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Annals of the American Thoracic Society Jun 2022The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical... (Meta-Analysis)
Meta-Analysis
The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD). To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic pirfenidone. A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using pirfenidone to treat patients with PPF. Mortality, disease progression, lung function, and adverse event data were extracted. Meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group approach was used to assess the quality of evidence. Two studies met inclusion criteria. Meta-analyses revealed that changes in forced vital capacity (FVC) percent predicted (mean difference [MD], 2.3%; 95% confidence interval [CI], 0.5-4.1%), the FVC in milliliters (MD, 100.0 ml; 95% CI, 98.1-101.9 ml), and the 6-minute-walk distance in meters (MD, 25.2 m; 95% CI, 8.3-42.1 m) all favored pirfenidone over placebo. The changes in the diffusing capacity of the lung for carbon monoxide (DLCO) in millimoles per kilopascal per minute (MD, 0.40 mmol/kPa/min; 95%, CI 0.10-0.70 mmol/kPa/min) and risk of DLCO declining more than 15% (relative risk [RR], 0.27; 95% CI, 0.08-0.95) also favored pirfenidone. The risks of gastrointestinal discomfort (RR, 1.83; 95% CI, 1.29-2.60) and photosensitivity (RR, 4.88; 95% CI, 1.09-21.83) were higher with pirfenidone. The quality of the evidence was low or very low according to the Grading of Recommendations, Assessment, Development and Evaluation criteria, depending on the outcome. Pirfenidone use in patients with PPF is associated with a statistically significant decrease in disease progression and with protection of lung function. However, there is very low certainty in the estimated effects because of limitations in the available evidence. Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.
Topics: Disease Progression; Humans; Lung Diseases, Interstitial; Pulmonary Fibrosis; Pyridones
PubMed: 35499847
DOI: 10.1513/AnnalsATS.202103-342OC -
The Journal of Allergy and Clinical... Nov 2022The comparative safety and efficacy of the biologics currently approved for asthma are unclear. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The comparative safety and efficacy of the biologics currently approved for asthma are unclear.
OBJECTIVE
We compared the safety and efficacy of mepolizumab, benralizumab, and dupilumab in individuals with severe eosinophilic asthma.
METHODS
We performed a systematic review of peer-reviewed literature published 2000 to 2021. We studied Bayesian network meta-analyses of exacerbation rates, prebronchodilator FEV, the Asthma Control Questionnaire, and serious adverse events in individuals with eosinophilic asthma.
RESULTS
Eight randomized clinical trials (n = 6461) were identified. We found in individuals with eosinophils ≥300 cells/μL the following: in reducing exacerbation rates compared to placebo: dupilumab (risk ratio [RR], 0.32; 95% credible interval [CI], 0.23 to 0.45), mepolizumab (RR, 0.37; 95% CI, 0.30 to 0.45), and benralizumab (RR, 0.49; 95% CI, 0.43 to 0.55); in improving FEV: dupilumab (mean difference in milliliters [MD] 230; 95% CI, 160 to 300), benralizumab (MD, 150; 95% CI, 100 to 200), and mepolizumab (MD, 150; 95% CI, 66 to 220); and in reducing Asthma Control Questionnaire scores: mepolizumab (MD, -0.63; 95% CI, -0.81 to -0.45), dupilumab (MD, -0.48; 95% CI, -0.83 to -0.14), and benralizumab (MD, -0.32; 95% CI, -0.43 to -0.21). In individuals with eosinophils 150-299 cells/μL, benralizumab (RR, 0.62; 95% CI, 0.52 to 0.73) and dupilumab (RR, 0.60; 95% CI, 0.38 to 0.95) were associated with lower exacerbation rates; and only benralizumab (MD, 81; 95% CI, 8 to 150) significantly improved FEV. These differences were minimal compared to clinically important thresholds. For serious adverse events in the overall population, mepolizumab (odds ratio, 0.67; 95% CI, 0.48 to 0.92) and benralizumab (odds ratio, 0.74; 95% CI, 0.59 to 0.93) were associated with lower odds of a serious adverse event, while dupilumab was not different from placebo (odds ratio, 1.0; 95% CI, 0.74 to 1.4).
CONCLUSION
There are minimal differences in the efficacy and safety of mepolizumab, benralizumab, and dupilumab in eosinophilic asthma.
