Efficacy and safety of a synbiotic infant formula for the prevention of respiratory and gastrointestinal infections: a randomized controlled trial.

BACKGROUND: Early life nutrition is crucial for the development of the gut microbiota that, in turn, plays an essential role in the maturation of the immune system and the prevention of infections. OBJECTIVES: The aim of this study was to investigate whether feeding synbiotic infants and follow-on formulas during the first year of life reduces the incidence rate (IR) of infectious diarrhea compared with standard formulas. Secondary endpoints included the IR of other infectious diseases as well as fecal milieu parameters. METHODS: In this double-blind, controlled trial, 460 healthy, 1-mo-old infants were randomly assigned to receive a synbiotic [galacto-oligosaccharides (GOS)/Limosilactobacillus fermentum CECT 5716] (IF, n = 230) or a control formula (CF, n = 230) until 12 mo of age. A reference group of breastfed infants (HM, n = 80) was included. Data on infections were recorded throughout the study period and stool samples were collected at 4 and 12 mo of age. RESULTS: IR of infectious diarrhea during the first year of life was 0.60 (CF), 0.56 (IF), and 0.29 (HM), with no statistically significant difference between groups. The IR of lower respiratory tract infections, 1 of the secondary endpoints, however, was lower in IF than in CF [0.79 compared with 1.01, IR ratio = 0.77 (0.60-1.00)]. Additionally, fecal pH was significantly lower at 4 mo (P < 0.0001), whereas secretory IgA was significantly higher at 12 mo of age (P = 0.015) in IF compared with CF. CONCLUSIONS: Although no difference is observed in the incidence of diarrhea, consumption of a synbiotic formula containing L. fermentum CECT5716 and GOS in infancy may reduce the incidence of lower respiratory tract infections and affect the immune system and fecal milieu. Additional research is warranted to further investigate the potential interaction of the gut-lung axis. This trial was registered at clinicaltrials.gov as NCT02221687.

Microbiological Diagnosis of Osteoarticular Infections: Comparison between BacT/Alert Bottles and Schaedler Broth.

Microbiological diagnosis of osteoarticular infections (OAIs) is based on culture on several media. Experts recommend the use of liquid media, such as Schaedler broth, but many laboratories use blood culture media with automated detection instead for convenience. We aimed to evaluate the performance of culturing in BacT/Alert (bioMérieux) bottles for the microbiological diagnosis of OAI versus culturing in Schaedler broth. This prospective study was conducted on all osteoarticular specimens sent to the microbiology laboratories of the Versailles and Diaconesses Croix Saint-Simon hospitals between October 2016 and February 2017. Each sample was inoculated onto solid agar, into BacT/Alert bottles incubated for 14 days, and into a Schaedler broth incubated for 14 days with daily reading. The gold standard was defined as follow: OAI was diagnosed for a patient if at least two samples were positive for a nonskin microorganism and at least three for a cutaneous species. The times to detection were compared. A total of 1,616 specimens from 349 patients were collected. BacT/Alert bottles were significantly more sensitive than the Schaedler process for OAI diagnosis (114/135 OAI detected by BacT/Alert bottles; 91/135 OAI detected by Schaedler broth; +17.0% [95% confidence interval {CI}, 6.8%, 27.3%]; P = 0.0004). The time to detection was significantly shorter using BacT/Alert bottles (2.0 ± 2.2 days) than using Schaedler broth (4.6 ± 3.6 days, P < 0.0001). The culture of osteoarticular specimens in BacT/Alert bottles allows bacterial enrichment with an automated detection of positivity. Their use decreased detection time and increased sensitivity, making it a useful tool for the diagnosis of OAI that should be included among the recommended media. IMPORTANCE Microbiological diagnosis of OAI is based on culture on several media. French experts recommend the use of liquid media such as Schaedler broth, but many laboratories use blood culture media with automated detection in substitution because it is more convenient. We report here a prospective multicentric study evaluating the performance of culture in BacT/Alert (bioMérieux) bottles for microbiological diagnosis of OAI in comparison with culture in Schaedler broth. A total of 1,616 osteoarticular specimens from 349 patients were collected and inoculated onto agar, into BacT/Alert aerobic and anaerobic bottles, and into a Schaedler broth. BacT/Alert bottles were significantly more sensitive than the Schaedler process for OAI diagnosis (+17.0% [95% CI, 6.8%, 27.3%], P = 0.0004). The time to detection was significantly shorter for the BacT/Alert bottles (2.0 ± 2.2 days) than for Schaedler broth (4.6 ± 3.6 days, P < 0.0001). This study suggests that the use of BacT/Alert bottles should be recommended in microbiological diagnosis of OAI.

