Rapid diagnostic tests and antimicrobial stewardship programs for the management of bloodstream infection: What is their relative contribution to improving clinical outcomes? A systematic review and network meta-analysis.

BACKGROUND: Evidence about the clinical impact of rapid diagnostic tests (RDT) for the diagnosis of bloodstream infections is limited, and whether RDT are superior to conventional blood cultures (BC) embedded within antimicrobial stewardship programs (ASP) is unknown. METHODS: We performed network meta-analyses (NMA) using results from studies of patients with bloodstream infection with the aim of comparing the clinical impact of RDT (applied on positive BC broth or whole blood) to conventional BC, both assessed with and without ASP with respect to mortality, length of stay (LOS) and time to optimal therapy (TOT). RESULTS: Eighty-eight papers were selected, including 25,682 patient encounters. There was an appreciable amount of statistical heterogeneity within each meta-analysis. The NMA showed a significant reduction in mortality associated with the use of RDT + ASP vs BC alone (OR 0.72, 95%CI 0.59, 0.87) and with the use of RDT + ASP vs BC + ASP (OR 0.78 95%CI 0.63, 0.96). No benefit in survival was found associated with the use of RDT alone nor with BC + ASP compared to BC alone. A reduction in LOS was associated with RDT + ASP vs BC alone (0.91, 95%CI 0.84, 0.98) while no difference in LOS was shown between any other groups. A reduced TOT was shown when RDT + ASP was compared to BC alone (-29 h, 95%CI -35, -23), BC + ASP (-18 h, 95%CI -27, -10) and to RDT alone (-12 h, 95%CI -20, -3). CONCLUSION: The use of RDT + ASP may lead to a survival benefit even when introduced in settings already adopting effective ASP in association with conventional BC.

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

The provision of sexual and reproductive health information and services to travellers: an exploratory survey of Australian travel medicine clinicians.

BACKGROUND: International travel can increase the risk of exposure to infectious diseases including sexually transmissible infections (STI). Pre-travel medical consultation provides an opportunity for travel-related health risk assessments and advice. This study explored how travel medicine clinicians integrate sexual and reproductive health (SRH) services into clinical practice. METHODS: A convenience sample of travel medicine clinicians completed a cross-sectional survey online or via hard-copy disseminated at an annual national Australian travel medicine conference. RESULTS: Of the 67 respondents, most (n , 51; 76.1%) had a postgraduate qualification relevant to travel medicine and 55.2% (n , 37) had worked in travel medicine for over 10years. Only 22.4% (n , 15) reported conducting a SRH history/STI risk assessment for all travel patients. STI testing pre-departure was conducted on patient request (48, 71.6%), if symptomatic (32, 47.8%) or based on risk history (28, 41.8%). SRH information pre-departure was most frequently provided if prompted by patient questions (n , 42; 62.7%), or based on the patient's history (n , 37; 55.2%). Over half the sample (n , 40; 59.7%) expressed interest in further training in SRH. CONCLUSION: Providing and engaging with additional training may assist travel medicine clinicians to take a more proactive approach to SRH consultations and STI testing. Additional research is needed to explore models of care that will allow comprehensive SRH and STI services to be integrated into standard pre- and post-travel care.

Japanese Encephalitis Emergence in Australia: The Potential Population at Risk.

In Australia, Japanese encephalitis virus circulated in tropical north Queensland between 1995 and 2005. In 2022, a dramatic range expansion across the southern states has resulted in 30 confirmed human cases and 6 deaths. We discuss the outbreak drivers and estimate the potential size of the human population at risk.