Topics: Humans; Network Meta-Analysis; Bayes Theorem; Asthma; Pulmonary Eosinophilia; Eosinophils; Anti-Asthmatic Agents
PubMed: 35772597
DOI: 10.1016/j.jaci.2022.05.024 -
The Cochrane Database of Systematic... Feb 2022Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Description of the condition Malaria, an infectious disease transmitted by the bite of female mosquitoes from several Anopheles species, occurs in 87 countries with ongoing transmission (WHO 2020). The World Health Organization (WHO) estimated that, in 2019, approximately 229 million cases of malaria occurred worldwide, with 94% occurring in the WHO's African region (WHO 2020). Of these malaria cases, an estimated 409,000 deaths occurred globally, with 67% occurring in children under five years of age (WHO 2020). Malaria also negatively impacts the health of women during pregnancy, childbirth, and the postnatal period (WHO 2020). Sulfadoxine/pyrimethamine (SP), an antifolate antimalarial, has been widely used across sub-Saharan Africa as the first-line treatment for uncomplicated malaria since it was first introduced in Malawi in 1993 (Filler 2006). Due to increasing resistance to SP, in 2000 the WHO recommended that one of several artemisinin-based combination therapies (ACTs) be used instead of SP for the treatment of uncomplicated malaria caused by Plasmodium falciparum (Global Partnership to Roll Back Malaria 2001). However, despite these recommendations, SP continues to be advised for intermittent preventive treatment in pregnancy (IPTp) and intermittent preventive treatment in infants (IPTi), whether the person has malaria or not (WHO 2013). Description of the intervention Folate (vitamin B9) includes both naturally occurring folates and folic acid, the fully oxidized monoglutamic form of the vitamin, used in dietary supplements and fortified food. Folate deficiency (e.g. red blood cell (RBC) folate concentrations of less than 305 nanomoles per litre (nmol/L); serum or plasma concentrations of less than 7 nmol/L) is common in many parts of the world and often presents as megaloblastic anaemia, resulting from inadequate intake, increased requirements, reduced absorption, or abnormal metabolism of folate (Bailey 2015; WHO 2015a). Pregnant women have greater folate requirements; inadequate folate intake (evidenced by RBC folate concentrations of less than 400 nanograms per millilitre (ng/mL), or 906 nmol/L) prior to and during the first month of pregnancy increases the risk of neural tube defects, preterm delivery, low birthweight, and fetal growth restriction (Bourassa 2019). The WHO recommends that all women who are trying to conceive consume 400 micrograms (µg) of folic acid daily from the time they begin trying to conceive through to 12 weeks of gestation (WHO 2017). In 2015, the WHO added the dosage of 0.4 mg of folic acid to the essential drug list (WHO 2015c). Alongside daily oral iron (30 mg to 60 mg elemental iron), folic acid supplementation is recommended for pregnant women to prevent neural tube defects, maternal anaemia, puerperal sepsis, low birthweight, and preterm birth in settings where anaemia in pregnant women is a severe public health problem (i.e. where at least 40% of pregnant women have a blood haemoglobin (Hb) concentration of less than 110 g/L). How the intervention might work Potential interactions between folate status and malaria infection The malaria parasite requires folate for survival and growth; this has led to the hypothesis that folate status may influence malaria risk and severity. In rhesus monkeys, folate deficiency has been found to be protective against Plasmodium cynomolgi malaria infection, compared to folate-replete animals (Metz 2007). Alternatively, malaria may induce or exacerbate folate deficiency due to increased folate utilization from haemolysis and fever. Further, folate status measured via RBC folate is not an appropriate biomarker of folate status in malaria-infected individuals since RBC folate values in these individuals are indicative of both the person's stores and the parasite's folate synthesis. A study in Nigeria found that children with malaria infection had significantly higher RBC folate concentrations compared to children without malaria infection, but plasma folate levels were similar (Bradley-Moore 1985). Why it is important to do this review The malaria parasite needs folate for survival and growth in humans. For individuals, adequate folate levels are critical for health and well-being, and for the prevention of anaemia and neural tube defects. Many countries rely on folic acid supplementation to ensure adequate folate status in at-risk populations. Different formulations for folic acid supplements are available in many international settings, with dosages ranging from 400 µg to 5 mg. Evaluating folic acid dosage levels used in supplementation efforts may increase public health understanding of its potential impacts on malaria risk and severity and on treatment failures. Examining folic acid interactions with antifolate antimalarial medications and with malaria disease progression may help countries in malaria-endemic areas determine what are the most appropriate lower dose folic acid formulations for at-risk populations. The WHO has highlighted the limited evidence available and has indicated the need for further research on biomarkers of folate status, particularly interactions between RBC folate concentrations and tuberculosis, human immunodeficiency virus (HIV), and antifolate antimalarial drugs (WHO 2015b). An earlier Cochrane Review assessed the effects and safety of iron supplementation, with or without folic acid, in children living in hyperendemic or holoendemic malaria areas; it demonstrated that iron supplementation did not increase the risk of malaria, as indicated by fever and the presence of parasites in the blood (Neuberger 2016). Further, this review stated that folic acid may interfere with the efficacy of SP; however, the efficacy and safety of folic acid supplementation on these outcomes has not been established. This review will provide evidence on the effectiveness of daily folic acid supplementation in healthy and malaria-infected individuals living in malaria-endemic areas. Additionally, it will contribute to achieving both the WHO Global Technical Strategy for Malaria 2016-2030 (WHO 2015d), and United Nations Sustainable Development Goal 3 (to ensure healthy lives and to promote well-being for all of all ages) (United Nations 2021), and evaluating whether the potential effects of folic acid supplementation, at different doses (e.g. 0.4 mg, 1 mg, 5 mg daily), interferes with the effect of drugs used for prevention or treatment of malaria.
OBJECTIVES
To examine the effects of folic acid supplementation, at various doses, on malaria susceptibility (risk of infection) and severity among people living in areas with various degrees of malaria endemicity. We will examine the interaction between folic acid supplements and antifolate antimalarial drugs. Specifically, we will aim to answer the following. Among uninfected people living in malaria endemic areas, who are taking or not taking antifolate antimalarials for malaria prophylaxis, does taking a folic acid-containing supplement increase susceptibility to or severity of malaria infection? Among people with malaria infection who are being treated with antifolate antimalarials, does folic acid supplementation increase the risk of treatment failure?