G-computation, propensity score-based methods, and targeted maximum likelihood estimator for causal inference with different covariates sets: a comparative simulation study.

Controlling for confounding bias is crucial in causal inference. Distinct methods are currently employed to mitigate the effects of confounding bias. Each requires the introduction of a set of covariates, which remains difficult to choose, especially regarding the different methods. We conduct a simulation study to compare the relative performance results obtained by using four different sets of covariates (those causing the outcome, those causing the treatment allocation, those causing both the outcome and the treatment allocation, and all the covariates) and four methods: g-computation, inverse probability of treatment weighting, full matching and targeted maximum likelihood estimator. Our simulations are in the context of a binary treatment, a binary outcome and baseline confounders. The simulations suggest that considering all the covariates causing the outcome led to the lowest bias and variance, particularly for g-computation. The consideration of all the covariates did not decrease the bias but significantly reduced the power. We apply these methods to two real-world examples that have clinical relevance, thereby illustrating the real-world importance of using these methods. We propose an R package RISCA to encourage the use of g-computation in causal inference.

Impact of pemetrexed chemotherapy on the gut microbiota and intestinal inflammation of patient-lung-derived tumor xenograft (PDX) mouse models.

Chemotherapy remains the gold standard for advanced cancer. Pemetrexed, a chemotherapeutic agent used in non-small cell lung cancer, can induce significant side effects in patients. Although microbiota's role in the efficacy and/or toxicity of chemotherapy agents has been demonstrated, the impacts of pemetrexed on the gut microbiota and on gastrointestinal inflammation remain unknown. The objective of this study was to evaluate the impact of pemetrexed and the tumor graft on the gut microbiota composition in immunodeficient mice. The faecal microbiota composition was studied with metabarcoding before, 24-h and one week after treatment. The colon epithelial barrier integrity was evaluated by histological examination, intestinal permeability measurement, and selected cytokines quantification. The tumor graft induced some variations in the microbiota composition. Pemetrexed further increased the relative abundance of Enterobacteriaceae and 3 families from the Firmicutes phylum: Enterococcaceae, Lactobacillaceae and Streptococcaceae. Pemetrexed also significantly altered the epithelial barrier integrity, which was associated with early inflammation. This pilot study shows that the association of a lung tumor graft with pemetrexed causes an alteration in the microbiota composition. Such information increases our knowledge about the impact of chemotherapy on the microbiota, which could help to minimize side effects and improve therapeutic effectiveness in the future.

Structural valve deterioration of bioprosthetic aortic valves: An underestimated complication.

OBJECTIVES: Structural valve deterioration (SVD) remains a major bioprosthesis-related complication, as recently described for the Mitroflow valve (models LX and 12A) (LivaNova, London, United Kingdom). The real incidence of the SVD risk remains unclear, often due to methodologic pitfalls by systematically using the Kaplan-Meier estimator and/or the Cox model. In this report, we propose for the first time a precise statistical modeling of this issue. METHODS: Five hundred sixty-one patients who underwent aortic valve replacement with the aortic Mitroflow valve between 2002 and 2007 were included. We used an illness-death model for interval-censored data. Median follow-up was 6.6 years; 103 cases of SVD were diagnosed. RESULTS: The 4-year and 7-year SVD cumulative incidences after the first anniversary of surgery were 15.2% (95% confidence interval, 11.9-19.1) and 31.0% (95% confidence interval, 25.8-37.2), respectively. Female gender, dyslipidemia, chronic obstructive pulmonary disease, and severe patient-prosthesis mismatch were significant risk factors of SVD. The occurrence of SVD was associated with a 2-fold increase in the risk of death. CONCLUSIONS: Appropriate statistical models should be used to avoid underestimating the SVD complication associated with worse long-term survival.