The impact of inpatient bloodstream infections caused by antibiotic-resistant bacteria in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Bloodstream infections (BSIs) produced by antibiotic-resistant bacteria (ARB) cause a substantial disease burden worldwide. However, most estimates come from high-income settings and thus are not globally representative. This study quantifies the excess mortality, length of hospital stay (LOS), intensive care unit (ICU) admission, and economic costs associated with ARB BSIs, compared to antibiotic-sensitive bacteria (ASB), among adult inpatients in low- and middle-income countries (LMICs). METHODS AND FINDINGS: We conducted a systematic review by searching 4 medical databases (PubMed, SCIELO, Scopus, and WHO's Global Index Medicus; initial search n = 13,012 from their inception to August 1, 2022). We only included quantitative studies. Our final sample consisted of n = 109 articles, excluding studies from high-income countries, without our outcomes of interest, or without a clear source of bloodstream infection. Crude mortality, ICU admission, and LOS were meta-analysed using the inverse variance heterogeneity model for the general and subgroup analyses including bacterial Gram type, family, and resistance type. For economic costs, direct medical costs per bed-day were sourced from WHO-CHOICE. Mortality costs were estimated based on productivity loss from years of potential life lost due to premature mortality. All costs were in 2020 USD. We assessed studies' quality and risk of publication bias using the MASTER framework. Multivariable meta-regressions were employed for the mortality and ICU admission outcomes only. Most included studies showed a significant increase in crude mortality (odds ratio (OR) 1.58, 95% CI [1.35 to 1.80], p < 0.001), total LOS (standardised mean difference "SMD" 0.49, 95% CI [0.20 to 0.78], p < 0.001), and ICU admission (OR 1.96, 95% CI [1.56 to 2.47], p < 0.001) for ARB versus ASB BSIs. Studies analysing Enterobacteriaceae, Acinetobacter baumanii, and Staphylococcus aureus in upper-middle-income countries from the African and Western Pacific regions showed the highest excess mortality, LOS, and ICU admission for ARB versus ASB BSIs per patient. Multivariable meta-regressions indicated that patients with resistant Acinetobacter baumanii BSIs had higher mortality odds when comparing ARB versus ASB BSI patients (OR 1.67, 95% CI [1.18 to 2.36], p 0.004). Excess direct medical costs were estimated at $12,442 (95% CI [$6,693 to $18,191]) for ARB versus ASB BSI per patient, with an average cost of $41,103 (95% CI [$30,931 to $51,274]) due to premature mortality. Limitations included the poor quality of some of the reviewed studies regarding the high risk of selective sampling or failure to adequately account for relevant confounders. CONCLUSIONS: We provide an overview of the impact ARB BSIs in limited resource settings derived from the existing literature. Drug resistance was associated with a substantial disease and economic burden in LMICs. Although, our results show wide heterogeneity between WHO regions, income groups, and pathogen-drug combinations. Overall, there is a paucity of BSI data from LMICs, which hinders implementation of country-specific policies and tracking of health progress.

The normality assumption on between-study random effects was questionable in a considerable number of Cochrane meta-analyses.

BACKGROUND: Studies included in a meta-analysis are often heterogeneous. The traditional random-effects models assume their true effects to follow a normal distribution, while it is unclear if this critical assumption is practical. Violations of this between-study normality assumption could lead to problematic meta-analytical conclusions. We aimed to empirically examine if this assumption is valid in published meta-analyses. METHODS: In this cross-sectional study, we collected meta-analyses available in the Cochrane Library with at least 10 studies and with between-study variance estimates > 0. For each extracted meta-analysis, we performed the Shapiro-Wilk (SW) test to quantitatively assess the between-study normality assumption. For binary outcomes, we assessed between-study normality for odds ratios (ORs), relative risks (RRs), and risk differences (RDs). Subgroup analyses based on sample sizes and event rates were used to rule out the potential confounders. In addition, we obtained the quantile-quantile (Q-Q) plot of study-specific standardized residuals for visually assessing between-study normality. RESULTS: Based on 4234 eligible meta-analyses with binary outcomes and 3433 with non-binary outcomes, the proportion of meta-analyses that had statistically significant non-normality varied from 15.1 to 26.2%. RDs and non-binary outcomes led to more frequent non-normality issues than ORs and RRs. For binary outcomes, the between-study non-normality was more frequently found in meta-analyses with larger sample sizes and event rates away from 0 and 100%. The agreements of assessing the normality between two independent researchers based on Q-Q plots were fair or moderate. CONCLUSIONS: The between-study normality assumption is commonly violated in Cochrane meta-analyses. This assumption should be routinely assessed when performing a meta-analysis. When it may not hold, alternative meta-analysis methods that do not make this assumption should be considered.

