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.

Basal procalcitonin, C-reactive protein, interleukin-6, and presepsin for prediction of mortality in critically ill septic patients: a systematic review and meta-analysis.

BACKGROUND: Numerous biomarkers have been proposed for diagnosis, therapeutic, and prognosis in sepsis. Previous evaluations of the value of biomarkers for predicting mortality due to this life-threatening condition fail to address the complexity of this condition and the risk of bias associated with prognostic studies. We evaluate the predictive performance of four of these biomarkers in the prognosis of mortality through a methodologically sound evaluation. METHODS: We conducted a systematic review a systematic review and meta-analysis to determine, in critically ill adults with sepsis, whether procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), and presepsin (sCD14) are independent prognostic factors for mortality. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to March 2023. Only Phase-2 confirmatory prognostic factor studies among critically ill septic adults were included. Random effects meta-analyses pooled the prognostic association estimates. RESULTS: We included 60 studies (15,681 patients) with 99 biomarker assessments. Quality of the statistical analysis and reporting domains using the QUIPS tool showed high risk of bias in > 60% assessments. The biomarker measurement as a continuous variable in models adjusted by key covariates (age and severity score) for predicting mortality at 28-30 days showed a null or near to null association for basal PCT (pooled OR = 0.99, 95% CI = 0.99-1.003), CRP (OR = 1.01, 95% CI = 0.87 to 1.17), and IL-6 (OR = 1.02, 95% CI = 1.01-1.03) and sCD14 (pooled HR = 1.003, 95% CI = 1.000 to 1.006). Additional meta-analyses accounting for other prognostic covariates had similarly null findings. CONCLUSION: Baseline, isolated measurement of PCT, CRP, IL-6, and sCD14 has not been shown to help predict mortality in critically ill patients with sepsis. The role of these biomarkers should be evaluated in new studies where the patient selection would be standardized and the measurement of biomarker results. TRIAL REGISTRATION: PROSPERO (CRD42019128790).

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 .

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/).

Use of benznidazole to treat chronic Chagas disease: An updated systematic review with a meta-analysis.

BACKGROUND: Approximately 6 million people worldwide are affected by Chagas disease, with many in the chronic phase of the disease (CCD). It is crucial to evaluate the effectiveness of benznidazole for CCD treatment. METHODS/PRINCIPAL FINDINGS: We updated a meta-analysis published in 2009 up to February 2021, including controlled trials (RCT) and prospective observational studies (OBS) that compared benznidazole vs placebo/no-treatment (P/nT). Main outcomes evaluated were clinical progression (CP) and seroreversion with subgroup analysis performed according to study design and participants' age. Parasitological response and safety were also described. We identified 879 articles and selected nine for inclusion (corresponding to eight studies). After adding the nine articles from the previous meta-analysis, 17 studies were analyzed corresponding to 6640 patients. The odds ratio (OR) for seroreversion in children treated with benznidazole vs P/nT was 38.3 (95%CI: 10.7-137) and 34.9 (95%CI: 1.96-624.09) in RCT and OBS, respectively. In adults the OR for seroreversion in OBS was 17.1 (95%CI: 2.3-129.1). CP was only evaluated in adults, where benznidazole did not demonstrate a beneficial effect: OR 0.93 (95%CI: 0.8-1.1) and OR 0.49 (95%CI:0.2-1.2) for RCT and OBS, respectively. Most outcomes were deemed to have a low level of certainty, except for the beneficial effect in children and the low efficacy in adults (moderate certainty). CONCLUSIONS: Benznidazole should be recommended for CCD in children, though this is only based on serological response and a moderate grade of evidence, while in adults benznidazole efficacy remains uncertain. More data on clinical efficacy of benznidazole in CCD is needed in both children and adults.

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.

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.

Recommendations for SARS-CoV-2/COVID-19 testing: a scoping review of current guidance.