Standardized and weighted time-dependent receiver operating characteristic curves to evaluate the intrinsic prognostic capacities of a marker by taking into account confounding factors.

Time-dependent receiver operating characteristic curves allow to evaluate the capacity of a marker to discriminate between subjects who experience the event up to a given prognostic time from those who are free of this event. In this article, we propose an inverse probability weighting estimator of a standardized and weighted time-dependent receiver operating characteristic curve. This estimator provides a measure of the prognostic capacities by taking into account potential confounding factors. We illustrate the robustness of the estimator by a simulation-based study and its usefulness by two applications in kidney transplantation.

Inverse probability weighting to control confounding in an illness-death model for interval-censored data.

Multistate models with interval-censored data, such as the illness-death model, are still not used to any considerable extent in medical research regardless of the significant literature demonstrating their advantages compared to usual survival models. Possible explanations are their uncommon availability in classical statistical software or, when they are available, by the limitations related to multivariable modelling to take confounding into consideration. In this paper, we propose a strategy based on propensity scores that allows population causal effects to be estimated: the inverse probability weighting in the illness semi-Markov model with interval-censored data. Using simulated data, we validated the performances of the proposed approach. We also illustrated the usefulness of the method by an application aiming to evaluate the relationship between the inadequate size of an aortic bioprosthesis and its degeneration or/and patient death. We have updated the R package multistate to facilitate the future use of this method.

Is pre-transplant sensitization against angiotensin II type 1 receptor still a risk factor of graft and patient outcome in kidney transplantation in the anti-HLA Luminex era? A retrospective study.

We aimed to assess the correlation of anti-angiotensin II type 1 receptor antibodies (anti-AT1R-Abs) before transplantation on a multicentric cohort of kidney transplant recipients (2008-2012), under tacrolimus and mycophenolate mofetil (MMF), screened by Luminex technology for anti-HLA immunization. Anti-AT1R antibody levels were measured by ELISA in pretransplantation sera of 940 kidney recipients from three French centers of the DIVAT cohort. Multivariable Cox models estimated the association between pretransplant anti-angiotensin II type 1 receptor antibodies and time to acute rejection episodes (ARE) or time to graft failure. Within our cohort, 387 patients (41.2%) had pretransplant AT1R-Abs higher than 10 U/ml and only 8% (72/970) greater than 17 U/ml. The cumulative probability of clinically relevant (cr)-ARE was 22.5% at 1 year post-transplantation [95% CI (19.9-25.4%)]. The cumulative probability of graft failure and patient death were 10.6% [95% CI (8.4-13.3%)] and 5.7% [95% CI (4.0-8.1%)] at 3 years post-transplantation, respectively. Multivariate Cox models indicated that pretransplant anti-AT1R antibody levels higher than 10 U/ml were not significantly independently associated with higher risks of acute rejection episodes [HR = 1.04, 95% CI (0.80-1.35)] nor with risk of graft failure [HR = 0.86, 95% CI (0.56-1.33)]. Our study did not confirm an association between pretransplant anti-AT1R antibody levels and kidney transplant outcomes.

A multistate additive relative survival semi-Markov model.

Medical researchers are often interested to investigate the relationship between explicative variables and times-to-events such as disease progression or death. Such multiple times-to-events can be studied using multistate models. For chronic diseases, it may be relevant to consider semi-Markov multistate models because the transition intensities between two clinical states more likely depend on the time already spent in the current state than on the chronological time. When the cause of death for a patient is unavailable or not totally attributable to the disease, it is not possible to specifically study the associations with the excess mortality related to the disease. Relative survival analysis allows an estimate of the net survival in the hypothetical situation where the disease would be the only possible cause of death. In this paper, we propose a semi-Markov additive relative survival (SMRS) model that combines the multistate and the relative survival approaches. The usefulness of the SMRS model is illustrated by two applications with data from a French cohort of kidney transplant recipients. Using simulated data, we also highlight the effectiveness of the SMRS model: the results tend to those obtained if the different causes of death are known.

