European Stroke Organisation (ESO) guideline on screening for subclinical atrial fibrillation after stroke or transient ischaemic attack of undetermined origin

We aimed to provide practical recommendations for the screening of subclinical atrial fibrillation (AF) in patients with ischaemic stroke or transient ischaemic attack (TIA) of undetermined origin. These guidelines are based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Five relevant Population, Intervention, Comparator, Outcome questions were defined by a multidisciplinary module working group (MWG). Longer duration of cardiac rhythm monitoring increases the detection of subclinical AF, but the optimal monitoring length is yet to be defined. We advise longer monitoring to increase the rate of anticoagulation, but whether longer monitoring improves clinical outcomes needs to be addressed. AF detection does not differ from in- or out-patient ECG-monitoring with similar monitoring duration, so we consider it reasonable to initiate in-hospital monitoring as soon as possible and continue with outpatient monitoring for more than 48 h. Although insertable loop recorders (ILR) increase AF detection based on their longer monitoring duration, comparison with non-implantable ECG devices for similar monitoring time is lacking. We suggest the use of implantable devices, if feasible, for AF detection instead of non-implantable devices to increase the detection of subclinical AF. There is weak evidence of a useful role for blood, ECG and brain imaging biomarkers for the identification of patients at high risk of AF. In patients with patent foramen ovale, we found insufficient evidence from RCT, but prolonged cardiac monitoring in patients >55 years is advisable for subclinical AF detection. To conclude, in adult patients with ischaemic stroke or TIA of undetermined origin, we recommend longer duration of cardiac rhythm monitoring of more than 48 h and if feasible with IRL to increase the detection of subclinical AF

Prophylaxis against covid-19: living systematic review and network meta-analysis

Abstract Objective To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. Design Living systematic review and network meta-analysis. Data sources World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021. Study selection Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. Methods Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. Results The first iteration of this living network meta-analysis includes nine randomised trials—six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. Conclusions Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. Systematic review registration This review was not registered. The protocol established a priori is included as a supplement. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. </jats:sec

A living WHO guideline on drugs to prevent covid-19

Abstract Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. Recommendation The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the new recommendation The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity. </jats:sec

Drug treatments for covid-19: living systematic review and network meta-analysis

Abstract Objective To compare the effects of treatments for coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 12 February 2021 were included in the analysis. Study selection Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. Results 196 trials enrolling 76 767 patients were included; 111 (56.6%) trials and 35 098 (45.72%) patients are new from the previous iteration; 113 (57.7%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, corticosteroids probably reduce death (risk difference 20 fewer per 1000 patients, 95% credible interval 36 fewer to 3 fewer, moderate certainty), mechanical ventilation (25 fewer per 1000, 44 fewer to 1 fewer, moderate certainty), and increase the number of days free from mechanical ventilation (2.6 more, 0.3 more to 5.0 more, moderate certainty). Interleukin-6 inhibitors probably reduce mechanical ventilation (30 fewer per 1000, 46 fewer to 10 fewer, moderate certainty) and may reduce length of hospital stay (4.3 days fewer, 8.1 fewer to 0.5 fewer, low certainty), but whether or not they reduce mortality is uncertain (15 fewer per 1000, 30 fewer to 6 more, low certainty). Janus kinase inhibitors may reduce mortality (50 fewer per 1000, 84 fewer to no difference, low certainty), mechanical ventilation (46 fewer per 1000, 74 fewer to 5 fewer, low certainty), and duration of mechanical ventilation (3.8 days fewer, 7.5 fewer to 0.1 fewer, moderate certainty). The impact of remdesivir on mortality and most other outcomes is uncertain. The effects of ivermectin were rated as very low certainty for all critical outcomes, including mortality. In patients with non-severe disease, colchicine may reduce mortality (78 fewer per 1000, 110 fewer to 9 fewer, low certainty) and mechanical ventilation (57 fewer per 1000, 90 fewer to 3 more, low certainty). Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to reduce risk of death or have an effect on any other patient-important outcome. The certainty in effects for all other interventions was low or very low. Conclusion Corticosteroids and interleukin-6 inhibitors probably confer important benefits in patients with severe covid-19. Janus kinase inhibitors appear to have promising benefits, but certainty is low. Azithromycin, hydroxychloroquine, lopinavir-ritonavir, and interferon-beta do not appear to have any important benefits. Whether or not remdesivir, ivermectin, and other drugs confer any patient-important benefit remains uncertain. Systematic review registration This review was not registered. The protocol is publicly available in the supplementary material. Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fourth version of the original article published on 30 July 2020 ( BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity. </jats:sec

