygen (one study; 29 participants; low-quality evidence).Pharmacological interventions (11 trials, 375 participants)All-cause mortality was not reported in the 11 included trials. One trial found a greater proportion of participants with complete relief of AMS symptoms after 12 and 16 hours when dexamethasone was administered in comparison with placebo (47.1% versus 0%, respectively; one study; 35 participants; low quality of evidence). Likewise, when acetazolamide was compared with placebo, the effects on symptom severity was uncertain (standardized mean difference (SMD) -1.15, 95% CI -2.56 to 0.27; 2 studies, 25 participants; low-quality evidence). One trial of dexamethasone in comparison with placebo in 35 participants found a reduction in symptom severity (difference on change in the AMS score: 3.7 units reported by authors; moderate quality of evidence). The effects from two additional trials comparing gabapentin with placebo and magnesium with placebo on symptom severity at the end of treatment were uncertain. For gabapentin versus placebo: mean visual analogue scale (VAS) score of 2.92 versus 4.75, respectively; 24 participants; low quality of evidence. For magnesium versus placebo: mean scores of 9 and 10.3 units, respectively; 25 participants; low quality of evidence). The trials did not find adverse events from either treatment (low quality of evidence). One trial comparing magnesium sulphate versus placebo found that flushing was a frequent event in the magnesium sulphate arm (percentage of flushing: 75% versus 7.7%, respectively; one study; 25 participants; low quality of evidence). AUTHORS' CONCLUSIONS: There is limited available evidence to determine the effects of non-pharmacological and pharmacological interventions in treating acute high altitude illness. Low-quality evidence suggests that dexamethasone and acetazolamide might reduce AMS score compared to placebo. However, the clinical benefits and harms related to these potential interventions remain unclear. Overall, the evidence is of limited practical significance in the clinical field. High-quality research in this field is needed, since most trials were poorly conducted and reported.

Needle gauge and tip designs for preventing post-dural puncture headache (PDPH).

BACKGROUND: Post-dural puncture headache (PDPH) is one of the most common complications of diagnostic and therapeutic lumbar punctures. PDPH is defined as any headache occurring after a lumbar puncture that worsens within 15 minutes of sitting or standing and is relieved within 15 minutes of the patient lying down. Researchers have suggested many types of interventions to help prevent PDPH. It has been suggested that aspects such as needle tip and gauge can be modified to decrease the incidence of PDPH. OBJECTIVES: To assess the effects of needle tip design (traumatic versus atraumatic) and diameter (gauge) on the prevention of PDPH in participants who have undergone dural puncture for diagnostic or therapeutic causes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and LILACS, as well as trial registries via the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal in September 2016. We adopted the MEDLINE strategy for searching the other databases. The search terms we used were a combination of thesaurus-based and free-text terms for both interventions (lumbar puncture in neurological, anaesthesia or myelography settings) and headache. SELECTION CRITERIA: We included randomized controlled trials (RCTs) conducted in any clinical/research setting where dural puncture had been used in participants of all ages and both genders, which compared different tip designs or diameters for prevention of PDPH DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 70 studies in the review; 66 studies with 17,067 participants were included in the quantitative analysis. An additional 18 studies are awaiting classification and 12 are ongoing. Fifteen of the 18 studies awaiting classification mainly correspond to congress summaries published before 2010, in which the available information does not allow the complete evaluation of all their risks of bias and characteristics. Our main outcome was prevention of PDPH, but we also assessed the onset of severe PDPH, headache in general and adverse events. The quality of evidence was moderate for most of the outcomes mainly due to risk of bias issues. For the analysis, we undertook three main comparisons: 1) traumatic needles versus atraumatic needles; 2) larger gauge traumatic needles versus smaller gauge traumatic needles; and 3) larger gauge atraumatic needles versus smaller gauge atraumatic needles. For each main comparison, if data were available, we performed a subgroup analysis evaluating lumbar puncture indication, age and posture.For the first comparison, the use of traumatic needles showed a higher risk of onset of PDPH compared to atraumatic needles (36 studies, 9378 participants, risk ratio (RR) 2.14, 95% confidence interval (CI) 1.72 to 2.67, I2 = 9%).In the second comparison of traumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH, with the exception of one study comparing 26 and 27 gauge needles (one study, 658 participants, RR 6.47, 95% CI 2.55 to 16.43).In the third comparison of atraumatic needles, studies comparing various sizes of large and small gauges showed no significant difference in effects in terms of risk of PDPH.We observed no significant difference in the risk of paraesthesia, backache, severe PDPH and any headache between traumatic and atraumatic needles. Sensitivity analyses of PDPH results between traumatic and atraumatic needles omitting high risk of bias studies showed similar results regarding the benefit of atraumatic needles in the prevention of PDPH (three studies, RR 2.78, 95% CI 1.26 to 6.15; I2 = 51%). AUTHORS' CONCLUSIONS: There is moderate-quality evidence that atraumatic needles reduce the risk of post-dural puncture headache (PDPH) without increasing adverse events such as paraesthesia or backache. The studies did not report very clearly on aspects related to randomization, such as random sequence generation and allocation concealment, making it difficult to interpret the risk of bias in the included studies. The moderate quality of the evidence for traumatic versus atraumatic needles suggests that further research is likely to have an important impact on our confidence in the estimate of effect.

Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search. SELECTION CRITERIA: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality. AUTHORS' CONCLUSIONS: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

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.

Sun protection for preventing basal cell and squamous cell skin cancers.

BACKGROUND: 'Keratinocyte cancer' is now the preferred term for the most commonly identified skin cancers basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which were previously commonly categorised as non-melanoma skin cancers (NMSC). Keratinocyte cancer (KC) represents about 95% of malignant skin tumours. Lifestyle changes have led to increased exposure to the sun, which has, in turn, led to a significant increase of new cases of KC, with a worldwide annual incidence of between 3% and 8%. The successful use of preventive measures could mean a significant reduction in the resources used by health systems, compared with the high cost of the treatment of these conditions. At present, there is no information about the quality of the evidence for the use of these sun protection strategies with an assessment of their benefits and risks. OBJECTIVES: To assess the effects of sun protection strategies (i.e. sunscreen and barrier methods) for preventing keratinocyte cancer (that is, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) of the skin) in the general population. SEARCH METHODS: We searched the following databases up to May 2016: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registries and the bibliographies of included studies for further references to relevant trials. SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) of preventive strategies for keratinocyte cancer, such as physical barriers and sunscreens, in the general population (children and adults), which may provide information about benefits and adverse events related to the use of solar protection measures. We did not include trials focused on educational strategies to prevent KC or preventive strategies in high-risk groups. Our prespecified primary outcomes were BCC or cSCC confirmed clinically or by histopathology at any follow-up and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility using Early Review Organizing Software (EROS). Similarly, two review authors independently used predesigned data collection forms to extract information from the original study reports about the participants, methods of randomisation, blinding, comparisons of interest, number of participants originally randomised by arm, follow-up losses, and outcomes, and they assessed the risk of bias. We resolved any disagreement by consulting a third author and contacted trial investigators of identified trials to obtain additional information. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one RCT (factorial design) that randomised 1621 participants.This study compared the daily application of sunscreen compared with discretionary use of sunscreen, with or without beta-carotene administration, in the general population. The study was undertaken in Australia; 55.2% of participants had fair skin, and they were monitored for 4.5 years for new cases of BCC or cSCC assessed by histopathology. We found this study to be at low risk of bias for domains such as allocation, blinding, and incomplete outcome data. However, we found multiple unclear risks related to other biases, including an unclear assessment of possible interactions between the effects of the different interventions evaluated (that is, sunscreen and beta-carotene). We found no difference in terms of the number of participants developing BCC (n = 1621; risk ratio (RR) 1.03, 95% confidence interval (CI) 0.74 to 1.43) or cSCC (n = 1621; RR 0.88, 95% CI 0.50 to 1.54) when comparing daily application of sunscreen with discretionary use, even when analyses were restricted to groups without beta-carotene supplementation. This evidence was of low quality, which means that there is some certainty that future studies may alter our confidence in this evidence.We reported adverse events in a narrative way and included skin irritation or contact allergy.We identified no studies that evaluated other sun protection measures, such as the use of sun-protective clothing, sunglasses, or hats, or seeking the shade when outdoors. AUTHORS' CONCLUSIONS: In this review, we assessed the effect of solar protection in preventing the occurrence of new cases of keratinocyte cancer. We only found one study that was suitable for inclusion. This was a study of sunscreens, so we were unable to assess any other forms of sun protection. The study addressed our prespecified primary outcomes, but not most of our secondary outcomes. We were unable to demonstrate from the available evidence whether sunscreen was effective for the prevention of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (cSCC).Our certainty in the evidence was low because there was a lack of histopathological confirmation of BCC or cSCC in a significant percentage of cases. Amongst other sources of bias, it was not clear whether the study authors had assessed any interaction effects between the sunscreen and beta-carotene interventions. We think that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Leukoreduction for the prevention of adverse reactions from allogeneic blood transfusion.