BACKGROUND: Testing used in screening, diagnosis and follow-up of COVID-19 has been a subject of debate. Several organisations have developed formal advice about testing for COVID-19 to assist in the control of the disease. We collated, delineated and appraised current worldwide recommendations about the role and applications of tests to control SARS-CoV-2/COVID-19. METHODS: We searched for documents providing recommendations for COVID-19 testing in PubMed, EMBASE, LILACS, the Coronavirus Open Access Project living evidence database and relevant websites such as TRIP database, ECRI Guidelines Trust, the GIN database, from inception to 21 September 2020. Two reviewers applied the eligibility criteria to potentially relevant citations without language or geographical restrictions. We extracted data in duplicate, including assessment of methodological quality using the Appraisal of Guidelines for Research and Evaluation-II tool. RESULTS: We included 47 relevant documents and 327 recommendations about testing. Regarding the quality of the documents, we found that the domains with the lowest scores were 'Editorial independence' (Median=4%) and 'Applicability' (Median=6%). Only six documents obtained at least 50% score for the 'Rigour of development' domain. An important number of recommendations focused on the diagnosis of suspected cases (48%) and deisolation measures (11%). The most frequently recommended test was the reverse transcription-PCR (RT-PCR) assay (87 recommendations) and the chest CT (38 recommendations). There were 22 areas of agreement among guidance developers, including the use of RT-PCR for SARS-Cov-2 confirmation, the limited role of bronchoscopy, the use chest CT and chest X-rays for grading severity and the co-assessment for other respiratory pathogens. CONCLUSION: This first scoping review of recommendations for COVID-19 testing showed many limitations in the methodological quality of included guidance documents that could affect the confidence of clinicians in their implementation. Future guidance documents should incorporate a minimum set of key methodological characteristics to enhance their applicability for decision making.

Adverse events associated with the use of recommended vaccines during pregnancy: An overview of systematic reviews.

INTRODUCTION: Maternal immunization is aimed at reducing morbidity and mortality in pregnant women and their newborns. Updated evidence synthesis of maternal-fetal outcomes is constantly needed to ensure that the risk-benefit of vaccination during pregnancy remains positive. METHODS: An overview of systematic reviews (OoSRs) was performed. We searched The Cochrane Library, MEDLINE and EMBASE for SRs including recommended vaccines for maternal immunization reporting the following: abortion, stillbirth, chorioamnionitis, congenital anomalies, microcephaly, neonatal death, neonatal infection, preterm birth (PTB), low birth weight (LBW), maternal death and small for gestational age (SGA) from 2010 to April 2019. Quality and overlap of SRs was assessed. RESULTS: Seventeen SRs were identified, eight of them included meta-analysis; quality was high in three SRs, moderate in six SRs, low in two SRs, and critically low in six SRs. Stillbirth and PTB were the most frequently reported outcomes by 15 and 13 SRs, respectively, followed by abortion (9 SRs), congenital anomalies (9 SRs), SGA (8 SRs), neonatal death (8 SRs), LBW (4 SRs), chorioamnionitis (3 SRs), maternal death (1 SR). SRs included mainly observational evidence for influenza and Tdap vaccines (11 SRs and 4 SRs, respectively); limited evidence was found for hepatitis (1 SR), yellow fever (1 SR), and meningococcal (1 SR) vaccines. Most of the SRs found no effect. Eight SRs found benefit/protection of influenza vaccine (for stillbirth, neonatal death, preterm birth, LBW), or Tdap vaccine (for preterm birth and SGA); one found a probable risk (chorioamnionitis/Tdap). The SRs for Hepatitis B, meningococcal and yellow fever vaccines were inconclusive. CONCLUSIONS: Definite risks were not identified for any vaccine and outcome; however better evidence is needed for all outcomes and vaccines. The available evidence in the SRs to support vaccine safety was based mainly on observational data. More RCTs with adequate reporting of maternal-fetal outcomes and larger high-quality observational studies are needed.

