Excess resource use and cost of drug-resistant infections for six key pathogens in Europe: a systematic review and Bayesian meta-analysis.

BACKGROUND: Quantifying the resource use and cost of antimicrobial resistance establishes the magnitude of the problem and drives action. OBJECTIVES: Assessment of resource use and cost associated with infections with six key drug-resistant pathogens in Europe. METHODS: A systematic review and Bayesian meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), Econlit databases, and grey literature for the period 1 January 1990, to 21 June 2022. STUDY ELIGIBILITY CRITERIA: Resource use and cost outcomes (including excess length of stay, overall costs, and other excess in or outpatient costs) were compared between patients with defined antibiotic-resistant infections caused by carbapenem-resistant (CR) Pseudomonas aeruginosa and Acinetobacter baumannii, CR or third-generation cephalosporin Escherichia coli (3GCREC) and Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium, and patients with drug-susceptible or no infection. PARTICIPANTS: All patients diagnosed with drug-resistant bloodstream infections (BSIs). INTERVENTIONS: NA. ASSESSMENT OF RISK OF BIAS: An adapted version of the Joanna Briggs Institute assessment tool, incorporating case-control, cohort, and economic assessment frameworks. METHODS OF DATA SYNTHESIS: Hierarchical Bayesian meta-analyses were used to assess pathogen-specific resource use estimates. RESULTS: Of 5969 screened publications, 37 were included in the review. Data were sparse and heterogeneous. Most studies estimated the attributable burden by, comparing resistant and susceptible pathogens (32/37). Four studies analysed the excess cost of hospitalization attributable to 3GCREC BSIs, ranging from -€ 2465.50 to € 6402.81. Eight studies presented adjusted excess length of hospital stay estimates for methicillin-resistant S. aureus and 3GCREC BSIs (4 each) allowing for Bayesian hierarchical analysis, estimating means of 1.26 (95% credible interval [CrI], -0.72 to 4.17) and 1.78 (95% CrI, -0.02 to 3.38) days, respectively. CONCLUSIONS: Evidence on most cost and resource use outcomes and across most pathogen-resistance combinations was severely lacking. Given the importance of this evidence for rational policymaking, further research is urgently needed.

Frequency of bloodstream infections caused by six key antibiotic-resistant pathogens for prioritization of research and discovery of new therapies in Europe: a systematic review.

BACKGROUND: To prioritize healthcare investments, ranking of infections caused by antibiotic-resistant bacteria should be based on accurate incidence data. OBJECTIVES: We performed a systematic review to estimate frequency measures of antimicrobial resistance for six key bacteria causing bloodstream infections (BSI) in European countries. DATA SOURCES: We searched PubMed, Web of Science, Embase databases, and the ECRAID-Base Epidemiological-Network platform. STUDY ELIGIBILITY CRITERIA: We included studies and surveillance systems assessing resistance-percentage, prevalence, or incidence-density of BSI because of carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli, third-generation cephalosporins-resistant E. coli and K. pneumoniae, vancomycin-resistant Enterococcus faecium, and methicillin-resistant Staphylococcus aureus. METHODS: Reviewers independently assessed published data and evaluated study quality with the modified Joanna Briggs Institute critical appraisal tool. Pooled estimates were determined using random effects meta-analysis. Consistency of data was assessed using random effects meta-regression (Wald test, p > 0.05). RESULTS: We identified 271 studies and 52 surveillance systems from 32 European countries. Forty-five studies (16%) reported on BSI, including 180 frequency measures most commonly as resistance-percentage (88, 48.9%). Among 309 frequency measures extracted from 24 (46%) surveillance systems, 278 (89%) were resistance-percentages. Frequency measures of methicillin-resistant S. aureus and vancomycin-resistant E. faecium BSI were more frequently reported from Southern Europe and Western Europe (80%), whereas carbapenem-resistant P. aeruginosa BSI from Northern Europe and Western Europe (88%). Highest resistance-percentages were detected for carbapenem-resistant A. baumannii (66% in Central Eastern Europe) and carbapenem-resistant K. pneumoniae (62.8% in Southern Europe). Pooled estimates showed lower resistance-percentages in community versus healthcare-associated infections and in children versus adults. Estimates from studies and surveillance systems were mostly consistent among European regions. The included data was of medium quality. DISCUSSION: Pathogen-specific frequency measures of antimicrobial resistance in BSI are insufficient to inform antibiotic stewardship and research and development strategies. Improving data collection and standardization of frequency measures is urgently needed.

