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.

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.

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.

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.

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.

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.

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.

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.

Assessment of body cell mass at bedside in critically ill patients.

Critical illness affects body composition profoundly, especially body cell mass (BCM). BCM loss reflects lean tissue wasting and could be a nutritional marker in critically ill patients. However, BCM assessment with usual isotopic or tracer methods is impractical in intensive care units (ICUs). We aimed to modelize the BCM of critically ill patients using variables available at bedside. Fat-free mass (FFM), bone mineral (Mo), and extracellular water (ECW) of 49 critically ill patients were measured prospectively by dual-energy X-ray absorptiometry and multifrequency bioimpedance. BCM was estimated according to the four-compartment cellular level: BCM = FFM - (ECW/0.98) - (0.73 × Mo). Variables that might influence the BCM were assessed, and multivariable analysis using fractional polynomials was conducted to determine the relations between BCM and these data. Bootstrap resampling was then used to estimate the most stable model predicting BCM. BCM was 22.7 ± 5.4 kg. The most frequent model included height (cm), leg circumference (cm), weight shift (Δ) between ICU admission and body composition assessment (kg), and trunk length (cm) as a linear function: BCM (kg) = 0.266 × height + 0.287 × leg circumference + 0.305 × Δweight - 0.406 × trunk length - 13.52. The fraction of variance explained by this model (adjusted r(2)) was 46%. Including bioelectrical impedance analysis variables in the model did not improve BCM prediction. In summary, our results suggest that BCM can be estimated at bedside, with an error lower than ±20% in 90% subjects, on the basis of static (height, trunk length), less stable (leg circumference), and dynamic biometric variables (Δweight) for critically ill patients.

Diagnostic performance of one-step nucleic acid amplification for intraoperative sentinel node metastasis detection in breast cancer patients.

The purpose of this prospective multicenter study was to assess one-step nucleic acid amplification (OSNA) for intraoperative sentinel lymph node (SLN) metastasis detection in breast cancer patients, using final histology as the reference standard. OSNA results were also compared to intraoperative histology SLN evaluation and to standard clinicopathological risk markers. For this study, fresh SLNs were cut in four blocks, and alternate blocks were used for OSNA and histology. CK19 mRNA copy number was categorized as strongly positive, positive or negative. Positive histology was defined as presence of macrometastasis or micrometastasis. When discrepancies occurred, the entire SLNs were subjected to histological studies and the node lysates to additional molecular studies. Five hundred three SLN samples from 233 patients were studied. Mean time to evaluate two SLNs was 40 min. Sensitivity per patient was 91.4% (95% CI, 76.9-98.2%), specificity 93.3% (95% CI, 88.6-96.6%), positive likelihood ratio 13.7 and negative likelihood ratio 0.1. Sensitivity was 63.6% for frozen sections and 47.1% for touch imprint cytology. Both methods were 100% specific. Positive histology and positive OSNA were significantly associated with highest clinical stage, N1 status and vascular invasion; and OSNA results correlated with HER2/neu status and benefited patients with negative histology. These findings show that OSNA assay can allow detection of SLN metastasis in breast cancer patients intraoperatively with a good sensitivity, thus minimizing the need for second surgeries for axillary lymph node detection.

Evaluation of drug administration errors in a teaching hospital.

BACKGROUND: Medication errors can occur at any of the three steps of the medication use process: prescribing, dispensing and administration. We aimed to determine the incidence, type and clinical importance of drug administration errors and to identify risk factors. METHODS: Prospective study based on disguised observation technique in four wards in a teaching hospital in Paris, France (800 beds). A pharmacist accompanied nurses and witnessed the preparation and administration of drugs to all patients during the three drug rounds on each of six days per ward. Main outcomes were number, type and clinical importance of errors and associated risk factors. Drug administration error rate was calculated with and without wrong time errors. Relationship between the occurrence of errors and potential risk factors were investigated using logistic regression models with random effects. RESULTS: Twenty-eight nurses caring for 108 patients were observed. Among 1501 opportunities for error, 415 administrations (430 errors) with one or more errors were detected (27.6%). There were 312 wrong time errors, ten simultaneously with another type of error, resulting in an error rate without wrong time error of 7.5% (113/1501). The most frequently administered drugs were the cardiovascular drugs (425/1501, 28.3%). The highest risks of error in a drug administration were for dermatological drugs. No potentially life-threatening errors were witnessed and 6% of errors were classified as having a serious or significant impact on patients (mainly omission). In multivariate analysis, the occurrence of errors was associated with drug administration route, drug classification (ATC) and the number of patient under the nurse's care. CONCLUSION: Medication administration errors are frequent. The identification of its determinants helps to undertake designed interventions.