False-negative results of initial RT-PCR assays for COVID-19: A systematic review.

BACKGROUND: A false-negative case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is defined as a person with suspected infection and an initial negative result by reverse transcription-polymerase chain reaction (RT-PCR) test, with a positive result on a subsequent test. False-negative cases have important implications for isolation and risk of transmission of infected people and for the management of coronavirus disease 2019 (COVID-19). We aimed to review and critically appraise evidence about the rate of RT-PCR false-negatives at initial testing for COVID-19. METHODS: We searched MEDLINE, EMBASE, LILACS, as well as COVID-19 repositories, including the EPPI-Centre living systematic map of evidence about COVID-19 and the Coronavirus Open Access Project living evidence database. Two authors independently screened and selected studies according to the eligibility criteria and collected data from the included studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We calculated the proportion of false-negative test results using a multilevel mixed-effect logistic regression model. The certainty of the evidence about false-negative cases was rated using the GRADE approach for tests and strategies. All information in this article is current up to July 17, 2020. RESULTS: We included 34 studies enrolling 12,057 COVID-19 confirmed cases. All studies were affected by several risks of bias and applicability concerns. The pooled estimate of false-negative proportion was highly affected by unexplained heterogeneity (tau-squared = 1.39; 90% prediction interval from 0.02 to 0.54). The certainty of the evidence was judged as very low due to the risk of bias, indirectness, and inconsistency issues. CONCLUSIONS: There is substantial and largely unexplained heterogeneity in the proportion of false-negative RT-PCR results. The collected evidence has several limitations, including risk of bias issues, high heterogeneity, and concerns about its applicability. Nonetheless, our findings reinforce the need for repeated testing in patients with suspicion of SARS-Cov-2 infection given that up to 54% of COVID-19 patients may have an initial false-negative RT-PCR (very low certainty of evidence). SYSTEMATIC REVIEW REGISTRATION: Protocol available on the OSF website: https://tinyurl.com/vvbgqya.

[Diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders: A systematic review protocol]. / Precisión diagnóstica de biomarcadores salivales para cáncer oral y desórdenes potencialmente malignos: protocolo de revisión sistemática.

INTRODUCTION: Oral cancer has a 5-year survival rate of 50% because diagnosis is commonly performed at an advanced stage of the disease, so new diagnostic tools are needed. Nowadays, there is a vast number of publications suggesting the use of salivary biomarkers for oral cancer and potentially malignant disorders diagnosis, but their diagnostic accuracy is unclear. Thus, the goal of this systematic review is to evaluate the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders. METHODS: This protocol is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). We will include primary studies assessing the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders. Studies must report data about sensitivity and specificity; gold standard must be the histopathology diagnosis. We will search MEDLINE, EMBASE, the Cochrane Library, and gray literature. Two authors will independently select the studies and extract the data. The methodology quality of studies will be determined using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). EXPECTED RESULTS AND CONCLUSION: Our findings will provide information about the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders.

INTRODUCCIÓN: El cáncer oral tiene una tasa de supervivencia a los cinco años de 50%, debido a que frecuentemente su diagnóstico es realizado en estadios avanzados. Por lo tanto, son necesarias nuevas ayudas diagnósticas. Actualmente, existe un número significativo de publicaciones científicas sugiriendo el uso de biomarcadores salivales para el diagnóstico de cáncer oral. Sin embargo, son desconocidas las propiedades diagnósticas de estos biomarcadores. El objetivo de esta revisión sistemática es evaluar la evidencia sobre la precisión diagnóstica de biomarcadores salivales usados en la identificación de cáncer oral y desórdenes potencialmente malignos. MÉTODOS: Este protocolo es reportado en concordancia con el Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). Se incluirán estudios evaluando la precisión diagnóstica de biomarcadores salivales para cáncer oral y desórdenes potencialmente malignos. Estos deberán reportar sensibilidad y especificidad, y utilizar como estándar de referencia un diagnóstico histopatológico. Se realizará una búsqueda en MEDLINE, EMBASE, Cochrane Library y literatura gris. Dos autores independientemente seleccionarán los estudios y extraerán los datos. La calidad metodológica de los estudios será determinada usando The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULTADOS ESPERADOS Y CONCLUSIÓN: Los hallazgos de esta revisión sistemática proporcionarán información acerca de la precisión diagnóstica de los biomarcadores salivales para diagnóstico de cáncer oral y desórdenes potencialmente malignos.