Comparison of survival outcomes between Expanded Criteria Donor and Standard Criteria Donor kidney transplant recipients: a systematic review and meta-analysis.

In 2002, the United Network for Organ Sharing proposed increasing the pool of donor kidneys to include Expanded Criteria Donor (ECD). Outside the USA, the ECD definition remains the one used without questioning whether such a graft allocation criterion is valid worldwide. We performed a meta-analysis to quantify the differences between ECD and Standard Criteria Donor (SCD) transplants. We paid particular attention to select studies in which the methodology was appropriate and we took into consideration the geographical area. Thirty-two publications were included. Only five studies, all from the USA, reported confounder-adjusted hazard ratios comparing the survival outcomes between ECD and SCD kidney transplant recipients. These five studies confirmed that ECD recipients seemed to have poorer prognosis. From 29 studies reporting appropriate survival curves, we estimated the 5-year pooled nonadjusted survivals for ECD and SCD recipients. The relative differences between the two groups were lower in Europe than in North America, particularly for death-censored graft failure. It is of primary importance to propose appropriate studies for external validation of the ECD criteria in non-US kidney transplant recipients.

Vitamin D deficiency is an independent risk factor for PTDM after kidney transplantation.

An association between 25 hydroxyvitamin D [25(OH)D] deficiency and type 2 diabetes was observed in the general population. Such association was not investigated in kidney transplant recipients. We prospectively evaluated 444 patients following primary kidney transplantation between 2000 and 2010. The 25(OH)D level at transplantation was classified into three grades: deficiency (< 10 ng/ml), insufficiency (≥ 10 and < 30 ng/ml), and normal range (≥ 30 ng/ml). Time to Post-Transplant Diabetes Mellitus (PTDM) was defined according to the day of first prescription of hypoglycemic treatment. The 25(OH)D level at transplantation was deficient in 88 patients, insufficient in 264 patients, and normal in 92 patients. At 1 year post-transplantation, cumulative incidence of PTDM was 13.2%. Cox multivariate analysis indicated that 25(OH)D deficiency (≤ 10 ng/ml) at the time of transplantation was an independent risk factor for PTDM within the first year post-transplantation (HR = 2.41, 95% CI 1.01-5.75, P = 0.048), whereas insufficiency tended to increase this risk, although not significantly. 25(OH)D deficiency is a new independent risk factor for PTDM within the first year after kidney transplantation. Our study suggests that 25(OH)D may be a marker of general health in kidney transplant recipients and could alert clinicians for PTDM risk.

A simulation study of the interception of prescribing errors by clinical pharmacists in an acute hospital setting.

RATIONALE, AIMS AND OBJECTIVES: To evaluate the performance of several pharmacists in the same department who analysed the same prescriptions in a simulation study. METHODS: One hundred prescriptions were retrospectively extracted from the prospective database of our hospital. Five clinical pharmacists working in the same department were asked to analyse individually the order lines of each prescription as if it were part of their routine daily practice. Afterward, an independent committee of five other clinical pharmacists reviewed the same 100 prescriptions. We calculated the sensitivity and the specificity of error detection in a line order by using the results of the committee as the gold standard. RESULTS: A total of 908 order lines were analysed (mean 9 ± 3 order lines per prescription). Fifty-one medication errors were identified by the committee (5.6%), including 23 related to laboratory test results: renal failure, or therapeutic concentrations being too low or too high. The sensitivity of the five pharmacists ranged between 19.6% and 56.9% and the specificity between 92.8% and 98.7%. The rates of agreement between each pharmacist and the committee, assessed using kappa coefficient, were between 0.20 and 0.39. The main factors affecting sensitivity and/or specificity in univariate analysis were the number of drugs per prescription, type of drug prescribed (ATC classification) and the glomerular filtration rate. CONCLUSION: Discrepancies between the performances of pharmacists exist, as there are between other health care professionals. Pharmacist training, standardization of the pharmaceutical analysis of drug prescription, and implementation of a clinical decision support system allowing biological values to be linked to drug prescriptions could improve individual performance.

The consequences of sudden fluid shifts on body composition in critically ill patients.