EPI-Net One Health reporting guideline for antimicrobial consumption and resistance surveillance data: a Delphi approach.

Strategic and standardised approaches to analysis and reporting of surveillance data are essential to inform antimicrobial resistance (AMR) mitigation measures, including antibiotic policies. Targeted guidance on linking full-scale AMR and antimicrobial consumption (AMC)/antimicrobial residues (AR) surveillance data from the human, animal, and environmental sectors is currently needed. This paper describes the initiative whereby a multidisciplinary panel of experts (56 from 20 countries-52 high income, 4 upper middle or lower income), representing all three sectors, elaborated proposals for structuring and reporting full-scale AMR and AMC/AR surveillance data across the three sectors. An evidence-supported, modified Delphi approach was adopted to reach consensus among the experts for dissemination frequency, language, and overall structure of reporting; core elements and metrics for AMC/AR data; core elements and metrics for AMR data. The recommendations can support multisectoral national and regional plans on antimicrobials policy to reduce resistance rates applying a One Health approach.

External Validation of COVID-19 Risk Scores during Three Waves of Pandemic in a German Cohort-A Retrospective Study.

Several risk scores were developed during the COVID-19 pandemic to identify patients at risk for critical illness as a basic step to personalizing medicine even in pandemic circumstances. However, the generalizability of these scores with regard to different populations, clinical settings, healthcare systems, and new epidemiological circumstances is unknown. The aim of our study was to compare the predictive validity of qSOFA, CRB65, NEWS, COVID-GRAM, and 4C-Mortality score. In a monocentric retrospective cohort, consecutively hospitalized adults with COVID-19 from February 2020 to June 2021 were included; risk scores at admission were calculated. The area under the receiver operating characteristic curve and the area under the precision-recall curve were compared using DeLong's method and a bootstrapping approach. A total of 347 patients were included; 23.6% were admitted to the ICU, and 9.2% died in a hospital. NEWS and 4C-Score performed best for the outcomes ICU admission and in-hospital mortality. The easy-to-use bedside score NEWS has proven to identify patients at risk for critical illness, whereas the more complex COVID-19-specific scores 4C and COVID-GRAM were not superior. Decreasing mortality and ICU-admission rates affected the discriminatory ability of all scores. A further evaluation of risk assessment is needed in view of new and rapidly changing epidemiological evolution.

Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma.

Immune checkpoint inhibitors (ICIs) belong to the therapeutic armamentarium in advanced hepatocellular carcinoma (HCC). However, only a minority of patients benefit from immunotherapy. Therefore, we aimed to identify indicators of therapy response. This multicenter analysis included 99 HCC patients. Progression-free (PFS) and overall survival (OS) were studied by Kaplan-Meier analyses for clinical parameters using weighted log-rank testing. Next-generation sequencing (NGS) was performed in a subset of 15 patients. The objective response (OR) rate was 19% median OS (mOS)16.7 months. Forty-one percent reached a PFS > 6 months; these patients had a significantly longer mOS (32.0 vs. 8.5 months). Child-Pugh (CP) A and B patients showed a mOS of 22.1 and 12.1 months, respectively. Ten of thirty CP-B patients reached PFS > 6 months, including 3 patients with an OR. Tumor mutational burden (TMB) could not predict responders. Of note, antibiotic treatment within 30 days around ICI initiation was associated with significantly shorter mOS (8.5 vs. 17.4 months). Taken together, this study shows favorable outcomes for OS with low AFP, OR, and PFS > 6 months. No specific genetic pattern, including TMB, could identify responders. Antibiotics around treatment initiation were associated with worse outcome, suggesting an influence of the host microbiome on therapy success.

Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: a four-year quasi-experimental prospective study.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients' group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients' group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.

Variation of effect estimates in the analysis of mortality and length of hospital stay in patients with infections caused by bacteria-producing extended-spectrum beta-lactamases: a systematic review and meta-analysis.