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.

Currículos de salud sexual y reproductiva en programas de educación superior para América Latina / Sexual and reproductive health curricula in higher education programs for Latin America / Grades curriculares de saúde sexual e reprodutiva nos programas de ensino superior para a América Latina

Objetivo: identificar la inclusión de la propuesta temática curricular de la Federación Latinoamericana de Obstetricia y Ginecología (FLASOG) sobre salud sexual y reproductiva en programas de pregrado (Medicina) y posgrado (Obstetricia y Ginecología) en un grupo de universidades e instituciones de educación superior de Latinoamérica y el Caribe. Método: estudio descriptivo de corte transversal en el cual se aplicó una encuesta a universidades de Latinoamérica y El Caribe durante el año 2017 para determinar si los contenidos de los programas con relación a salud sexual y reproductiva corresponden a la propuesta temática de la FLASOG, tanto en pregrado (Medicina) como en posgrado (Obstetricia y Ginecología). Resultados: todos los programas de pregrado evaluados incluyen dentro del currículo los siguientes temas: m étodos anticonceptivos, aborto y morbimortalidad materna y el 36,4 % contemplan salud sexual en la tercera edad. Todos los programas de posgrado evaluados estudian métodos anticonceptivos, anticoncepci ón en posparto y posaborto, morbimortalidad materna, aborto, y maternidad saludable. Solo el 55,6 % de ellos tienen temáticas relacionadas con interrupción voluntaria del embarazo y salud sexual en la tercera edad. Conclusiones: los programas evaluados cuentan con docentes dedicados a educación en salud sexual y reproductiva en sus programas, aunque en la mayoría de las instituciones (76,9 % ) no existe un proceso formal de evaluación y retroalimentación. Todas las universidades que respondieron la encuesta trabajan tres temas en sus contenidos curriculares de pregrado: aborto, anticoncepción y morbimortalidad materna, t ópicos que han sido considerados de alto impacto en la salud sexual y reproductiva de las mujeres. La interrupción voluntaria del embarazo se discute en dos de cada tres universidades que respondieron la encuesta. El tema de salud sexual en la tercera edad no se incluye en los programas.

Objective: to identify if Latin American and Caribbean higher education institutions include in their curriculum the sexual and reproductive health topics proposed by the Latin American Federation of Obstetrics and Gynecology (FLASOG for its acronym in Spanish) in undergraduate and graduate programs. Methods: descriptive, cross sectional study developed in the year 2017. A survey was sent to universities in Latin America and the Caribbean to evaluate if the sexual and reproductive health contents in the curriculum of undergraduate (medicine) and graduate schools (obstetrics and gynecology) correspond to the ones proposed by FLASOG. Results: 100 % of assessed undergraduate programs include the following topics in their curriculum: birth control methods, abortion, maternal morbidity and mortality, and 36.4 % include sexual health in the elderly. 100 % of graduate programs evaluated include: birth control methods, maternal morbidity and mortality, abortion, and healthy maternity, and 55.6 % include legal pregnancy termination and sexual health in the elderly. Conclusions: All the higher education programs evaluated have faculty for sexual and reproductive health, but most institutions (76 .9 % ) do not have a formal process for evaluation and feedback. All the universities include in their undergraduate programs the following topics: abortion, birth control methods and maternal morbidity and mortality, all of which have been considered of high impact in sexual and reproductive health of women. However, topics such as legal termination of pregnancy are only included in two out of three universities evaluated, and sexual health in the elderly is rarely included in the curriculum.