METHODS
Criteria for considering studies for this review Types of studies Inclusion criteria Randomized controlled trials (RCTs) Quasi-RCTs with randomization at the individual or cluster level conducted in malaria-endemic areas (areas with ongoing, local malaria transmission, including areas approaching elimination, as listed in the World Malaria Report 2020) (WHO 2020) Exclusion criteria Ecological studies Observational studies In vivo/in vitro studies Economic studies Systematic literature reviews and meta-analyses (relevant systematic literature reviews and meta-analyses will be excluded but flagged for grey literature screening) Types of participants Inclusion criteria Individuals of any age or gender, living in a malaria endemic area, who are taking antifolate antimalarial medications (including but not limited to sulfadoxine/pyrimethamine (SP), pyrimethamine-dapsone, pyrimethamine, chloroquine and proguanil, cotrimoxazole) for the prevention or treatment of malaria (studies will be included if more than 70% of the participants live in malaria-endemic regions) Studies assessing participants with or without anaemia and with or without malaria parasitaemia at baseline will be included Exclusion criteria Individuals not taking antifolate antimalarial medications for prevention or treatment of malaria Individuals living in non-malaria endemic areas Types of interventions Inclusion criteria Folic acid supplementation Form: in tablet, capsule, dispersible tablet at any dose, during administration, or periodically Timing: during, before, or after (within a period of four to six weeks) administration of antifolate antimalarials Iron-folic acid supplementation Folic acid supplementation in combination with co-interventions that are identical between the intervention and control groups. Co-interventions include: anthelminthic treatment; multivitamin or multiple micronutrient supplementation; 5-methyltetrahydrofolate supplementation. Exclusion criteria Folate through folate-fortified water Folic acid administered through large-scale fortification of rice, wheat, or maize Comparators Placebo No treatment No folic acid/different doses of folic acid Iron Types of outcome measures Primary outcomes Uncomplicated malaria (defined as a history of fever with parasitological confirmation; acceptable parasitological confirmation will include rapid diagnostic tests (RDTs), malaria smears, or nucleic acid detection (i.e. polymerase chain reaction (PCR), loop-mediated isothermal amplification (LAMP), etc.)) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Severe malaria (defined as any case with cerebral malaria or acute P. falciparum malaria, with signs of severity or evidence of vital organ dysfunction, or both) (WHO 2010). This outcome is relevant for patients without malaria, given antifolate antimalarials for malaria prophylaxis. Parasite clearance (any Plasmodium species), defined as the time it takes for a patient who tests positive at enrolment and is treated to become smear-negative or PCR negative. This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Treatment failure (defined as the inability to clear malaria parasitaemia or prevent recrudescence after administration of antimalarial medicine, regardless of whether clinical symptoms are resolved) (WHO 2019). This outcome is relevant for patients with malaria, treated with antifolate antimalarials. Secondary outcomes Duration of parasitaemia Parasite density Haemoglobin (Hb) concentrations (g/L) Anaemia: severe anaemia (defined as Hb less than 70 g/L in pregnant women and children aged six to 59 months; and Hb less than 80 g/L in other populations); moderate anaemia (defined as Hb less than 100 g/L in pregnant women and children aged six to 59 months; and less than 110 g/L in others) Death from any cause Among pregnant women: stillbirth (at less than 28 weeks gestation); low birthweight (less than 2500 g); active placental malaria (defined as Plasmodium detected in placental blood by smear or PCR, or by Plasmodium detected on impression smear or placental histology). Search methods for identification of studies A search will be conducted to identify completed and ongoing studies, without date or language restrictions. Electronic searches A search strategy will be designed to include the appropriate subject headings and text word terms related to each intervention of interest and study design of interest (see Appendix 1). Searches will be broken down by these two criteria (intervention of interest and study design of interest) to allow for ease of prioritization, if necessary. The study design filters recommended by the Scottish Intercollegiate Guidelines Network (SIGN), and those designed by Cochrane for identifying clinical trials for MEDLINE and Embase, will be used (SIGN 2020). There will be no date or language restrictions. Non-English articles identified for inclusion will be translated into English. If translations are not possible, advice will be requested from the Cochrane Infectious Diseases Group and the record will be stored in the "Awaiting assessment" section of the review until a translation is available. The following electronic databases will be searched for primary studies. Cochrane Central Register of Controlled Trials. Cumulative Index to Nursing and Allied Health Literature (CINAHL). Embase. MEDLINE. Scopus. Web of Science (both the Social Science Citation Index and the Science Citation Index). We will conduct manual searches of ClinicalTrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the United Nations Children's Fund (UNICEF) Evaluation and Research Database (ERD), in order to identify relevant ongoing or planned trials, abstracts, and full-text reports of evaluations, studies, and surveys related to programmes on folic acid supplementation in malaria-endemic areas. Additionally, manual searches of grey literature to identify RCTs that have not yet been published but are potentially eligible for inclusion will be conducted in the following sources. Global Index Medicus (GIM). African Index Medicus (AIM). Index Medicus for the Eastern Mediterranean Region (IMEMR). Latin American & Caribbean Health Sciences Literature (LILACS). Pan American Health Organization (PAHO). Western Pacific Region Index Medicus (WPRO). Index Medicus for the South-East Asian Region (IMSEAR). The Spanish Bibliographic Index in Health Sciences (IBECS) (ibecs.isciii.es/). Indian Journal of Medical Research (IJMR) (journals.lww.com/ijmr/pages/default.aspx). Native Health Database (nativehealthdatabase.net/). Scielo (www.scielo.br/). Searching other resources Handsearches of the five journals with the highest number of included studies in the last 12 months will be conducted to capture any relevant articles that may not have been indexed in the databases at the time of the search. We will contact the authors of included studies and will check reference lists of included papers for the identification of additional records. For assistance in identifying ongoing or unpublished studies, we will contact the Division of Nutrition, Physical Activity, and Obesity (DNPAO) and the Division of Parasitic Diseases and Malaria (DPDM) of the CDC, the United Nations World Food Programme (WFP), Nutrition International (NI), Global Alliance for Improved Nutrition (GAIN), and Hellen Keller International (HKI). Data collection and analysis Selection of studies Two review authors will independently screen the titles and abstracts of articles retrieved by each search to assess eligibility, as determined by the inclusion and exclusion criteria. Studies deemed eligible for inclusion by both review authors in the abstract screening phase will advance to the full-text screening phase, and full-text copies of all eligible papers will be retrieved. If full articles cannot be obtained, we will attempt to contact the authors to obtain further details of the studies. If such information is not obtained, we will classify the study as "awaiting assessment" until further information is published or made available to us. The same two review authors will independently