INTRODUCTION: Estimation of body composition as fat-free mass (FFM) is subjected to many variations caused by injury and stress conditions in the intensive care unit (ICU). Body cell mass (BCM), the metabolically active part of FFM, is reported to be more specifically correlated to changes in nutritional status. Bedside estimation of BCM could help to provide more valuable markers of nutritional status and may promote understanding of metabolic consequences of energy deficit in the ICU patients. We aimed to quantify BCM, water compartments and FFM by methods usable at the bedside for evaluating the impact of sudden and massive fluid shifts on body composition in ICU patients. METHODS: We conducted a prospective experimental study over an 6 month-period in a 18-bed ICU. Body composition of 31 consecutive hemodynamically stable patients requiring acute renal replacement therapy for fluid overload (ultrafiltration ≥5% body weight) was investigated before and after the hemodialysis session. Intra-(ICW) and extracellular (ECW) water volumes were calculated from the raw values of the low- and high-frequency resistances measured by multi-frequency bioelectrical impedance. BCM was assessed by a calculated method recently developed for ICU patients. FFM was derived from BCM and ECW. RESULTS: Intradialytic weight loss was 3.8 ± 0.8 kg. Percentage changes of ECW (-7.99 ± 4.60%) and of ICW (-7.63 ± 5.11%) were similar, resulting ECW/ICW ratio constant (1.26 ± 0.20). The fall of FFM (-2.24 ± 1.56 kg, -4.43 ± 2.65%) was less pronounced than the decrease of ECW (P < 0.001) or ICW (P < 0.001). Intradialytic variation of BCM was clinically negligible (-0.38 ± 0.93 kg, -1.56 ± 3.94%) and was significantly less than FFM (P < 0.001). CONCLUSIONS: BCM estimation is less driven by sudden massive fluid shifts than FMM. Assessment of BCM should be preferred to FFM when severe hydration disturbances are present in ICU patients.

Randomization in clinical trials: stratification or minimization? The HERMES free simulation software.

OBJECTIVES: Operative clinical trials are often small and open-label. Randomization is therefore very important. Stratification and minimization are two randomization options in such trials. The first aim of this study was to compare stratification and minimization in terms of predictability and balance in order to help investigators choose the most appropriate allocation method. Our second aim was to evaluate the influence of various parameters on the performance of these techniques. MATERIALS AND METHODS: The created software generated patients according to chosen trial parameters (e.g., number of important prognostic factors, number of operators or centers, etc.) and computed predictability and balance indicators for several stratification and minimization methods over a given number of simulations. Block size and proportion of random allocations could be chosen. A reference trial was chosen (50 patients, 1 prognostic factor, and 2 operators) and eight other trials derived from this reference trial were modeled. Predictability and balance indicators were calculated from 10,000 simulations per trial. RESULTS: Minimization performed better with complex trials (e.g., smaller sample size, increasing number of prognostic factors, and operators); stratification imbalance increased when the number of strata increased. An inverse correlation between imbalance and predictability was observed. CONCLUSIONS: A compromise between predictability and imbalance still has to be found by the investigator but our software (HERMES) gives concrete reasons for choosing between stratification and minimization; it can be downloaded free of charge. CLINICAL RELEVANCE: This software will help investigators choose the appropriate randomization method in future two-arm trials.

Computerized advice on drug dosage to improve prescribing practice.