Objetivo: identificar a inclusão da proposta temática da Federação Latino-Americana de Obstetrícia e Ginecologia (FLASOG) em saúde sexual e reprodutiva nos programas de graduação (Medicina) e pós-graduação (Obstetrícia e Ginecologia) em um grupo de universidades e instituições de ensino superior da América Latina e do Caribe. Método: estudo descritivo transversal. Foi aplicado um questionário em programas de cursos de graduação e pós-graduação de universidades da América Latina e do Caribe em 2017, para determinar se o conteúdo dos programas relacionados à saúde sexual e reprodutiva correspondem à proposta temática da FLASOG no nível de graduação (Medicina) e de pós-graduação (Obstetrícia e Ginecologia). Resultados: todos os programas de graduação avaliados incluíram os seguintes tópicos no currículo: métodos contraceptivos, aborto e morbimortalidade materna; ainda, 36,4% dos programas abrangem temas relacionados à saúde sexual nos idosos. Todos os programas de pós-graduação avaliados estudam métodos contraceptivos, contracepção no pós-parto e pós-aborto, morbimortalidade materna, aborto e maternidade saudável. Apenas 55,6% desses programas têm tópicos relacionados à interrupção voluntária da gravidez e sobre a saúde sexual em idosos. Conclusões: os programas avaliados têm professores enfocados na educação da saúde sexual e reprodutiva, embora na maioria das instituições (76,9%) não exista um processo formal de avaliação e feedback. Todas as universidades que responderam à pesquisa trabalham com três tópicos em seu conteúdo curricular de graduação: aborto, contracepção e morbimortalidade materna, considerados de alto impacto na saúde sexual e reprodutiva das mulheres. A interrupção voluntária da gravidez é discutida em uma proporção de duas em cada três universidades que responderam ao questionário. A saúde sexual em idosos não está incluída nos programas

Therapeutic use of cannabis and cannabinoids: an evidence mapping and appraisal of systematic reviews.

BACKGROUND: Although cannabis and cannabinoids are widely used with therapeutic purposes, their claimed efficacy is highly controversial. For this reason, medical cannabis use is a broad field of research that is rapidly expanding. Our objectives are to identify, characterize, appraise, and organize the current available evidence surrounding therapeutic use of cannabis and cannabinoids, using evidence maps. METHODS: We searched PubMed, EMBASE, The Cochrane Library and CINAHL, to identify systematic reviews (SRs) published from their inception up to December 2017. Two authors assessed eligibility and extracted data independently. We assessed methodological quality of the included SRs using the AMSTAR tool. To illustrate the extent of use of medical cannabis, we organized the results according to identified PICO questions using bubble plots corresponding to different clinical scenarios. RESULTS: A total of 44 SRs published between 2001 and 2017 were included in this evidence mapping with data from 158 individual studies. We extracted 96 PICO questions in the following medical conditions: multiple sclerosis, movement disorders (e.g. Tourette Syndrome, Parkinson Disease), psychiatry conditions, Alzheimer disease, epilepsy, acute and chronic pain, cancer, neuropathic pain, symptoms related to cancer (e.g. emesis and anorexia related with chemotherapy), rheumatic disorders, HIV-related symptoms, glaucoma, and COPD. The evidence about these conditions is heterogeneous regarding the conclusions and the quality of the individual primary studies. The quality of the SRs was moderate to high according to AMSTAR scores. CONCLUSIONS: Evidence on medical uses of cannabis is broad. However, due to methodological limitations, conclusions were weak in most of the assessed comparisons. Evidence mapping methodology is useful to perform an overview of available research, since it is possible to systematically describe the extent and distribution of evidence, and to organize scattered data.