assess the eligibility of full-text articles for inclusion in the systematic review. If any discrepancies occur between the studies selected by the two review authors, a third review author will provide arbitration. Each trial will be scrutinized to identify multiple publications from the same data set, and the justification for excluded trials will be documented. A PRISMA flow diagram of the study selection process will be presented to provide information on the number of records identified in the literature searches, the number of studies included and excluded, and the reasons for exclusion (Moher 2009). The list of excluded studies, along with their reasons for exclusion at the full-text screening phase, will also be created. Data extraction and management Two review authors will independently extract data for the final list of included studies using a standardized data specification form. Discrepancies observed between the data extracted by the two authors will be resolved by involving a third review author and reaching a consensus. Information will be extracted on study design components, baseline participant characteristics, intervention characteristics, and outcomes. For individually randomized trials, we will record the number of participants experiencing the event and the number analyzed in each treatment group or the effect estimate reported (e.g. risk ratio (RR)) for dichotomous outcome measures. For count data, we will record the number of events and the number of person-months of follow-up in each group. If the number of person-months is not reported, the product of the duration of follow-up and the number of children evaluated will be used to estimate this figure. We will calculate the rate ratio and standard error (SE) for each study. Zero events will be replaced by 0.5. We will extract both adjusted and unadjusted covariate incidence rate ratios if they are reported in the original studies. For continuous data, we will extract means (arithmetic or geometric) and a measure of variance (standard deviation (SD), SE, or confidence interval (CI)), percentage or mean change from baseline, and the numbers analyzed in each group. SDs will be computed from SEs or 95% CIs, assuming a normal distribution of the values. Haemoglobin values in g/dL will be calculated by multiplying haematocrit or packed cell volume values by 0.34, and studies reporting haemoglobin values in g/dL will be converted to g/L. In cluster-randomized trials, we will record the unit of randomization (e.g. household, compound, sector, or village), the number of clusters in the trial, and the average cluster size. The statistical methods used to analyze the trials will be documented, along with details describing whether these methods adjusted for clustering or other covariates. We plan to extract estimates of the intra-cluster correlation coefficient (ICC) for each outcome. Where results are adjusted for clustering, we will extract the treatment effect estimate and the SD or CI. If the results are not adjusted for clustering, we will extract the data reported. Assessment of risk of bias in included studies Two review authors (KSC, LFY) will independently assess the risk of bias for each included trial using the Cochrane 'Risk of bias 2' tool (RoB 2) for randomized studies (Sterne 2019). Judgements about the risk of bias of included studies will be made according to the recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Disagreements will be resolved by discussion, or by involving a third review author. The interest of our review will be to assess the effect of assignment to the interventions at baseline. We will evaluate each primary outcome using the RoB2 tool. The five domains of the Cochrane RoB2 tool include the following. Bias arising from the randomization process. Bias due to deviations from intended interventions. Bias due to missing outcome data. Bias in measurement of the outcome. Bias in selection of the reported result. Each domain of the RoB2 tool comprises the following. A series of 'signalling' questions. A judgement about the risk of bias for the domain, facilitated by an algorithm that maps responses to the signalling questions to a proposed judgement. Free-text boxes to justify responses to the signalling questions and 'Risk of bias' judgements. An option to predict (and explain) the likely direction of bias. Responses to signalling questions elicit information relevant to an assessment of the risk of bias. These response options are as follows. Yes (may indicate either low or high risk of bias, depending on the most natural way to ask the question). Probably yes. Probably no. No. No information (may indicate no evidence of that problem or an absence of information leading to concerns about there being a problem). Based on the answer to the signalling question, a 'Risk of bias' judgement is assigned to each domain. These judgements include one of the following. High risk of bias Low risk of bias Some concerns To generate the risk of bias judgement for each domain in the randomized studies, we will use the Excel template, available at www.riskofbias.info/welcome/rob-2-0-tool/current-version-of-rob-2. This file will be stored on a scientific data website, available to readers. Risk of bias in cluster randomized controlled trials For the cluster randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 1b (bias arising from the timing of identification or recruitment of participants) and its related signalling questions. To generate the risk of bias judgement for each domain in the cluster RCTs, we will use the Excel template available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-cluster-randomized-trials. This file will be stored on a scientific data website, available to readers. Risk of bias in cross-over randomized controlled trials For cross-over randomized trials, we will be using the RoB2 tool to analyze the five standard domains listed above along with Domain 2 (bias due to deviations from intended interventions), and Domain 3 (bias due to missing outcome data), and their respective signalling questions. To generate the risk of bias judgement for each domain in the cross-over RCTs, we will use the Excel template, available at https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/rob-2-for-crossover-trials, for each risk of bias judgement of cross-over randomized studies. This file will be stored on a scientific data website, available to readers. Overall risk of bias The overall 'Risk of bias' judgement for each specific trial being assessed will be based on each domain-level judgement. The overall judgements include the following. Low risk of bias (the trial is judged to be at low risk of bias for all domains). Some concerns (the trial is judged to raise some concerns in at least one domain but is not judged to be at high risk of bias for any domain). High risk of bias (the trial is judged to be at high risk of bias in at least one domain, or is judged to have some concerns for multiple domains in a way that substantially lowers confidence in the result). The 'risk of bias' assessments will inform our GRADE evaluations of the certainty of evidence for our primary outcomes presented in the 'Summary of findings' tables and will also be used to inform the sensitivity analyses; (see Sensitivity analysis). If there is insufficient information in study reports to enable an assessment of the risk of bias, studies will be classified as "awaiting assessment" until further information is published or made available to us. Measures of treatment effect Dichotomous data For dichotomous data, we will present proportions and, for two-group comparisons, results as average RR or odds ratio (OR) with 95% CIs. Ordered categorical data Continuous data We will report results for continuous outcomes as the mean difference (MD) with 95% CIs, if outcomes are measured in the same way between trials. Where some studies have reported endpoint data and others have reported change-from-baseline data (with errors), we will combine these in the meta-analysis, if the outcomes were