Measuring the impact of zero-cases studies in evidence synthesis practice using the harms index and benefits index (Hi-Bi).

OBJECTIVES: In evidence synthesis practice, dealing with studies with no cases in both arms has been a tough problem, for which there is no consensus in the research community. In this study, we propose a method to measure the potential impact of studies with no cases for meta-analysis results which we define as harms index (Hi) and benefits index (Bi) as an alternative solution for deciding how to deal with such studies. METHODS: Hi and Bi are defined by the minimal number of cases added to the treatment arm (Hi) or control arm (Bi) of studies with no cases in a meta-analysis that lead to a change of the direction of the estimates or its statistical significance. Both exact and approximating methods are available to calculate Hi and Bi. We developed the "hibi" module in Stata so that researchers can easily implement the method. A real-world investigation of meta-analyses from Cochrane reviews was employed to evaluate the proposed method. RESULTS: Based on Hi and Bi, our results suggested that 21.53% (Hi) to 26.55% (Bi) of Cochrane meta-analyses may be potentially impacted by studies with no cases, for which studies with no cases could not be excluded from the synthesis. The approximating method shows excellent specificity (100%) for both Hi and Bi, moderate sensitivity (68.25%) for Bi, and high sensitivity (80.61%) for Hi compared to the exact method. CONCLUSIONS: The proposed method is practical and useful for systematic reviewers to measure whether studies with no cases impact the results of meta-analyses and may act as an alternative solution for review authors to decide whether to include studies with no events for the synthesis or not.

ß-Lactam-Resistant Streptococcus pneumoniae Dynamics Following Treatment: A Dose-Response Meta-analysis.

BACKGROUND: Patient exposure to antibiotics promotes the emergence of drug-resistant pathogens. The aim of this study was to identify whether the temporal dynamics of resistance emergence at the individual-patient level were predictable for specific pathogen-drug classes. METHODS: Following a systematic review, a novel robust error meta-regression method for dose-response meta-analysis was used to estimate the odds ratio (OR) for carrying resistant bacteria during and following treatment compared to baseline. Probability density functions fitted to the resulting dose-response curves were then used to optimize the period during and/or after treatment when resistant pathogens were most likely to be identified. RESULTS: Studies of Streptococcus pneumoniae treatment with ß-lactam antibiotics demonstrated a peak in resistance prevalence among patients 4 days after completing treatment with a 3.32-fold increase in odds (95% confidence interval [CI], 1.71-6.46). Resistance waned more gradually than it emerged, returning to preexposure levels 1 month after treatment (OR, 0.98 [95% CI, .55-1.75]). Patient isolation during the peak dose-response period would be expected to reduce the risk that a transmitted pathogen is resistant equivalently to a 50% longer isolation window timed from the first day of treatment. CONCLUSIONS: Predictable temporal dynamics of resistance levels have implications both for surveillance and control.

Performance of BioFire Blood Culture Identification 2 Panel (BCID2) for the detection of bloodstream pathogens and their associated resistance markers: a systematic review and meta-analysis of diagnostic test accuracy studies.