OBJECTIVE: To assess the variation of effect estimates in the analysis of mortality and length of stay (LOS) in patients with infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. DESIGN: Systematic review and meta-analysis METHODS: Literature search for clinical studies from 1 January 1960 to 1 October 2018 was conducted in PubMed. Primary outcomes were risk ratios (RRs) of all-cause and attributable mortality and weighted mean differences (WMDs) in LOS in patients with bloodstream infections (BSIs) and non-invasive infections. Any change in the effect estimates was assessed by grouping studies according to design, setting, economy-based country classification, reporting period, microbiological aetiology, infection type and adjustment for appropriateness of empirical treatment. The impact of ESBL production was calculated using random-effect meta-analysis and heterogeneity was evaluated by I2 statistics and metaregression. RESULTS: Eighty-four studies including 22 030 patients and 149 outcome measures were included in the meta-analysis. Most studies were retrospective cohorts from high-income countries, providing unadjusted estimates. ESBL production in patients with BSIs (56 studies) increased the RR for all-cause mortality by a factor of 1.70 (95% CI 1.52 to 1.90; p<0.001), attributable mortality (16 studies) by 1.75 (95% CI 1.448 to 2.108; p<0.001) and WMD in the intensive care unit by 3.07 days (95% CI 1.61 to 4.54; p<0.001). WMD in hospital LOS was significantly higher in BSIs (4.41 days; 95% CI 3.37 to 5.46; p<0.001) and non-invasive (2.19 days; 95% CI 1.56 to 2.81; p<0.001). Subgroup analyses showed variation of estimates by study design, population, strain and assessment of appropriateness of empiric treatment. High heterogeneity was observed in all analyses. CONCLUSIONS: Current evidence of the clinical burden of infections caused by ESBL-producing bacteria is highly heterogeneous and based mainly on unadjusted estimates derived from retrospective studies. Despite these limitations, ESBL production in strains causing BSIs seems associated with higher all-cause and attributable mortality and longer hospitalisation.

Gross national income and antibiotic resistance in invasive isolates: analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO priority list.

OBJECTIVES: To assess the association between country income status and national prevalence of invasive infections caused by the top-ranked bacteria on the WHO priority list: carbapenem-resistant (CR) Acinetobacter spp., Klebsiella spp. and Pseudomonas aeruginosa; third-generation cephalosporin-resistant (3GCR) Escherichia coli and Klebsiella spp.; and MRSA and vancomycin-resistant Enterococcus faecium (VR E. faecium). METHODS: Active surveillance systems providing yearly prevalence data from 2012 onwards for the selected bacteria were included. The gross national income (GNI) per capita was used as the indicator for income status of each country and was log transformed to account for non-linearity. The association between antibiotic prevalence data and GNI per capita was investigated individually for each bacterium through linear regression. RESULTS: Surveillance data were available from 67 countries: 38 (57%) were high income, 16 (24%) upper-middle income, 11 (16%) lower-middle income and two (3%) low income countries. The regression showed significant inverse association (P<0.0001) between resistance prevalence of invasive infections and GNI per capita. The highest rate of increase per unit decrease in log GNI per capita was observed in 3GCR Klebsiella spp. (22.5%, 95% CI 18.2%-26.7%), CR Acinetobacter spp. (19.2% 95% CI 11.3%-27.1%) and 3GCR E. coli (15.3%, 95% CI 11.6%-19.1%). The rate of increase per unit decrease in log GNI per capita was lower in MRSA (9.5%, 95% CI 5.2%-13.7%). CONCLUSIONS: The prevalence of invasive infections caused by the WHO top-ranked antibiotic-resistant bacteria is inversely associated with GNI per capita at the global level. Public health interventions designed to limit the burden of antimicrobial resistance should also consider determinants of poverty and inequality, especially in lower-middle income and low income countries.

Estimating the number of infections caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae in 2014: a modelling study.