Evidence Synthesis and Evaluation in Nutrition

Chronic non-communicable diseases affect a large proportion of the population and are associated with significant morbidity, mortality, and social and economic impact. Large cohort and modelling studies estimate that a substantial proportion of these conditions can be attributed to dietary habits. Clinicians, guideline developers, policymakers, and researchers use systematic reviews that address the relationship between dietary exposures and health outcomes to advise the public on optimal dietary habits, formulate recommendations and policies, and plan future research. A growing body of evidence, however, suggests that there are serious problems with current methods for evidence synthesis and evaluation in nutrition, examples of which include overreliance on expert opinion and consensus, failure to follow standard systematic review methods, and the application of inconsistent criteria for the assessment of the certainty of evidence. These issues have led to ineffective (at best) or harmful (at worst) dietary recommendations and policies and the proliferation of research that cannot be confidently applied to guide dietary decisions. The objective of this thesis is to advance methods for evidence synthesis and evaluation in nutrition. The thesis begins by reviewing contemporary challenges in evidence synthesis and evaluation for dietary guideline development and offering novel insight on opportunities for future improvement. The thesis subsequently provides a descriptive analysis of limitations of recently published systematic reviews and meta-analyses of nutritional epidemiology studies. This thesis then presents two systematic reviews and meta-analyses addressing the health effects of red and processed meat consumption that serve as examples of the application of rigorous systematic review methods in nutrition. This thesis ends by describing opportunities and challenges for future evidence synthesis and evaluation in nutrition.ThesisDoctor of Science (PhD

Fused Filament Fabrication (FFF) for Manufacturing of Microfluidic Micromixers: An Experimental Study on the Effect of Process Variables in Printed Microfluidic Micromixers

The need for accessible and inexpensive microfluidic devices requires new manufacturing methods and materials as a replacement for traditional soft lithography and polydimethylsiloxane (PDMS). Recently, with the advent of modern additive manufacturing (AM) techniques, 3D printing has attracted attention for its use in the fabrication of microfluidic devices and due to its automated, assembly-free 3D fabrication, rapidly decreasing cost, and fast-improving resolution and throughput. Here, fused filament fabrication (FFF) 3D printing was used to create microfluidic micromixers and enhance the mixing process, which has been identified as a challenge in microfluidic devices. A design of experiment (DoE) was performed on the effects of studied parameters in devices that were printed by FFF. The results of the colorimetric approach showed the effects of different parameters on the mixing process and on the enhancement of the mixing performance in printed devices. The presence of the geometrical features on the microchannels can act as ridges due to the nature of the FFF process. In comparison to passive and active methods, no complexity was added in the fabrication process, and the ridges are an inherent property of the FFF process.</jats:p

Fused Filament Fabrication (FFF) for Manufacturing of Microfluidic Micromixers: An Experimental Study on the Effect of Process Variables in Printed Microfluidic Micromixers

The need for accessible and inexpensive microfluidic devices requires new manufacturing methods and materials as a replacement for traditional soft lithography and polydimethylsiloxane (PDMS). Recently, with the advent of modern additive manufacturing (AM) techniques, 3D printing has attracted attention for its use in the fabrication of microfluidic devices and due to its automated, assembly-free 3D fabrication, rapidly decreasing cost, and fast-improving resolution and throughput. Here, fused filament fabrication (FFF) 3D printing was used to create microfluidic micromixers and enhance the mixing process, which has been identified as a challenge in microfluidic devices. A design of experiment (DoE) was performed on the effects of studied parameters in devices that were printed by FFF. The results of the colorimetric approach showed the effects of different parameters on the mixing process and on the enhancement of the mixing performance in printed devices. The presence of the geometrical features on the microchannels can act as ridges due to the nature of the FFF process. In comparison to passive and active methods, no complexity was added in the fabrication process, and the ridges are an inherent property of the FFF process