BACKGROUND: Maintaining therapeutic concentrations of drugs with a narrow therapeutic window is a complex task. Several computer systems have been designed to help doctors determine optimum drug dosage. Significant improvements in health care could be achieved if computer advice improved health outcomes and could be implemented in routine practice in a cost-effective fashion. This is an updated version of an earlier Cochrane systematic review, first published in 2001 and updated in 2008. OBJECTIVES: To assess whether computerized advice on drug dosage has beneficial effects on patient outcomes compared with routine care (empiric dosing without computer assistance). SEARCH METHODS: The following databases were searched from 1996 to January 2012: EPOC Group Specialized Register, Reference Manager; Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Ovid; EMBASE, Ovid; and CINAHL, EbscoHost. A "top up" search was conducted for the period January 2012 to January 2013; these results were screened by the authors and potentially relevant studies are listed in Studies Awaiting Classification. The review authors also searched reference lists of relevant studies and related reviews. SELECTION CRITERIA: We included randomized controlled trials, non-randomized controlled trials, controlled before-and-after studies and interrupted time series analyses of computerized advice on drug dosage. The participants were healthcare professionals responsible for patient care. The outcomes were any objectively measured change in the health of patients resulting from computerized advice (such as therapeutic drug control, clinical improvement, adverse reactions). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed study quality. We grouped the results from the included studies by drug used and the effect aimed at for aminoglycoside antibiotics, amitriptyline, anaesthetics, insulin, anticoagulants, ovarian stimulation, anti-rejection drugs and theophylline. We combined the effect sizes to give an overall effect for each subgroup of studies, using a random-effects model. We further grouped studies by type of outcome when appropriate (i.e. no evidence of heterogeneity). MAIN RESULTS: Forty-six comparisons (from 42 trials) were included (as compared with 26 comparisons in the last update) including a wide range of drugs in inpatient and outpatient settings. All were randomized controlled trials except two studies. Interventions usually targeted doctors, although some studies attempted to influence prescriptions by pharmacists and nurses. Drugs evaluated were anticoagulants, insulin, aminoglycoside antibiotics, theophylline, anti-rejection drugs, anaesthetic agents, antidepressants and gonadotropins. Although all studies used reliable outcome measures, their quality was generally low.This update found similar results to the previous update and managed to identify specific therapeutic areas where the computerized advice on drug dosage was beneficial compared with routine care:1. it increased target peak serum concentrations (standardized mean difference (SMD) 0.79, 95% CI 0.46 to 1.13) and the proportion of people with plasma drug concentrations within the therapeutic range after two days (pooled risk ratio (RR) 4.44, 95% CI 1.94 to 10.13) for aminoglycoside antibiotics;2. it led to a physiological parameter more often within the desired range for oral anticoagulants (SMD for percentage of time spent in target international normalized ratio +0.19, 95% CI 0.06 to 0.33) and insulin (SMD for percentage of time in target glucose range: +1.27, 95% CI 0.56 to 1.98);3. it decreased the time to achieve stabilization for oral anticoagulants (SMD -0.56, 95% CI -1.07 to -0.04);4. it decreased the thromboembolism events (rate ratio 0.68, 95% CI 0.49 to 0.94) and tended to decrease bleeding events for anticoagulants although the difference was not significant (rate ratio 0.81, 95% CI 0.60 to 1.08). It tended to decrease unwanted effects for aminoglycoside antibiotics (nephrotoxicity: RR 0.67, 95% CI 0.42 to 1.06) and anti-rejection drugs (cytomegalovirus infections: RR 0.90, 95% CI 0.58 to 1.40);5. it tended to reduce the length of time spent in the hospital although the difference was not significant (SMD -0.15, 95% CI -0.33 to 0.02) and to achieve comparable or better cost-effectiveness ratios than usual care;6. there was no evidence of differences in mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants.For all outcomes, statistical heterogeneity quantified by I(2) statistics was moderate to high. AUTHORS' CONCLUSIONS: This review update suggests that computerized advice for drug dosage has some benefits: it increases the serum concentrations for aminoglycoside antibiotics and improves the proportion of people for which the plasma drug is within the therapeutic range for aminoglycoside antibiotics.It leads to a physiological parameter more often within the desired range for oral anticoagulants and insulin. It decreases the time to achieve stabilization for oral anticoagulants. It tends to decrease unwanted effects for aminoglycoside antibiotics and anti-rejection drugs, and it significantly decreases thromboembolism events for anticoagulants. It tends to reduce the length of hospital stay compared with routine care while comparable or better cost-effectiveness ratios were achieved.However, there was no evidence that decision support had an effect on mortality or other clinical adverse events for insulin (hypoglycaemia), anaesthetic agents, anti-rejection drugs and antidepressants. In addition, there was no evidence to suggest that some decision support technical features (such as its integration into a computer physician order entry system) or aspects of organization of care (such as the setting) could optimize the effect of computerized advice.Taking into account the high risk of bias of, and high heterogeneity between, studies, these results must be interpreted with caution.