BACKGROUND: A blood transfusion is an acute intervention, implemented to solve life and health-threatening conditions on a short-term basis. However, blood transfusions have adverse events, some of them potentially related to immune modulation or to a direct transmission of infectious agents (e.g. cytomegalovirus). Leukoreduction is a process in which the white blood cells are intentionally reduced in packed red blood cells (PRBCs) in order to reduce the risk of adverse reactions. The potential benefits of leukoreduced PRBCs in all types of transfused patients for decreasing infectious and non-infectious complications remain unclear. OBJECTIVES: To determine the clinical effectiveness of leukoreduction of packed red blood cells for preventing adverse reactions following allogeneic blood transfusion. SEARCH METHODS: We ran the most recent search on 10th November 2015. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), MEDLINE (OvidSP), Embase(OvidSP), CINAHL Plus (EBSCO), LILACS (BIREME), and clinical trials registers. In addition, we checked the reference lists of all relevant trials and reviews identified in the literature searches. SELECTION CRITERIA: Randomised clinical trials including patients of all ages requiring PRBC allogeneic transfusion. Any study was eligible for inclusion, regardless of the length of participant follow-up or country where the study was performed. The primary outcome was transfusion-related acute lung injury (TRALI). Secondary outcomes were death from any cause, infection from any cause, non-infectious complications and any other adverse event. DATA COLLECTION AND ANALYSIS: At least two review authors independently performed study selection, 'Risk of bias' assessments and data extraction. We estimated pooled relative risk for dichotomous outcomes, and we measured statistical heterogeneity using I² statistic. The random-effects model was used to synthesise results. We conducted a trial sequential analysis to assess the risk of random errors in cumulative meta-analyses. MAIN RESULTS: Thirteen studies, most including adult patients, met the eligibility criteria. We found no clear evidence of an effect of leukoreduced PRBC versus non-leukoreduced PRBC in patients that were randomised to receive transfusion for the following outcomes: TRALI: RR 0.96, 95% CI 0.67 to 1.36, P = 0.80 from one trial reporting data on 1864 trauma patients. The accrued information of 1864 participants constituted only 28.5% of the diversity-adjusted required information size (DARIS) of 6548 participants. The quality of evidence was low. Death from any cause: RR 0.81, 95% CI 0.58 to 1.12, I² statistic = 63%, P = 0.20 from nine trials reporting data on 6485 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6485 participants constituted only 55.3% of the DARIS of 11,735 participants. The quality of evidence was very low. Infection from any cause: RR 0.80, 95% CI 0.62 to 1.03, I² statistic = 84%, P = 0.08 from 10 trials reporting data on 6709 cardiovascular surgical patients, gastro-oncology surgical patients, trauma patients and HIV infected patients. The accrued information of 6709 participants constituted only 60.6% of the DARIS of 11,062 participants. The quality of evidence was very low. Adverse events: The only adverse event reported as an adverse event was fever (RR 0.81, 95% CI 0.64 to 1.02; I² statistic= 0%, P = 0.07). Fever was reported in two trials on 634 cardiovascular surgical and gastro-oncology surgical patients. The accrued information of 634 participants constituted only 84.4% of the DARIS of 751 participants. The quality of evidence was low. Incidence of other non-infectious complications: This outcome was not assessed in any included trial. AUTHORS' CONCLUSIONS: There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI, death, infection, non-infectious complications and other adverse events. As the quality of evidence is very low to low, more evidence is needed before a definitive conclusion can be drawn.