BACKGROUND: Early identification of bloodstream pathogens and their associated antimicrobial resistance may shorten time to optimal therapy in patients with sepsis. The BioFire Blood Culture Identification 2 Panel (BCID2) is a novel multiplex PCR detecting 43 targets directly from positive blood cultures, reducing turnaround times. METHODS: We have performed a systematic review and meta-analysis of diagnostic test accuracy studies to assess the BCID2 performance for pathogen identification and resistance markers detection compared to gold standard culture-based methods (including phenotypic and/or genotypic characterization). RESULTS: Nine studies were identified reporting data to build 2 × 2 tables for each BCID2 target, including 2005 blood cultures. The pooled specificity of the assay was excellent (> 97%) across most subgroups of targets investigated, with a slightly broader confidence interval for S. epidermidis (98.1%, 95% CI 93.1 to 99.5). Pooled sensitivity was also high for the major determinants of bloodstream infection, including Enterobacterales (98.2%, 95% CI 96.3 to 99.1), S. aureus (96.0%, 95% CI 90.4 to 98.4), Streptococcus spp. (96.7%, 95% CI 92.8 to 98.5), P. aeruginosa (92.7%, 95% CI 83.1 to 97.0), E. faecalis (92.3%, 95% CI 83.5 to 96.6), as well as blaCTX-M (94.9, 95% CI 85.7 to 98.3), carbapenemases (94.9%, 95% CI 83.4 to 98.6) and mecA/C & MREJ (93.9%, 95% CI 83.0 to 98.0). Sensitivity for less common targets was slightly lower, possibly due to their under-representation in the included studies. CONCLUSIONS: BCID2 showed good performance for detecting major determinants of bloodstream infection and could support early antimicrobial treatment, especially for ESBL or carbapenemase-producing Gram-negative bacilli and methicillin-resistant S. aureus.

Incidence and predictors of Escherichia coli producing extended-spectrum beta-lactamase (ESBL-Ec) in Queensland, Australia from 2010 to 2019: a population-based spatial analysis.

The dissemination of Escherichia coli producing extended-spectrum beta-lactamase (ESBL-Ec) is evident in the community. A population-based spatial analysis is necessary to investigate community risk factors for ESBL-Ec occurrence. The study population was defined as individuals with ESBL-Ec isolated in Queensland, Australia, from 2010 to 2019. Choropleth maps, global Moran's index and Getis-Ord Gi* were used to describe ESBL-Ec distribution and identify hot spots. Multivariable Poisson regression models with or without spatially structured random effects were performed. A total of 12 786 individuals with ESBL-Ec isolate were identified. The crude incidence rate increased annually from 9.1 per 100 000 residents in 2010 to 49.8 per 100 000 residents in 2019. The geographical distribution of ESBL-Ec changed from random to clustered after 2014, suggesting presence of community-specific factors that can enhance occurrence. Hot spots were more frequently identified in Outback and Far North Queensland, future public health measures to reduce transmission should prioritise these communities. Communities with higher socioeconomic status (RR = 0.66, 95% CI 0.55-0.79, per 100 units increase) and higher proportion of residents employed in the agricultural industry (RR = 0.79, 95% CI 0.67-0.95, per 10% increase) had lower ESBL-Ec incidence. Risk factors for occurrence appear differential between remote and city settings and this should be further investigated.

Determinants of Atrial Fibrillation Development among Patients undergoing Ibrutinib Therapy.

Objective: Within the last decade, the use of ibrutinib, a first-generation, non-selective, irreversible Burton's tyrosine kinase inhibitor for the treatment of hematological malignancies has proven highly effective in improving patient outcomes.Background: Ibrutinib has been associated with an increase in atrial fibrillation (AF). The predisposing factors are thought to be pre-existing cardiovascular risk factors, but these have not been directly evaluated.Methods: We conducted a nested case-control study, recruiting consecutive ibrutinib treated subjects to evaluate cardiovascular risk factors associated with the development of AF in patients diagnosed with hematological B-cell malignancies.Results: Of the 189 patients treated with ibrutinib and without AF at baseline, 54 (29%) developed AF. Cardiovascular risk factors associated with AF development were, older age, prior hypertension (HTN), history of heart failure (HF) and congenital heart disease. A patient with HF at baseline had a 1, 2, 6, and 12 month cumulative hazard of AF of 40%, 48%, 64%, and 71%, respectively. Patients with prior HTN without HF at baseline had a 1, 2, 6, and 12 month cumulative hazard of AF of 5%, 10%, 23%, and 31%, respectively while on ibrutinib therapy.Conclusions: The relationship between ibrutinib, cardiovascular comorbidities, and AF is through pre-existing cardiovascular disease. An individualized, multidisciplinary approach involving cardiologists should be considered when initiating ibrutinib, particularly when there is a history of HTN, HF or congenital heart disease. In such patients, there should be close cardiovascular monitoring and prompt intervention when AF develops to improve patient outcomes.