reported using the same scale. We will use the standardized mean difference (SMD), with 95% CIs, to combine trials that measured the same outcome but used different methods. If we do not find three or more studies for a pooled analysis, we will summarize the results in a narrative form. Unit of analysis issues Cluster-randomized trials We plan to combine results from both cluster-randomized and individually randomized studies, providing there is little heterogeneity between the studies. If the authors of cluster-randomized trials conducted their analyses at a different level from that of allocation, and they have not appropriately accounted for the cluster design in their analyses, we will calculate the trials' effective sample sizes to account for the effect of clustering in data. When one or more cluster-RCT reports RRs adjusted for clustering, we will compute cluster-adjusted SEs for the other trials. When none of the cluster-RCTs provide cluster-adjusted RRs, we will adjust the sample size for clustering. We will divide, by the estimated design effects (DE), the number of events and number evaluated for dichotomous outcomes and the number evaluated for continuous outcomes, where DE = 1 + ((average cluster size 1) * ICC). The derivation of the estimated ICCs and DEs will be reported. We will utilize the intra-cluster correlation coefficient (ICC), derived from the trial (if available), or from another source (e.g., using the ICCs derived from other, similar trials) and then calculate the design effect with the formula provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). If this approach is used, we will report it and undertake sensitivity analysis to investigate the effect of variations in ICC. Studies with more than two treatment groups If we identify studies with more than two intervention groups (multi-arm studies), where possible we will combine groups to create a single pair-wise comparison or use the methods set out in the Cochrane Handbook to avoid double counting study participants (Higgins 2021). For the subgroup analyses, when the control group was shared by two or more study arms, we will divide the control group (events and total population) over the number of relevant subgroups to avoid double counting the participants. Trials with several study arms can be included more than once for different comparisons. Cross-over trials From cross-over trials, we will consider the first period of measurement only and will analyze the results together with parallel-group studies. Multiple outcome events In several outcomes, a participant might experience more than one outcome event during the trial period. For all outcomes, we will extract the number of participants with at least one event. Dealing with missing data We will contact the trial authors if the available data are unclear, missing, or reported in a format that is different from the format needed. We aim to perform a 'per protocol' or 'as observed' analysis; otherwise, we will perform a complete case analysis. This means that for treatment failure, we will base the analyses on the participants who received treatment and the number of participants for which there was an inability to clear malarial parasitaemia or prevent recrudescence after administration of an antimalarial medicine reported in the studies. Assessment of heterogeneity Heterogeneity in the results of the trials will be assessed by visually examining the forest plot to detect non-overlapping CIs, using the Chi2 test of heterogeneity (where a P value of less than 0.1 indicates statistical significance) and the I2 statistic of inconsistency (with a value of greater than 50% denoting moderate levels of heterogeneity). When statistical heterogeneity is present, we will investigate the reasons for it, using subgroup analysis. Assessment of reporting biases We will construct a funnel plot to assess the effect of small studies for the main outcome (when including more than 10 trials). Data synthesis The primary analysis will include all eligible studies that provide data regardless of the overall risk of bias as assessed by the RoB2 tool. Analyses will be conducted using Review Manager 5.4 (Review Manager 2020). Cluster-RCTs will be included in the main analysis after adjustment for clustering (see the previous section on cluster-RCTs). The meta-analysis will be performed using the Mantel-Haenszel random-effects model or the generic inverse variance method (when adjustment for clustering is performed by adjusting SEs), as appropriate. Subgroup analysis and investigation of heterogeneity The overall risk of bias will not be used as the basis in conducting our subgroup analyses. However, where data are available, we plan to conduct the following subgroup analyses, independent of heterogeneity. Dose of folic acid supplementation: higher doses (4 mg or more, daily) versus lower doses (less than 4 mg, daily). Moderate-severe anaemia at baseline (mean haemoglobin of participants in a trial at baseline below 100 g/L for pregnant women and children aged six to 59 months, and below 110 g/L for other populations) versus normal at baseline (mean haemoglobin above 100 g/L for pregnant women and children aged six to 59 months, and above 110 g/L for other populations). Antimalarial drug resistance to parasite: known resistance versus no resistance versus unknown/mixed/unreported parasite resistance. Folate status at baseline: Deficient (e.g. RBC folate concentration of less than 305 nmol/L, or serum folate concentration of less than 7nmol/L) and Insufficient (e.g. RBC folate concentration from 305 to less than 906 nmol/L, or serum folate concentration from 7 to less than 25 nmol/L) versus Sufficient (e.g. RBC folate concentration above 906 nmol/L, or serum folate concentration above 25 nmol/L). Presence of anaemia at baseline: yes versus no. Mandatory fortification status: yes, versus no (voluntary or none). We will only use the primary outcomes in any subgroup analyses, and we will limit subgroup analyses to those outcomes for which three or more trials contributed data. Comparisons between subgroups will be performed using Review Manager 5.4 (Review Manager 2020). Sensitivity analysis We will perform a sensitivity analysis, using the risk of bias as a variable to explore the robustness of the findings in our primary outcomes. We will verify the behaviour of our estimators by adding and removing studies with a high risk of bias overall from the analysis. That is, studies with a low risk of bias versus studies with a high risk of bias. Summary of findings and assessment of the certainty of the evidence For the assessment across studies, we will use the GRADE approach, as outlined in (Schünemann 2021). We will use the five GRADE considerations (study limitations based on RoB2 judgements, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence as it relates to the studies which contribute data to the meta-analyses for the primary outcomes. The GRADEpro Guideline Development Tool (GRADEpro) will be used to import data from Review Manager 5.4 (Review Manager 2020) to create 'Summary of Findings' tables. The primary outcomes for the main comparison will be listed with estimates of relative effects, along with the number of participants and studies contributing data for those outcomes. These tables will provide outcome-specific information concerning the overall certainty of evidence from studies included in the comparison, the magnitude of the effect of the interventions examined, and the sum of available data on the outcomes we considered. We will include only primary outcomes in the summary of findings tables. For each individual outcome, two review authors (KSC, LFY) will independently assess the certainty of the evidence using the GRADE approach (Balshem 2011). For assessments of the overall certainty of evidence for each outcome that includes pooled data from included trials, we will downgrade the evidence from 'high certainty' by one level for serious (or by two for very serious) study limitations (risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias).