BACKGROUND: The number of infections caused by resistant organisms is largely unknown. We estimated the number of infections worldwide that are caused by the WHO priority pathogens third-generation cephalosporin-resistant and carbapenem-resistant Escherichia coli and Klebsiella pneumoniae. METHODS: We calculated a uniform weighted mean incidence of serious infections caused by antibiotic-susceptible E coli and K pneumoniae using data from 17 countries. Using this uniform incidence, as well as population sizes and country-specific resistance levels, we estimated the number of infections caused by third-generation cephalosporin-resistant and carbapenem-resistant E coli and K pneumoniae in 193 countries in 2014. We also calculated interval estimates derived from changing the fixed incidence of susceptible infections to 1 SD below and above the weighted mean. We compared an additive model with combination models in which resistant infections were replaced by susceptible infections. We distinguished between higher-certainty regions (those with good-quality data sources for resistance levels and resistance ≤30%), moderate-certainty regions (those with good-quality data sources for resistance levels and including some countries with resistance >30%), and low-certainty regions (those in which good-quality data sources for resistance levels were unavailable for countries comprising at least 20% of the region's population, regardless of resistance level). FINDINGS: Using the additive model, we estimated that third-generation cephalosporin-resistant E coli and K pneumoniae caused 6·4 million (interval estimate 3·5-9·2) bloodstream infections and 50·1 million (27·5-72·8) serious infections in 2014; estimates were 5·5 million (3·0-7·9) bloodstream infections and 43·1 million (23·6-62·2) serious infections in the 25% replacement model, 4·6 million (2·5-6·6) bloodstream infections and 36·0 million (19·7-52·2) serious infections in the 50% replacement model, and 3·7 million (2·0-5·3) bloodstream infections and 28·9 million (15·8-41·9) serious infections in the 75% replacement model. Carbapenem-resistant strains caused 0·5 million (0·3-0·7) bloodstream infections and 3·1 million (1·8-4·5) serious infections based on the additive model, 0·5 million (0·3-0·7) bloodstream infections and 3·0 million (1·7-4·3) serious infections based on the 25% replacement model, 0·4 million (0·2-0·6) bloodstream infections and 2·8 million (1·6-4·1) serious infections based on the 50% replacement model, and 0·4 million (0·2-0·6) bloodstream infections and 2·7 million (1·5-3·8) serious infections based on the 75% replacement model. INTERPRETATION: To our knowledge, this study is the first to report estimates of the global number of infections caused by antibiotic-resistant priority pathogens. Uncertainty stems from scant data on resistance levels from low-income and middle-income countries and insufficient knowledge regarding resistance dynamics when resistance is high. FUNDING: Innovative Medicines Initiative.

Antimicrobial resistance rates in gram-positive bacteria do not drive glycopeptides use.

Surveillance data are considered essential to appropriate empiric antibiotic therapy and stewardship. The objective of this study was to determine if a change in the rates of antibiotic resistance impacts antibiotic use in European hospitals. Glycopeptides use was selected to study the correlation between resistance rates and antibiotic use because of the restricted spectrum against resistant gram positive bacteria. PubMed, ECDC databases and national/regional surveillance systems were searched to identify glycopeptides´ consumption in defined daily dose per 1000 inhabitant-days (DID) and rate of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase negative staphylococci (MRCoNS), and vancomycin-resistant enterococci (VRE) in bloodstream infections (BSIs) in European countries between 1997 and 2015. Time trends were studied and associations between DID and BSI resistance rates were tested using multi-level mixed effect models. To account for the gap in the publication and dissemination of the yearly resistance data, a 2-year lag in the resistance rates was applied. Data on glycopeptides´ DID and resistance rates of target microorganisms in blood cultures were identified among 31 countries over a 19-year period. Glycopeptides use significantly increased (p<0·0001) while rates of MRSA BSIs decreased in majority of the countries (p<0·0001) and MRCoNS and VRE BSIs remained stable. Variation in glycopeptides' DID was not associated with variation in BSIs due to MRSA (p = 0·136) and VRE (p = 0·613). After adjusting for MRCoNS and VRE resistance rates, among 21 countries, 11 (52%) had a concordant and 10 (48%) a discordant trend in yearly glycopeptides´ DID and MRSA BSI rates. No correlation was found between resistance rates and DID data even among 8 countries with more than 5% decrease in MRSA rates over time. (RC -0·009, p = 0·059). Resistance rate of MRSA, MRCoNS, and VRE BSIs does not impact DID of glycopeptides in European hospitals. This finding is key to redefining the role and structure of antimicrobial surveillance and stewardship programmes.

Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis.