Utilization of the evidence from studies with no events in meta-analyses of adverse events: an empirical investigation.

BACKGROUNDS: Zero-events studies frequently occur in systematic reviews of adverse events, which consist of an important source of evidence. We aimed to examine how evidence of zero-events studies was utilized in the meta-analyses of systematic reviews of adverse events. METHODS: We conducted a survey of systematic reviews published in two periods: January 1, 2015, to January 1, 2020, and January 1, 2008, to April 25, 2011. Databases were searched for systematic reviews that conducted at least one meta-analysis of any healthcare intervention and used adverse events as the exclusive outcome. An adverse event was defined as any untoward medical occurrence in a patient or subject in healthcare practice. We summarized the frequency of occurrence of zero-events studies in eligible systematic reviews and how these studies were dealt with in the meta-analyses of these systematic reviews. RESULTS: We included 640 eligible systematic reviews. There were 406 (63.45%) systematic reviews involving zero-events studies in their meta-analyses, among which 389 (95.11%) involved single-arm-zero-events studies and 223 (54.93%) involved double-arm-zero-events studies. The majority (98.71%) of these systematic reviews incorporated single-arm-zero-events studies into the meta-analyses. On the other hand, the majority (76.23%) of them excluded double-arm-zero-events studies from the meta-analyses, of which the majority (87.06%) did not discuss the potential impact of excluding such studies. Systematic reviews published at present (2015-2020) tended to incorporate zero-events studies in meta-analyses than those published in the past (2008-2011), but the difference was not significant (proportion difference=-0.09, 95% CI -0.21 to 0.03, p = 0.12). CONCLUSION: Systematic review authors routinely treated studies with zero-events in both arms as "non-informative" carriers and excluded them from their reviews. Whether studies with no events are "informative" or not largely depends on the methods and assumptions applied, thus sensitivity analyses using different methods should be considered in future meta-analyses.

Metformin is comparable to insulin for pharmacotherapy in gestational diabetes mellitus: A network meta-analysis evaluating 6046 women.

CONTEXT: The comparative efficacy of gestational diabetes (GDM) treatments lack conclusive evidence for choice of first-line treatment. OBJECTIVES: The aim of this study was to compare the efficacy of metformin and glibenclamide to insulin using a core outcome set (COS) to unify outcomes across trials investigating the treatment of gestational diabetes mellitus. STUDY DESIGN: A network meta-analysis (NMA) was conducted. DATA-SOURCE: PubMed, Embase, and Cochrane Controlled Register of Trials were searched from inception to January 2020. STUDY SELECTION: RCTs that enrolled pregnant women who were diagnosed with GDM and that compared the efficacy of different pharmacological interventions for the treatment of GDM were included. META-ANALYSIS: A generalized pairwise modelling framework was employed. RESULTS: A total of 38 RCTs with 6046 participants were included in the network meta-analysis. Compared to insulin, the estimated effect of metformin indicated improvements for weight gain (WMD -2·39 kg; 95% CI -3·31 to -1·46), maternal hypoglycemia (OR 0.34; 95% CI 0.12 to 0·97) and LGA (OR 0.61; 95% CI 0.38 to 0·98). There were also improvements in estimated effects for neonatal hypoglycemia (OR 0.48; 95% CI 0.19 to 1·25), pregnancy induced hypertension (OR 0.63; 95% CI 0.37 to 1·06), and preeclampsia (OR 0.74; 95% CI 0.538 to 1·04), though with limited evidence against our model hypothesis of equivalence with insulin for these outcomes. CONCLUSION: Metformin is, at least, comparable to insulin for the treatment of GDM. Glibenclamide appears less favorable, in comparison to insulin, than metformin.