Topics: Child; Infant; Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Antimalarials; Sulfadoxine; Pyrimethamine; Folic Acid Antagonists; Birth Weight; Parasitemia; Vitamins; Folic Acid; Anemia; Neural Tube Defects; Dietary Supplements; Iron; Recurrence
PubMed: 36321557
DOI: 10.1002/14651858.CD014217 -
Neurology Nov 2022White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
White matter hyperintensities (WMHs) are frequent imaging features of small vessel disease (SVD) and related to poor clinical outcomes. WMH progression over time is well described, but regression was also noted recently, although the frequency and associated factors are unknown. This systematic review and meta-analysis aims to assess longitudinal intraindividual WMH volume changes in sporadic SVD.
METHODS
We searched EMBASE and MEDLINE for articles up to 28 January 2022 on WMH volume changes using MRI on ≥2 time points in adults with sporadic SVD. We classified populations (healthy/community-dwelling, stroke, cognitive, other vascular risk factors, and depression) based on study characteristics. We performed random-effects meta-analyses with Knapp-Hartung adjustment to determine mean WMH volume change (change in milliliters, percentage of intracranial volume [%ICV], or milliliters per year), 95% CI, and prediction intervals (PIs, limits of increase and decrease) using unadjusted data. Risk of bias assessment tool for nonrandomized studies was used to assess risk of bias. We followed Preferred Reporting in Systematic Review and Meta-Analysis guidelines.
RESULTS
Forty-one articles, 12,284 participants, met the inclusion criteria. Thirteen articles had low risk of bias across all domains. Mean WMH volume increased over time by 1.74 mL (95% CI 1.23-2.26; PI -1.24 to 4.73 mL; 27 articles, N = 7,411, mean time interval 2.7 years, SD = 1.65); 0.25 %ICV (95% CI 0.14-0.36; PI -0.06 to 0.56; 6 articles, N = 1,071, mean time interval 3.5 years, SD = 1.54); or 0.58 mL/y (95% CI 0.35-0.81; PI -0.26 to 1.41; 8 articles, N = 3,802). In addition, 13 articles specifically mentioned and/or provided data on WMH regression, which occurred in asymptomatic, stroke, and cognitive disorders related to SVD.
DISCUSSION
Net mean WMH volume increases over time mask wide-ranging change (e.g., mean increase of 1.75 mL ranging from 1.25 mL decrease to 4.75 mL increase), with regression documented explicitly in up to one-third of participants. More knowledge on underlying mechanisms, associated factors, and clinical correlates is needed, as WMH regression could be an important intervention target.
Topics: Adult; Humans; Cerebral Small Vessel Diseases; White Matter; Leukoaraiosis; Magnetic Resonance Imaging; Stroke
PubMed: 36123130
DOI: 10.1212/WNL.0000000000201205 -
Annals of Surgery May 2023To conduct a systematic review and meta-analysis of randomized controlled trials compared laparoscopic pancreatoduodenectomy (LPD) versus open pancreatoduodenectomy... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To conduct a systematic review and meta-analysis of randomized controlled trials compared laparoscopic pancreatoduodenectomy (LPD) versus open pancreatoduodenectomy (OPD) in patients with periampullary tumors.
BACKGROUND
LPD has gained attention; however, its safety and efficacy versus OPD remain debatable.
METHODS
We searched PubMed and Embase. Primary outcomes were the length of hospital stay (LOS) (day), Clavien-Dindo grade ≥III complications, and 90-day mortality. Secondary outcomes were blood loss (milliliter), blood transfusion, duration of operation (minute), readmission, reoperation, comprehensive complication index score, bile leak, gastrojejunostomy or duodenojejunostomy leak, postoperative pancreatic fistula, postpancreatectomy hemorrhage, delayed gastric emptying, surgical site infection, intra-abdominal infection, number of harvested lymph nodes, and R0 resection. Pooled odds ratio (OR) or mean difference (MD) of data was calculated using the random-effect model. The grading of recommendations, assessment, development and evaluation approach was used for grading the level of evidence.
RESULTS
Four randomized controlled trials yielding 818 patients were included, of which 411 and 407 patients underwent LPD and OPD, respectively. The meta-analysis concluded that 2 approaches were similar, except in the LPD group, the LOS tended to be shorter [MD=-2.54 (-5.17, 0.09), P =0.06], LOS in ICU was shorter [MD=-1 (-1.8, -0.2), P =0.01], duration of operation was longer [MD=75.16 (23.29, 127.03), P =0.005], blood loss was lower [MD=-115.40 (-152.13, -78.68), P <0.00001], blood transfusion was lower [OR=0.66 (0.47, 0.92), P =0.01], and surgical site infection was lower [OR=0.35 (0.12, 0.96), P =0.04]. The overall certainty of the evidence was moderate.
CONCLUSIONS
Within the hands of highly skilled surgeons in high-volume centers, LPD is feasible and as safe and efficient as OPD.