GRADE Guidelines 28: Use of GRADE for the assessment of evidence about prognostic factors: rating certainty in identification of groups of patients with different absolute risks.

OBJECTIVE: The objective of this study was to provide guidance on the use of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to determine certainty in estimates of association between prognostic factors and future outcomes. STUDY DESIGN AND SETTING: We developed our guidance through an iterative process that involved review of published systematic reviews and meta-analyses of prognostic factors, consultation with members, feedback, presentation, and discussion at the GRADE Working Group meetings. RESULTS: For questions of prognosis, a body of observational evidence (potentially including patients enrolled in randomized controlled trials) begins as high certainty in the evidence. The five domains of GRADE for rating down certainty in the evidence, that is, risk of bias, imprecision, inconsistency, indirectness, and publication bias, as well as the domains for rating up, also apply to estimates of associations between prognostic factors and outcomes. One should determine if their ratings do not consider (noncontextualized) or consider (contextualized) the clinical context as this will may result in variable judgments on certainty of the evidence. CONCLUSIONS: The same principles GRADE proposed for bodies of evidence addressing treatment and overall prognosis work well in assessing individual prognostic factors, both in noncontextualized and contextualized settings.

Defining ranges for certainty ratings of diagnostic accuracy: a GRADE concept paper.

OBJECTIVE: The objective of the study was to clarify how the Grading of Recommendations Assessment, Development and Evaluation (GRADE) concept of certainty of evidence applies to certainty ratings of test accuracy. STUDY DESIGN AND SETTING: After initial brainstorming with GRADE Working Group members, we iteratively refined and clarified the approaches for defining ranges when assessing the certainty of evidence for test accuracy within a systematic review, health technology assessment, or guideline. RESULTS: Ranges can be defined both for single test accuracy and for comparative accuracy of multiple tests. For systematic reviews and health technology assessments, approaches for defining ranges include some that do not require value judgments regarding downstream health outcomes. Key challenges arise in the context of a guideline that requires ranges for sensitivity and specificity that are set considering possible effects on all critical outcomes. We illustrate possible approaches and provide an example from a systematic review of a direct comparison between two test strategies. CONCLUSIONS: This GRADE concept paper provides a framework for assessing, presenting, and making decisions based on the certainty of evidence for test accuracy. More empirical research is needed to support future GRADE guidance on how to best operationalize the candidate approaches.

Precisión diagnóstica de biomarcadores salivales para cáncer oral y desórdenes potencialmente malignos: protocolo de revisión sistemática / Diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders: a systematic review protocol

INTRODUCCIÓN: El cáncer oral tiene una tasa de supervivencia a los cinco años de 50%, debido a que frecuentemente su diagnóstico es realizado en estadios avanzados. Por lo tanto, son necesarias nuevas ayudas diagnósticas. Actualmente, existe un número significativo de publicaciones científicas sugiriendo el uso de biomarcadores salivales para el diagnóstico de cáncer oral. Sin embargo, son desconocidas las propiedades diagnósticas de estos biomarcadores. El objetivo de esta revisión sistemática es evaluar la evidencia sobre la precisión diagnóstica de biomarcadores salivales usados en la identificación de cáncer oral y desórdenes potencialmente malignos. MÉTODOS: Este protocolo es reportado en concordancia con el Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). Se incluirán estudios evaluando la precisión diagnóstica de biomarcadores salivales para cáncer oral y desórdenes potencialmente malignos. Estos deberán reportar sensibilidad y especificidad, y utilizar como estándar de referencia un diagnóstico histopatológico. Se realizará una búsqueda en MEDLINE, EMBASE, Cochrane Library y literatura gris. Dos autores independientemente seleccionarán los estudios y extraerán los datos. La calidad metodológica de los estudios será determinada usando The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). RESULTADOS ESPERADOS Y CONCLUSIÓN: Los hallazgos de esta revisión sistemática proporcionarán información acerca de la precisión diagnóstica de los biomarcadores salivales para diagnóstico de cáncer oral y desórdenes potencialmente malignos.