Prevalence and determinants of symptomatic COVID-19 infection among children and adolescents in Qatar: a cross-sectional analysis of 11 445 individuals.

There is a paucity of evidence about the prevalence and risk factors for symptomatic infection among children. This study aimed to describe the prevalence of symptomatic coronavirus disease 2019 (COVID-19) and its risk factors in children and adolescents aged 0-18 years in Qatar. We conducted a cross-sectional study of all children aged 0-18 years diagnosed with COVID-19 using polymerase chain reaction in Qatar during the period 1st March to 31st July 2020. A generalised linear model with a binomial family and identity link was used to assess the association between selected factors and the prevalence of symptomatic infection. A total of 11 445 children with a median age of 8 years (interquartile range (IQR) 3-13 years) were included in this study. The prevalence of symptomatic COVID-19 was 36.6% (95% confidence interval (CI) 35.7-37.5), and it was similar between children aged <5 years (37.8%), 5-9 years (34.3%) and 10 + years (37.3%). The most frequently reported symptoms among the symptomatic group were fever (73.5%), cough (34.8%), headache (23.2%) and sore throat (23.2%). Fever (82.8%) was more common in symptomatic children aged <5 years, while cough (38.7%) was more prevalent in those aged 10 years or older, compared to other age groups. Variables associated with an increased risk of symptomatic infection were; contact with confirmed cases (RD 0.21; 95% CI 0.20-0.23; P = 0.001), having visited a health care facility (RD 0.54; 95% CI 0.45-0.62; P = 0.001), and children aged under 5 years (RD 0.05; 95% CI 0.02-0.07; P = 0.001) or aged 10 years or older (RD 0.04; 95% CI 0.02-0.06; P = 0.001). A third of the children with COVID-19 were symptomatic with a higher proportion of fever in very young children and a higher proportion of cough in those between 10 and 18 years of age.

Association between response rates and monetary incentives in sample study: a systematic review and meta-analysis.

OBJECTIVE: To investigate the effect of monetary incentive and the dose-response relationship of participants' response rates in surveys. METHODS: Three databases were searched for randomised controlled trials (RCTs) that investigated the effect of monetary incentives on participants' first and final response rates. First response is defined as the responses after the participant was initially contacted and final response is defined as the responses after several reminders were sent. The potential dose-response relationship of the amount of monetary incentive on the relative response rate (RRR) was established by fitting a restricted cubic spline function based on the robust-error meta-regression model. RESULTS: 105 RCTs were identified. The first RRR increased by 49% (RRR=1.49; 95% CI 1.29 to 1.72) when monetary incentives were provided. Dose-response analysis revealed that an amount between US$6.25 and US$8 had the maximum effect on increasing the first response rate. On average, the final RRR increased almost by 20% (RRR=1.18; 95% CI 1.11 to 1.25) with monetary incentive compared to no-monetary incentive. An amount between US$10 and US$15 had the maximum effect on the final response rate, with an increase in the final RRR of 34% (RRR=1.34; 95% CI 1.19 to 1.51). There was a significant increase in the response rate when two or more reminders were sent. CONCLUSION: Monetary incentives and reminders improve the response rates. Future studies need to consider providing monetary incentives and sending at least two reminders to increase the response rate and reduce the chances of non-response bias.