BACKGROUND: Antibiotic stewardship programmes have been shown to reduce antibiotic use and hospital costs. We aimed to evaluate evidence of the effect of antibiotic stewardship on the incidence of infections and colonisation with antibiotic-resistant bacteria. METHODS: For this systematic review and meta-analysis, we searched PubMed, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Web of Science for studies published from Jan 1, 1960, to May 31, 2016, that analysed the effect of antibiotic stewardship programmes on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infections in hospital inpatients. Two authors independently assessed the eligibility of trials and extracted data. Studies involving long-term care facilities were excluded. The main outcomes were incidence ratios (IRs) of target infections and colonisation per 1000 patient-days before and after implementation of antibiotic stewardship. Meta-analyses were done with random-effect models and heterogeneity was calculated with the I2 method. FINDINGS: We included 32 studies in the meta-analysis, comprising 9 056 241 patient-days and 159 estimates of IRs. Antibiotic stewardship programmes reduced the incidence of infections and colonisation with multidrug-resistant Gram-negative bacteria (51% reduction; IR 0·49, 95% CI 0·35-0·68; p<0·0001), extended-spectrum ß-lactamase-producing Gram-negative bacteria (48%; 0·52, 0·27-0·98; p=0·0428), and meticillin-resistant Staphylococcus aureus (37%; 0·63, 0·45-0·88; p=0·0065), as well as the incidence of C difficile infections (32%; 0·68, 0·53-0·88; p=0·0029). Antibiotic stewardship programmes were more effective when implemented with infection control measures (IR 0·69, 0·54-0·88; p=0·0030), especially hand-hygiene interventions (0·34, 0·21-0·54; p<0·0001), than when implemented alone. Antibiotic stewardship did not affect the IRs of vancomycin-resistant enterococci and quinolone-resistant and aminoglycoside-resistant Gram-negative bacteria. Significant heterogeneity between studies was detected, which was partly explained by the type of interventions and co-resistance patterns of the target bacteria. INTERPRETATION: Antibiotic stewardship programmes significantly reduce the incidence of infections and colonisation with antibiotic-resistant bacteria and C difficile infections in hospital inpatients. These results provide stakeholders and policy makers with evidence for implementation of antibiotic stewardship interventions to reduce the burden of infections from antibiotic-resistant bacteria. FUNDING: German Center for Infection Research.

EpideMiology and control measures of outBreaks due to Antibiotic-Resistant orGanisms in EurOpe (EMBARGO): a systematic review protocol.

INTRODUCTION: Improving our understanding of outbreaks due to antibiotic-resistant bacteria (ARB) and their control is critical in the current public health scenario. The threat of outbreaks due to ARB requires multifaceted efforts. However, a global overview of epidemiological characteristics of outbreaks due to ARB and effective infection control measures is missing. In this paper, we describe the protocol of a systematic review aimed at mapping and characterising the epidemiological aspects of outbreaks due to ARB and infection control measures in European countries. METHODS AND ANALYSIS: The databases MEDLINE, Web of Knowledge and Cochrane library will be searched using a 3-step search strategy. Selection of articles for inclusion will be performed by 2 reviewers using predefined eligibility criteria. All study designs will be included if they report an outbreak and define the microbiological methods used for microorganism identification. The target bacteria will be methicillin-resistant and vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, ceftazidime-resistant and carbapenem-resistant Acinetobacter baumannii, ceftazidime-resistant and carbapenem-resistant Pseudomonas aeruginosa, ciprofloxacin-resistant Escherichia coli, extended-spectrum ß-lactamase-producing E. coli and Klebsiella pneumoniae, carbapenem-resistant and carbapenamase-producing Enterobacteriaceae. Data will be extracted using a tailored pilot tested form and the quality of reporting will be assessed using the ORION (Outbreak Reports and Intervention Studies Of Nosocomial infections) tool. Data will be synthesised and reported by the type of ARB, setting and country. Infection control measures and bundles of measures will be described. The effectiveness will be reported as defined by the authors. Regression analysis will be used to define independent factors associated with outbreaks' control. Heterogeneity between studies will be assessed by forest plots and I² statistics. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study. Findings will be disseminated through journal publication and conference presentations and talks.

Aortic Atherosclerosis Determines Increased Retrograde Blood Flow as a Potential Mechanism of Retrograde Embolic Stroke.