INTRODUCTION: Oral cancer has a 5-year survival rate of 50% because diagnosis is commonly performed at an advanced stage of the disease, so new diagnostic tools are needed. Nowadays, there is a vast number of publications suggesting the use of salivary biomarkers for oral cancer and potentially malignant disorders diagnosis, but their diagnostic accuracy is unclear. Thus, the goal of this systematic review is to evaluate the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders. METHODS: This protocol is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). We will include primary studies assessing the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders. Studies must report data about sensitivity and specificity; gold standard must be the histopathology diagnosis. We will search MEDLINE, EMBASE, the Cochrane Library, and gray literature. Two authors will independently select the studies and extract the data. The methodology quality of studies will be determined using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). EXPECTED RESULTS AND CONCLUSION: Our findings will provide information about the diagnostic accuracy of salivary biomarkers for oral cancer and potentially malignant disorders.

Rapid reviews of medical tests used many similar methods to systematic reviews but key items were rarely reported: a scoping review.

BACKGROUND AND OBJECTIVES: Rapid reviews provide an efficient alternative to standard systematic reviews in response to a high priority or urgent need. Although rapid reviews of interventions have been extensively evaluated, little is known about the characteristics of rapid reviews of diagnostic evidence. STUDY DESIGN AND SETTING: We performed a scoping review for rapid reviews of medical tests published from 2013 to 2018. We extracted information on review characteristics and methods used to assess the evidence. RESULTS: We identified 191 rapid reviews. All reviews were developed within a short time (less than 12 months) and were relatively concise (less than 10 pages). The reviews involved multiple index tests (44%), multiple outcomes (88%), and several test applications (29%). Well-known methodological tailoring strategies were infrequently used. Although reporting of several key features was limited, we found that, in general, rapid reviews have similar characteristics to broader knowledge syntheses. CONCLUSION: Our scoping review is the first to describe the characteristics and methods of rapid reviews of diagnostic evidence. Future research should identify the most appropriate methods for performing rapid reviews of medical tests. Standards for reporting of rapid reviews are needed.

Challenges of rapid reviews for diagnostic test accuracy questions: a protocol for an international survey and expert consultation.

BACKGROUND: Assessment of diagnostic tests, broadly defined as any element that aids in the collection of additional information for further clarification of a patient's health status, has increasingly become a critical issue in health policy and decision-making. Diagnostic evidence, including the accuracy of a medical test for a target condition, is commonly appraised using standard systematic review methodology. Owing to the considerable time and resources required to conduct these, rapid reviews have emerged as a pragmatic alternative by tailoring methods according to the decision maker's circumstances. However, it is not known if streamlining methodological aspects has an impact on the validity of evidence synthesis. Furthermore, due to the particular nature and complexity of the appraisal of diagnostic accuracy, there is need for detailed guidance on how to conduct rapid reviews of diagnostic tests. In this study, we aim to identify the methods currently used by rapid review developers to synthesize evidence on diagnostic test accuracy, as well as to analyze potential shortcomings and challenges related to these methods. METHODS: We will carry out a two-fold approach: (1) an international survey of professionals working in organizations that develop rapid reviews of diagnostic tests, in terms of the methods and resources used by these agencies when conducting rapid reviews, and (2) semi-structured interviews with senior-level individuals to further explore and validate the findings from the survey and to identify challenges in conducting rapid reviews. We will use STATA 15.0 for quantitative analyses and framework analysis for qualitative analyses. We will ensure protection of data during all stages. DISCUSSION: The main result of this research will be a map of methods and resources currently used for conducting rapid reviews of diagnostic test accuracy, as well as methodological shortcomings and potential solutions in diagnostic knowledge synthesis that require further research.

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.