Assessing the risk of angiotensin receptor blockers on major cardiovascular events: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Angiotensin receptor blockers (ARBs) are commonly used as a treatment for many cardiovascular diseases, but their safety has been called into question. The VALUE trial found an increased risk of myocardial infarction in participants receiving ARBs compared to other antihypertensive. The aim of the meta-analysis was to synthetize the available evidence of randomised controlled trials (RCTs) and elucidate if ARBs increase the risk of cardiovascular events. METHODS: A comprehensive search was conducted to identify RCTs that assessed the safety of ARBs. Titles and abstracts of all papers were independently screened by two authors. Data extraction and quality assessment were also performed independently. The relative risk (RR) of all-cause mortality, myocardial infarction, and stroke were pooled using the IVhet model. Multiple sensitivity analyses were conducted to assess the effect of ARBs by restricting the analysis to different participants' characteristics. RESULTS: Forty-five RCTs comprising of 170,794 participants were included in the analysis. The pooled estimates revealed that ARBs do not increase the risk of all-cause mortality (RR 1.00; 95%CI 0.97-1.04), myocardial infarction (RR 1.01; 95%CI 0.96-1.06), and stroke (RR 0.92; 95%CI 0.83-1.01). The sensitivity analysis did not yield a particular group of patients at increased risk of cardiovascular events with ARBs. Risk of all-cause mortality and stroke decreased with ARB when the proportion of smokers in a population was < 25% (RR 0.91; 95%CI 0.84-0.98) and in females (RR 0.76; 95%CI 0.68-0.84), respectively. CONCLUSIONS: ARBs do not increase the risk of major cardiovascular events and are safe for use in patients.

Risk of wheezing and asthma exacerbation in children treated with paracetamol versus ibuprofen: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Paracetamol and ibuprofen are the most commonly used medications for fever and pain management in children. While the efficacy appears similar with both drugs, there are contradictory findings related to adverse events. In particular, incidence of wheezing and asthma among children taking paracetamol compared to ibuprofen, remain unsettled. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) that compared wheezing and asthma exacerbations in children taking paracetamol versus ibuprofen. A comprehensive search was conducted in five databases. RCTs reporting on cases of wheezing or asthma exacerbations in infants or children after the administration of paracetamol or ibuprofen were included. The pooled effect size was estimated using the Peto's odds ratio. RESULTS: Five RCTs with 85,095 children were included in the analysis. The pooled estimate (OR 1.05; 95%CI 0.76-1.46) revealed no difference in the odds of developing asthma or presenting an exacerbation of asthma in children who received paracetamol compared to ibuprofen. When the analysis was restricted to RCTs that examined the incidence of asthma exacerbation or wheezing, the pooled estimate remained similar (OR 1.01; 95%CI 0.63-1.64). Additional bias adjusted quality effect sensitivity model yielded similar results (RR 1.03; 95%CI 0.84-1.28). CONCLUSION: Although, Ibuprofen and paracetamol appear to have similar tolerance and safety profiles in terms of incidence of asthma exacerbations in children, we suggest high quality trials with clear definition of asthma outcomes after receiving ibuprofen or paracetamol at varying doses with longer follow-up are warranted for any conclusive finding.

Drug-free Holidays: Compliance, Tolerability, and Acceptability of a 3-Day Atovaquone/Proguanil Schedule for Pretravel Malaria Chemoprophylaxis in Australian Travelers.

BACKGROUND: Poor compliance with chemoprophylaxis is a major contributing factor to the risk of malaria in travelers. Pre-travel chemoprophylaxis may improve compliance by enabling "drug-free holidays." The standard treatment dose of atovaquone/proguanil (250 mg/100 mg, 4 tablets/day for 3 days) provides protection against malaria for at least 4 weeks, and could therefore potentially be used for pre-travel chemoprophylaxis. In this study, we assessed the compliance, tolerability, and acceptability of the 3-day atovaquone/proguanil schedule for malarial chemoprophylaxis. METHODS: Two hundred thirty-three participants were recruited from 4 specialized travel medicine clinics in Australia. Adults traveling to malaria-endemic areas with low/medium risk for ≤4 weeks were enrolled and prescribed the 3-day schedule of atovaquone/proguanil, completed at least 1 day before departure. Questionnaires were used to collect data on demographics, travel destination, medication compliance, side effects, and reasons for choosing the 3-day schedule. RESULTS: Overall, 97.7% of participants complied with the 3-day schedule. Although side effects were reported in 43.3% of the participants, these were well tolerated, and mainly occurred during the first and second days. None of the participants developed malaria. The main reasons for choosing the 3-day schedule over standard chemoprophylaxis options were that it was easier to remember (72.1%), required taking fewer tablets (54.0%), and to help scientific research (54.0%). CONCLUSIONS: The 3-day atovaquone/proguanil schedule had an impressively high compliance rate, and was well tolerated and accepted by travelers. Further studies are required to assess the effectiveness of this schedule for chemoprophylaxis in travelers. CLINICAL TRIALS REGISTRATION: ACTRN12616000640404.