BACKGROUND: Retrograde brain embolization from complex plaques of the proximal descending aorta (DAo) has been identified as a new potential mechanism of stroke. Our purpose was to identify predictors of increased retrograde aortic blood flow indicating an elevated risk of brain embolization from the DAo. METHODS: A total of 485 patients with acute ischemic stroke were prospectively included and underwent transesophageal echocardiography. Blood flow velocities in the proximal DAo were studied using 2D pulse-wave Doppler ultrasound. Velocity-time integrals (VTI) were calculated for antegrade and retrograde velocity directions. The ratio (VTIretrograde/VTIantegrade) was used to estimate retrograde flow extent. Associations between patient demographics, cardiovascular risk factors, echocardiographic parameters, and VTIratio were analyzed using multivariate linear regression. RESULTS: Retrograde blood flow in the DAo occurred in all patients. Velocity profiles in the proximal DAo were as follows (mean ± SD): VTIantegrade = 21.1 ± 6.5, VTIretrograde = 11.0 ± 3.6, and VTIratio = 0.54 ± 0.16. Diameter (r = 0.25, p < 0.001), presence of complex plaques (r = 0.12, p = 0.007), and reduced strain of the DAo (r = -0.23, p < 0.001) had significant partial effects in a predictor model based on predefined variables, which predicted 26% (adjusted R2 = 0.26) of the variance in VTIratio. A unit increase in the DAo diameter was associated with a 2% increase in VTIratio (95% CI 1-2.8%, p < 0.001). Presence of complex plaques increased VTIratio by 7% (95% CI 2-13%, p = 0.007) and an increase in strain by 0.1 indicated a decrease in VTIratio by about 11% (95% CI 6.2-15.5%, p < 0.001). Complex atheroma was found in the proximal DAo of 79 subjects, of which 40 (50.6%) had a VTIratio above average (VTIratio ≥0.54) compared to 87 of 261 (33.3%) patients without any complex plaques (p < 0.001). Twenty-five of 79 (31.7%) patients with complex DAo plaques had a VTIratio ≥0.60, which indicates a high likelihood of retrograde pathline length of ≥3 cm and thus increased risk of retrograde cerebral embolization. Stroke etiology of those 25 patients was determined in 13 and cryptogenic in 12 cases. CONCLUSIONS: Retrograde blood flow in the DAo was found in all stroke patients. However, it increased further in patients with concomitant complex plaques, low strain, and/or large aortic diameter, that is, in those with atherosclerosis of the DAo. Accordingly, such patients may be predisposed to retrograde embolization in case of occurrence of a complex plaque in proximity to a brain-supplying artery.

Gender differences in antibiotic prescribing in the community: a systematic review and meta-analysis.

OBJECTIVES: Determinants of inappropriate antibiotic prescription in the community are not clearly defined. The objective of this study was to perform a systematic review and meta-analysis evaluating gender differences in antibiotic prescribing in primary care. METHODS: All studies analysing antibiotic prescription in primary care were eligible. PubMed and MEDLINE entries with publication dates from 1976 until December 2013 were searched. The primary outcomes were the incidence rate ratio (IRR) (measured as DDD/1000 inhabitants/day) and the prevalence rate ratio (PRR) (measured as prevalence rate/1000 inhabitants) of antimicrobial prescription, stratified by gender, age and antibiotic class. Random-effects estimates of the IRR and PRR and standard deviations were calculated. RESULTS: Overall, 576 articles were reviewed. Eleven studies, comprising a total of 44 333 839 individuals, were included. The studies used data from prospective national (five studies) or regional (six studies) surveillance of community pharmacy, insurance or national healthcare systems. Women were 27% (PRR 1.27 ±â€Š0.12) more likely than men to receive an antibiotic prescription in their lifetimes. The amount of antibiotics prescribed to women was 36% (IRR 1.36 ±â€Š0.11) higher than that prescribed for men in the 16 to 34 years age group and 40% (IRR 1.40 ±â€Š0.03) greater in the 35 to 54 years age group. In particular, the amounts of cephalosporins and macrolides prescribed to women were 44% (IRR 1.44 ±â€Š0.30) and 32% (IRR 1.32 ±â€Š0.15) higher, respectively, than those prescribed for men. CONCLUSIONS: This meta-analysis shows that women in the 16 to 54 years age group receive a significantly higher number of prescriptions of cephalosporins and macrolides in primary care than men do. Prospective studies are needed to address reasons for gender inequality in prescription and to determine whether a difference in adverse events, including resistance development, also occurs.

A framework to assess the value of application of formal criteria to check clinical relevance in RCTs as part of a benefit assessment strategy.