Drug administration errors in hospital inpatients: a systematic review.

CONTEXT: Drug administration in the hospital setting is the last barrier before a possible error reaches the patient. OBJECTIVES: We aimed to analyze the prevalence and nature of administration error rate detected by the observation method. DATA SOURCES: Embase, MEDLINE, Cochrane Library from 1966 to December 2011 and reference lists of included studies. STUDY SELECTION: Observational studies, cross-sectional studies, before-and-after studies, and randomized controlled trials that measured the rate of administration errors in inpatients were included. DATA EXTRACTION: Two reviewers (senior pharmacists) independently identified studies for inclusion. One reviewer extracted the data; the second reviewer checked the data. The main outcome was the error rate calculated as being the number of errors without wrong time errors divided by the Total Opportunity for Errors (TOE, sum of the total number of doses ordered plus the unordered doses given), and multiplied by 100. For studies that reported it, clinical impact was reclassified into four categories from fatal to minor or no impact. Due to a large heterogeneity, results were expressed as median values (interquartile range, IQR), according to their study design. RESULTS: Among 2088 studies, a total of 52 reported TOE. Most of the studies were cross-sectional studies (N=46). The median error rate without wrong time errors for the cross-sectional studies using TOE was 10.5% [IQR: 7.3%-21.7%]. No fatal error was observed and most errors were classified as minor in the 18 studies in which clinical impact was analyzed. We did not find any evidence of publication bias. CONCLUSIONS: Administration errors are frequent among inpatients. The median error rate without wrong time errors for the cross-sectional studies using TOE was about 10%. A standardization of administration error rate using the same denominator (TOE), numerator and types of errors is essential for further publications.

Cross-sectional assessment of the roles of comorbidities in resting and activity-related dyspnea in severely obese women.

OBJECTIVES: Obesity has been associated with a lesser degree of asthma control that may be biased by other comorbidities. The objectives of this cross-sectional study were to describe resting and activity-related dyspnea complaints according to the presence of obesity-related comorbidities (asymptomatic airway hyperresponsiveness (AHR), asthma, gastroesophageal reflux disease (GERD) and sleep-disordered breathing (SDB)). We hypothesized that obese women can exhibit both resting and activity-related dyspnea, independently of the presence of asthma. METHODS: Severely obese (body mass index (BMI) > 35 kg m(-2)) women prospectively underwent description of resting and activity-related dyspnea (verbal descriptors and Medical Research Council (MRC) scale), pulmonary function testing (spirometry, absolute lung volumes, and methacholine challenge test), oesogastro-duodenal fibroscopy, and overnight polygraphy. Thirty healthy lean women without airway hyperresponsiveness were enrolled. RESULTS: Resting dyspnea complaints were significantly more prevalent in obesity (prevalence 41%) than in healthy lean women (prevalence 3%). Chest tightness and the need for deep inspirations were independently associated with both asthma and GERD while wheezing and cough were related to asthma only in obese women. Activity-related dyspnea was very prevalent (MRC score > 1, 75%), associated with obesity, with the exception of wheezing on exertion due to asthma. Asymptomatic AHR and SDB did not affect dyspneic complaints. CONCLUSIONS: In severely obese women referred for bariatric surgery, resting dyspnea complaints are observed in association with asthma or GERD, while activity-related dyspnea was mainly related to obesity only. Consequently, asthma does not explain all respiratory complaints of obese women.

Risk factors for airway hyperresponsiveness in severely obese women.

Obesity affects airway diameter and tidal ventilation pattern, which could perturb smooth muscle function. The objective was to assess the pathophysiology of airway hyperresponsiveness in obesity while controlling for gastro-oesophageal reflux disease. Obese women (n=118, mean±SD BMI 46.1±6.8kg/m(-2)) underwent pulmonary function testing (including tidal ventilation monitoring and methacholine challenge) and oesogastro-duodenal fibroscopy. Fifty-seven women (48%, 95% CI: 39-57%) exhibited hyperresponsiveness (dose-response slope ≥2.39% decrease/µmol) that was independently and positively correlated with predicted % FRC, Raw0.5 and negatively correlated with sigh frequency during tidal ventilation. Obese women had an increased breathing frequency but a similar sigh frequency than healthy lean women (n=30). Twenty-two obese women (19%, 95% CI: 12-26%) were classified as asthmatics (hyperresponsiveness and suggestive symptoms) without confounding effect of gastro-oesophageal reflux disease. In conclusion, in women referred for bariatric surgery, unloading of bronchial smooth muscle (reduced airway calibre and sigh frequency) is associated with hyperresponsiveness.