Mini-Mental State Examination (MMSE) for the detection of Alzheimer's disease and other dementias 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 diagnostic accuracy of the MMSE at various thresholds for detecting individuals with baseline MCI who would clinically convert to dementia in general, Alzheimer's disease dementia or other forms of dementia at follow-up. 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.

Diagnostic tools for alzheimer's disease dementia and other dementias: an overview of diagnostic test accuracy (DTA) systematic reviews.

BACKGROUND: Dementia includes a group of neurodegenerative disorders characterized by progressive loss of cognitive function and a decrease in the ability to perform activities of daily living. Systematic reviews of diagnostic test accuracy (DTA) focus on how well the index test detects patients with the disease in terms of figures such as sensitivity and specificity. Although DTA reviews about dementia are essential, at present there is no information about their quantity and quality. METHODS: We searched for DTA reviews in MEDLINE (1966-2013), EMBASE (1980-2013), The Cochrane Library (from its inception until December 2013) and the Database of Abstracts of Reviews of Effects (DARE). Two reviewers independently assessed the methodological quality of the reviews using the AMSTAR measurement tool, and the quality of the reporting using the PRISMA checklist. We describe the main characteristics of these reviews, including basic characteristics, type of dementia, and diagnostic test evaluated, and we summarize the AMSTAR and PRISMA scores. RESULTS: We selected 24 DTA systematic reviews. Only 10 reviews (41.6%), assessed the bias of included studies and few (33%) used this information to report the review results or to develop their conclusions Only one review (4%) reported all methodological items suggested by the PRISMA tool. Assessing methodology quality by means of the AMSTAR tool, we found that six DTA reviews (25%) pooled primary data with the aid of methods that are used for intervention reviews, such as Mantel-Haenszel and separate random-effects models (25%), while five reviews (20.8%) assessed publication bias by means of funnel plots and/or Egger's Test. CONCLUSIONS: Our assessment of these DTA reviews reveals that their quality, both in terms of methodology and reporting, is far from optimal. Assessing the quality of diagnostic evidence is fundamental to determining the validity of the operating characteristics of the index test and its usefulness in specific settings. The development of high quality DTA systematic reviews about dementia continues to be a challenge.

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. Therefore, it is necessary to take preventive measures to avoid this complication. Prolonged bed rest has been used as a therapeutic measure once PDPH has started, but it is unknown if it can be 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. 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 Controlled Trials Register, MEDLINE, EMBASE, and LILACS up to June 2013. SELECTION CRITERIA: We identified randomized controlled trials (RCTs) that compared the effects of bed rest versus early/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 solved 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. MAIN RESULTS: We included 23 trials (2477 participants) in this review. There was no beneficial effect associated with bed rest compared with immediate mobilization on the incidence of PDPH (risk for bed rest 26.4%; risk for mobilization 20.5%; risk ratio (RR) 1.30; 95% confidence interval (CI) 1.09 to 1.55), severe PDPH (risk for bed rest 10.6%; risk for mobilization 10.7%; RR 1.00; 95% CI 0.75 to 1.32), and presence of any headache after lumbar puncture (risk for bed rest 33.6%; risk for mobilization 28.6%; RR 1.18; 95% CI 1.05 to 1.32). Analyses restricted to the most methodologically rigorous trials gave similar results. Likewise, the two trials that assessed fluid supplementation did not find this preventive measure to be useful in the prevention of PDPH. AUTHORS' CONCLUSIONS: There is no evidence from RCTs that suggests 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.