Recently, the topic of assessing clinical relevance on top of statistical significance in the analysis of randomized control trials (RCTs) has got increasing attention, in particular as part of benefit assessments. Several formal criteria to serve this purpose have been published. In this paper, we present a framework to assess the value of the application of such criteria. We propose to quantify the need for the assessment of clinical relevance by the actual risk of having accepted a benefit for a treatment with an irrelevant effect in a successful RCT. We then study how this risk can be controlled by two popular criteria based on comparing the effect estimate or the lower bound of the confidence interval with a given threshold. We further propose to quantify the impact of using formal criteria by considering the expected costs when specifying error-specific costs for each of the three possible types of errors: A benefit may be accepted for a treatment, which is actually inferior, or which is not inferior, but only implies an irrelevant improvement, or a benefit may be rejected for a treatment implying a relevant improvement. This way we can demonstrate that the impact depends on parameters which are typically not explicitly defined in the frame of benefit assessments. Depending on the values of these parameters, formal checks of clinical relevance may imply better decisions on average, but they may also imply more harm than good on average.

Choice of non-inferiority (NI) margins does not protect against degradation of treatment effects on an average--an observational study of registered and published NI trials.

OBJECTIVE: NI margins have to be chosen appropriately to control the risk of degradation of treatment effects in non-inferiority (NI) trials. We aimed to study whether the current choice of NI margins protects sufficiently against a degradation of treatment effect on an average. STUDY DESIGN AND SETTING: NI trials reflecting current practice were assembled and for each trial, the NI margin was translated into a likelihood of degradation. The likelihood of degradation was calculated as the conditional probability of a treatment being harmful given that it is declared non-inferior in the trial, using simulation. Its distribution among the NI trials was then studied to assess the potential risk of degradation. RESULTS: The median (lower/upper quartile) NI margin among 112 binary outcome NI trials corresponded to an odds ratio of 0.57(0.45, 0.66), while among 38 NI trials with continuous outcome, to a Cohen's d of -0.42(-0.54, -0.31) and a hazard ratio of 0.82(0.73, 0.86) among 24 survival outcome NI trials. Overall, the median likelihood of degradation was 56% (45%, 62%). CONCLUSION: Only two fifths of the current NI trials had a likelihood of degradation lower than 50%, suggesting that, in majority of the NI trials, there is no sufficient protection against degradation on an average. We suggest a third hurdle for the choice of NI margins, thus contributing a sufficient degree of protection.

Motivational interventions in the management of HbA1c levels: a systematic review and meta-analysis.

AIMS: To review the diabetes literature in order to examine the effect of motivational interventions on treatment outcome as measured by changes in glycated haemoglobin. METHODS: Relevant databases were systematically searched for randomised controlled trials in which motivational interventions were examined in relation to treatment outcome in people with type 1 and type 2 diabetes mellitus. RESULTS: The 13 studies identified for review included 1223 participants diagnosed with type 1 diabetes and 1895 participants diagnosed with type 2 diabetes. The analysis showed a 0.17% (95% CI: -0.09, 0.43%) improvement in glycemic control in people who received a motivational intervention compared to a control group, however, the effect was not statistically significant. CONCLUSIONS: The impact of motivational interventions in the management of blood glucose levels appears to be limited. However, due to the small number of studies and issues of heterogeneity caution in interpreting the present findings is advised. Moreover, the unique contribution of motivational interventions may be better assessed by outcomes such as behaviour change and other intermediate outcomes. Further research examining the delivery and focus of motivational interventions in helping people manage their diabetes is recommended. The clinical implications of the present findings are therefore uncertain pending further research.

About half of the noninferiority trials tested superior treatments: a trial-register based study.

OBJECTIVES: A concern that noninferiority (NI) trials pose a risk of degradation of the treatment effects is prevalent. Thus, we aimed to determine the fraction of positive true effects (superiority rate) and the average true effect of current NI trials based on data from registered NI trials. STUDY DESIGN AND SETTING: All NI trials carried out between 2000 and 2007 analyzing the NI of efficacy as the primary objective and registered in one of the two major clinical trials registers were studied. Having retrieved results from these trials, random effects modeling of the effect estimates was performed to determine the distribution of true effects. RESULTS: Effect estimates were available for 79 of 99 eligible trials identified. For trials with binary outcome, we estimated a superiority rate of 49% (95% confidence interval = 27-70%) and a mean true log odds ratio of -0.005 (-0.112, 0.102). For trials with continuous outcome, the superiority rate was 58% (41-74%) and the mean true effect as Cohen's d of 0.06 (-0.064, 0.192). CONCLUSIONS: The unanticipated finding of a positive average true effect and superiority of the new treatment in most NI trials suggest that the current practice of choosing NI designs in clinical trials makes degradation on average unlikely. However, the distribution of true treatment effects demonstrates that, in some NI trials, the new treatment is distinctly inferior.