Topics: Humans; Pancreaticoduodenectomy; Pancreas; Pancreatic Neoplasms; Pancreatic Fistula; Surgical Wound Infection; Laparoscopy; Postoperative Complications; Length of Stay; Retrospective Studies; Randomized Controlled Trials as Topic
PubMed: 36519444
DOI: 10.1097/SLA.0000000000005785 -
The Spine Journal : Official Journal of... Dec 2017Aspirin is typically discontinued in spinal surgery because of increased risk of hemorrhagic complications. The risk of perioperative continuation of aspirin in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND CONTEXT
Aspirin is typically discontinued in spinal surgery because of increased risk of hemorrhagic complications. The risk of perioperative continuation of aspirin in neurosurgery needed to be evaluated.
PURPOSE
This study aimed to evaluate all available evidence about continuation of aspirin and to compare peri- and postoperative blood loss and complication rates between patients that continued aspirin and those who discontinued aspirin perioperatively in spinal surgery.
STUDY SETTING
Systematic review and meta-analysis were carried out.
METHOD
A meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies comparing aspirin continuation with discontinuation were included. Studies using a combination of anticlotting agents or non-spinal procedures were excluded. Operative outcomes (blood loss and operative length) and different complications (surgical site infection [SSI]), stroke, myocardial infarction within 30 days postoperatively) were extracted. Overall prevalence and means were calculated for the reported outcomes in fixed-effects models with heterogeneity (I-squared [I]) and effect modification (P-interaction) assessment.
RESULTS
Out of 1,339 studies, three case series were included in the meta-analysis. No significant differences in mean operating time were seen between the aspirin-continuing group (mean=201.8 minutes, 95% confidence interval [CI]=193.3; 210.3; I=95.4%; 170 patients) and the aspirin-discontinuing group (mean=178.4 minutes, 95% CI=119.1; 237.6; I=93.5%; 200 patients); (P-interaction=0.78). No significant differences in mean perioperative blood loss were seen between the aspirin-continuing group (mean=553.9 milliliters, 95% CI=468.0; 639.9; I=83.4%; 170 patients) and the aspirin-discontinuing group (mean=538.7 milliliters, 95% CI=427.6; 649.8; I=985.5%; 200 patients); (P-interaction=0.96). Similar non-significant differences between the two groups were found for cardiac events, stroke, and surgical site infections.
CONCLUSIONS
This meta-analysis showed an absence of significant differences in perioperative complications between aspirin continuation and discontinuation. Because of the paucity of included studies, further well-designed prospective trials are imperative to demonstrate potential benefit and safety.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Humans; Neurosurgical Procedures; Postoperative Hemorrhage; Risk; Spinal Diseases
PubMed: 28823937
DOI: 10.1016/j.spinee.2017.08.238 -
American Journal of Orthodontics and... Apr 2013The objective of this systematic review was to assess the short- and long-term release of components of orthodontic adhesives and polycarbonate brackets in the oral... (Review)
Review
INTRODUCTION
The objective of this systematic review was to assess the short- and long-term release of components of orthodontic adhesives and polycarbonate brackets in the oral environment.
METHODS
Electronic database searches of published and unpublished literature were performed. The following electronic databases with no language and publication date restrictions were searched: MEDLINE (via Ovid and PubMed), EMBASE (via Ovid), Cochrane Oral Health Group's Trials Register, and CENTRAL. Unpublished literature was searched on ClinicalTrials.gov, the National Research Register, and Pro-Quest Dissertation Abstracts and Thesis database. The reference lists of all eligible studies were checked for additional studies. Two review authors performed data extraction independently and in duplicate using data collection forms. Disagreements were resolved by discussion or the involvement of an arbiter.
RESULTS
No randomized controlled trial was identified. In the absence of randomized controlled trials, observational studies were included. Eleven studies met the inclusion criteria. All were observational studies conducted in vivo or in vitro. The bisphenol-A release from orthodontic bonding resins was found to be between 0.85 and 20.88 ng per milliliter in vivo, and from traces to 65.67 ppm in vitro. Polycarbonate brackets released amounts of 22.24 μg per gram in ethanol solution and 697 μg per gram after 40 months in water. Bis-GMA and TEGDMA leaching in vitro reached levels of 64 and 174 mg per 10 μL, respectively. Because of the heterogeneity in methodologies and reporting, only qualitative synthesis was performed.
CONCLUSIONS
The available evidence on this topic derived from observational in-vivo and in-vitro studies that represent a moderate level of evidence. The variety of setups and the different units allied to the diversity of reporting among studies did not allow calculation of pooled estimates.
Topics: Benzhydryl Compounds; Bisphenol A-Glycidyl Methacrylate; Estrogens, Non-Steroidal; Humans; Orthodontic Brackets; Phenols; Polycarboxylate Cement; Polyethylene Glycols; Polymethacrylic Acids; Resin Cements
PubMed: 23540625
DOI: 10.1016/j.ajodo.2012.11.015 -
Physiotherapy Canada. Physiotherapie... 2021A systematic review was conducted to investigate the effect of respiratory physiotherapy on mortality, quality of life, functional recovery, intensive care length of...
A systematic review was conducted to investigate the effect of respiratory physiotherapy on mortality, quality of life, functional recovery, intensive care length of stay, duration of ventilation, oxygenation, secretion clearance, and pulmonary mechanics for invasively ventilated adults with pneumonia. Five databases were searched for randomized trials published between January 1995 and November 2018. Study quality was assessed using a standardized Joanna Briggs Institute critical appraisal tool, and Review Manager software was used to pool the studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the level of certainty of the evidence. A total of 14 studies of moderate quality included 251 subjects with pneumonia. Eight studies were pooled for meta-analysis. Interventions that increased inspiratory volume appeared to benefit secretion clearance by nearly 2 grams (mean difference [MD] 1.97; 95% CI: 0.80, 3.14; very low GRADE evidence) and increase static lung compliance immediately after treatment by more than 5 millilitres/centimetre H0 (MD 5.40 mL/cm HO; 95% CI: 2.37, 8.43; very low GRADE evidence) or by more than 6 millilitres/centimetre HO after a 20- to 30-minute delay (MD 6.86 mL/cm HO; 95% CI: 2.86, 10.86; very low GRADE evidence). No adverse events were found. Respiratory physiotherapy that increases tidal volume may benefit secretion clearance and lung compliance in invasively ventilated adults with pneumonia, but its impact on other outcomes, including mortality, length of stay, and other patient-centred outcomes, is unclear, and further research is required.