Using the human blood index to investigate host biting plasticity: a systematic review and meta-regression of the three major African malaria vectors.

BACKGROUND: The proportion of mosquito blood-meals that are of human origin, referred to as the 'human blood index' or HBI, is a key determinant of malaria transmission. METHODS: A systematic review was conducted followed by meta-regression of the HBI for the major African malaria vectors. RESULTS: Evidence is presented for higher HBI among Anopheles gambiae (M/S forms and Anopheles coluzzii/An. gambiae sensu stricto are not distinguished for most studies and, therefore, combined) as well as Anopheles funestus when compared with Anopheles arabiensis (prevalence odds ratio adjusted for collection location [i.e. indoor or outdoor]: 1.62; 95% CI 1.09-2.42; 1.84; 95% CI 1.35-2.52, respectively). This finding is in keeping with the entomological literature which describes An. arabiensis to be more zoophagic than the other major African vectors. However, analysis also revealed that HBI was more associated with location of mosquito captures (R2 = 0.29) than with mosquito (sibling) species (R2 = 0.11). CONCLUSIONS: These findings call into question the appropriateness of current methods of assessing host preferences among disease vectors and have important implications for strategizing vector control.

Health Outcomes from Multidrug-Resistant Salmonella Infections in High-Income Countries: A Systematic Review and Meta-Analysis.

BACKGROUND: Salmonella is a leading cause of foodborne enterocolitis worldwide. Antimicrobial use in food animals is the driving force for antimicrobial resistance among Salmonella particularly in high-income countries. Nontyphoidal Salmonella (NTS) infections that are multidrug resistant (MDR) (nonsusceptible to ≥1 agent in ≥3 antimicrobial categories) may result in more severe health outcomes, although these effects have not been systematically examined. We conducted a systematic review and meta-analysis to examine impacts of MDR NTS on disease outcomes in high-income settings. METHODS: We systematically reviewed the literature from scientific databases, including PubMed, Scopus, and grey literature sources, using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. We included peer-reviewed publications of case-control and cohort studies, outbreak investigations, and published theses, imposing no language restriction. We included publications from January 1, 1990 through September 15, 2016 from high-income countries as classified by the World Bank, and extracted data on duration of illness, hospitalization, morbidity and mortality of MDR, and pan-susceptible NTS infections. RESULTS: After removing duplicates, the initial search revealed 4258 articles. After further screening, 16 eligible studies were identified for the systematic review, but, only 9 of these were included in the meta-analysis. NTS serotypes differed among the reported studies, but serotypes Typhimurium, Enteritidis, Newport, and Heidelberg were the most often reported MDR pathogens. Salmonella infections that were MDR were associated with excess bloodstream infections (odds ratio [OR] 1.73; 95% confidence interval [CI] 1.32-2.27), more frequent hospitalizations (OR 2.51; 95% CI 1.38-4.58), and higher mortality (OR 3.54; 95% CI 1.10-11.40) when compared with pan-susceptible isolates. CONCLUSIONS: Our study suggests that MDR NTS infections have more serious health outcomes compared with pan-susceptible strains. With the emergence of MDR Salmonella strains in high-income countries, it is crucial to reduce the use of antimicrobials in animals and humans, and intervene to prevent foodborne infections.