Optimal follow-up in adult patients with congenital heart disease and chronic pulmonary regurgitation: towards tailored use of cardiac magnetic resonance imaging.

BACKGROUND: Pulmonary regurgitation (PR) is a common complication of right ventricular outflow tract (RVOT) reconstruction and leads to right ventricular (RV) dilatation and dysfunction. Although cardiac magnetic resonance (CMR) is the gold standard for evaluating PR and RV dysfunction, cost and limited availability are problems in many centres. AIMS: To determine clinical, electrocardiographic and echocardiographic predictors of these complications and optimize patient selection for their short-term follow-up by CMR. METHODS: Ninety-four patients with a history of RVOT repair were prospectively included. All patients had a clinical examination, electrocardiography, echocardiography and CMR. RESULTS: QRS duration, indexed end-diastolic RV (EDRV) diameter and area on echocardiography were significantly associated with RV dilatation on CMR (P<0.001). The distal localization of Doppler PR flow was the strongest echocardiographic criterion associated with severe PR (P<0.001). Arrhythmia history and high Tei index were significantly associated with low RV ejection fraction (P<0.001 and P=0.017, respectively). In multivariable analysis, grade of PR, QRS duration, arrhythmia and valvulotomy were strongly associated with severe PR and RV dilatation or systolic RV dysfunction. From these results, an approach based on a scaled scoring system for selecting patients who need short-term CMR evaluation and close follow-up was evaluated. This method should avoid 31% of CMR examinations, with a sensitivity of 97.7%. CONCLUSION: Clinical, electrocardiographic and echocardiographic criteria can be used to accurately evaluate patients with RVOT repair. The combination of such features facilitates identification of patients who do or do not require close CMR evaluation.

The sentinel node technique detects unexpected drainage pathways and allows nodal ultrastaging in early cervical cancer: insights from the multicenter prospective SENTICOL study.

BACKGROUND: Sentinel lymph node (SLN) biopsy may improve nodal staging in cervical cancer. The aims of this study are to determine the rate of unusual patterns of cervical lymphatic drainage, to determine the rates of micrometastases and isolated tumor cells (ITCs) in SLNs, and to assess the clinical impact of SLN biopsy. METHODS: Multicenter prospective study conducted between January 2005 and June 2007 in women undergoing laparoscopic surgery for early cervical cancer. Combined technetium/Patent Blue labeling was used. Lymphoscintigraphy was performed before surgery. SLN location was recorded, and factors associated with location were explored. SLNs underwent step sectioning ± immunohistochemistry. RESULTS: 145 patients were enrolled and 139 included in a modified intention-to-diagnose analysis. Although 80.6 % of SLNs were in external iliac and interiliac areas, 38.2 % of patients had at least one SLN in an unexpected area and 5.1 % had SLNs only in unexpected areas. In unexpected areas, the number of SLNs per patient was not significantly different between lymphoscintigraphy and intraoperative detection (0.79 [0.62-1.02] versus 0.50 [0.37-0.68]; P = 0.096). In expected locations, there were significantly more blue and hot SLNs per patient than blue or hot SLNs (1.70 [1.45-1.99], 0.42 [0.30-0.57], 0.52 [0.39-0.69]). Of 28 metastatic SLNs, 17 contained micrometastases or ITCs. SLN involvement was found only by immunohistochemistry in 39.1 % of patients with positive nodes, and involved SLNs were located in unexpected areas in 17 % of those patients. CONCLUSIONS: Sentinel lymph node biopsy detects unusual drainage pathways and micrometastases in a substantial proportion of patients, thus improving nodal staging.