PubMed: 35106019
DOI: 10.3138/ptc-2019-0025 -
Bioengineering (Basel, Switzerland) Mar 2022Dental impressions are contaminated with potentially pathogenic microorganisms when they come into contact with patient blood, saliva, and plaque. Numerous disinfectants... (Review)
Review
Dental impressions are contaminated with potentially pathogenic microorganisms when they come into contact with patient blood, saliva, and plaque. Numerous disinfectants are used; however, no sole disinfectant can be designated as universal for all the impression materials. Thus, the aim of this study is to systemically review the literature to evaluate the effect of the existing disinfection procedures on the bacterial colonization of dental impression materials. This systematic review and meta-analysis was conducted according to the PRISMA statement. PubMed (MEDLINE), Web of Science, Scopus, EMBASE, and SciELO databases were screened up to April 2021. Eligibility criteria included in vitro studies reporting the antibacterial activity of disinfectant solutions in dental impression materials. The meta-analysis was performed using Review Manager (version 5.3.5). A global comparison was performed with the standardized mean difference based on random-effect models at a significance level of α = 0.05. A total of seven studies were included in the meta-analysis. The included studies described the effect of disinfection processes with chlorhexidine gluconate, alcohol, sodium hypochlorite, glutaraldehyde, and hydrogen peroxide in alginate, polyvinyl siloxane, and polyether impression materials. The meta-analyses showed that the use of chlorhexidine, alcohol, glutaraldehyde, and sodium hypochlorite reduced the colony-forming units by a milliliter (CFU/mL) in alginate (p < 0.001). On the other hand, glutaraldehyde, sodium hypochlorite, and alcohol reduced the CFU/mL in polyvinyl siloxane (p < 0.001). Finally, alcohol and glutaraldehyde reduced the CFU/mL in polyether material (p < 0.001). High heterogenicity was observed for the alginate and polyvinyl siloxane materials (I2 = 74%; I2 = 90%). Based on these in vitro studies, the disinfection of impression materials with several disinfection agents reduces the CFU/mL count.
PubMed: 35324812
DOI: 10.3390/bioengineering9030123 -
Photodiagnosis and Photodynamic Therapy Jun 2023The present study aimed to perform a systematic review and meta-analysis to investigate the effectiveness of the contemporary photoactivated disinfection methods on the... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
The present study aimed to perform a systematic review and meta-analysis to investigate the effectiveness of the contemporary photoactivated disinfection methods on the mechanical features and/or antimicrobial activity of polymethyl methacrylate (PMMA) dentures bases.
METHODS
THE FOCUSED RESEARCH QUESTION WAS: "What is the effect of contemporary photoactivated disinfection methods as compared to conventional disinfection protocols on the mechanical features and/or antimicrobial activity of PMMA dentures bases?". An electronic literature search was carried out by the author and a senior librarian specialized in health sciences on Web of Science, PubMed, and Scopus. In vitro investigations evaluating the antimicrobial and/or mechanical effects of photoactivated disinfectants as compared to conventional chemical disinfectants on the microbes formed on PMMA denture bases were included. Meta-analysis was performed for calculating the standard mean difference (SMD) with a 95% confidence interval.
RESULTS
Four out of eight studies concluded that photoactivated disinfectants, including riboflavin-mediated photodynamic therapy (PDT), hematoporphyrin-mediated PDT, poly-l-glycolic acid loaded with methylene blue, Erbium, chromium-doped yttrium, scandium, gallium, and garnet (Er,Cr:YSGG) laser, erbium-doped yttrium-aluminum-garnet (Er:YAG) laser, and chitosan-mediated PDT, demonstrated a significant reduction in colony-forming unit per milliliter (CFU/mL) of exposed viable colonies of Escherichia coli (E. coli), Streptococcus mutans (S. mutans), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans) comparable to the conventionally used chemical disinfectants of PMMA denture bases. Contrarily, two studies concluded that the PMMA denture base colonized with C. albicans and disinfected with conventional chemical disinfectants showed the greatest anti-fungal efficaciousness. All the included studies concluded that the application of photoactivated disinfectants does not negatively impact the mechanical features of the PMMA denture bases colonized with microbes including E. coli, S. mutans, S. aureus, and C. albicans. The meta-analysis revealed statistically significant reduction in C. albicans counts (CFU/mL [Log10]) (p < 0.00001) and improvement in the flexural strength (p = 0.0002) of PMMA-based denture base after the application of conventional disinfectants, while a statistically significant improvement in the fracture strength of PMMA-based denture base was observed after the application of photoactivated disinfectants (p = 0.03).
CONCLUSION
According to the systematic review (qualitative synthesis), photoactivated disinfectants demonstrated comparable mechanical features and antimicrobial activity of PMMA dentures bases to conventional chemical disinfectants suggesting their potential to be utilized as an alternative to conventional chemical disinfectants. However, the meta-analysis (quantitative synthesis) revealed that the application of conventional disinfectants demonstrated better outcomes related to antimicrobial activity and flexural strength of PMMA-based denture based.
Topics: Polymethyl Methacrylate; Disinfection; Denture Bases; Escherichia coli; Staphylococcus aureus; Erbium; Photochemotherapy; Photosensitizing Agents; Anti-Infective Agents; Disinfectants; Materials Testing; Candida albicans
PubMed: 36958538
DOI: 10.1016/j.pdpdt.2023.103523