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.

Diagnostic value of intraoperative examination of sentinel lymph node in early cervical cancer: a prospective, multicenter study.

OBJECTIVES: Sentinel lymph node (SLN) biopsy is a surgical procedure proposed in early cervical cancer. This technique yields the potential interest to reduce the morbidity of complete lymphadenectomy, which could then be performed only in case of positive SLN. Intraoperative examination has a major per-operative role in predicting nodal involvement and preventing a second step procedure. The aim of this study was to assess the diagnostic value of intraoperative examination with frozen section (FS) or imprint cytology (IC) of SLNs in early cervical cancer. METHODS: Prospective study in 7 centers (01/2005-06/2007) including patients with stage IA1 and lymphovascular space involvement to IB1 cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma). SLNs were detected with a combined method (Tc99m+blue dye) and then removed laparoscopically. Intraoperative examination (FS or IC) was not systematically performed but recommended in case of macroscopical nodal enlargement in 5 centers. Results of intraoperative examination were compared with final histology performed by Hematoxylin-Eosin-Safran staining and immunohistochemistry. The diagnostic value of intraoperative examination was calculated. RESULTS: One hundred and thirty-nine patients were analyzed in the study. The combined detection rate was 97.8% per patient, with 454 detected SLNs. One hundred and two patients (73.4%) had an intraoperative examination (97 patients with FS and 5 with IC). Among patients with intraoperative examination, 5 SLNs were positive (all with macrometastasis at final histology), as compared with 22 metastatic nodes at final result. The 17 false negative SLNs were: 4 macrometastasis, 4 micrometastasis and 9 isolated tumor cells. Sensitivity of the intraoperative examination per node was 20.7% [95%CI: 7.8%-45.4%] and the negative predictive value 93.0% [95%CI: 89.0%-95.9%]. CONCLUSIONS: Intraoperative examination of SLNs by FS and IC has a poor diagnostic value. This is mainly related to micrometastasis and isolated tumor cells, which are not detected by intraoperative techniques. Other techniques, like new molecular assays, should be investigated to improve intraoperative assessment of SLNs.

Effects of automated alerts on unnecessarily repeated serology tests in a cardiovascular surgery department: a time series analysis.

BACKGROUND: Laboratory testing is frequently unnecessary, particularly repetitive testing. Among the interventions proposed to reduce unnecessary testing, Computerized Decision Support Systems (CDSS) have been shown to be effective, but their impact depends on their technical characteristics. The objective of the study was to evaluate the impact of a Serology-CDSS providing point of care reminders of previous existing serology results, embedded in a Computerized Physician Order Entry at a university teaching hospital in Paris, France. METHODS: A CDSS was implemented in the Cardiovascular Surgery department of the hospital in order to decrease inappropriate repetitions of viral serology tests (HBV).A time series analysis was performed to assess the impact of the alert on physicians' practices. The study took place between January 2004 and December 2007. The primary outcome was the proportion of unnecessarily repeated HBs antigen tests over the periods of the study. A test was considered unnecessary when it was ordered within 90 days after a previous test for the same patient. A secondary outcome was the proportion of potentially unnecessary HBs antigen test orders cancelled after an alert display. RESULTS: In the pre-intervention period, 3,480 viral serology tests were ordered, of which 538 (15.5%) were unnecessarily repeated. During the intervention period, of the 2,095 HBs antigen tests performed, 330 unnecessary repetitions (15.8%) were observed. Before the intervention, the mean proportion of unnecessarily repeated HBs antigen tests increased by 0.4% per month (absolute increase, 95% CI 0.2% to 0.6%, p < 0.001). After the intervention, a significant trend change occurred, with a monthly difference estimated at -0.4% (95% CI -0.7% to -0.1%, p = 0.02) resulting in a stable proportion of unnecessarily repeated HBs antigen tests. A total of 380 unnecessary tests were ordered among 500 alerts displayed (compliance rate 24%). CONCLUSIONS: The proportion of unnecessarily repeated tests immediately dropped after CDSS implementation and remained stable, contrasting with the significant continuous increase observed before. The compliance rate confirmed the effect of the alerts. It is necessary to continue experimentation with dedicated systems in order to improve understanding of the diversity of CDSS and their impact on clinical practice.

Chronology of prescribing error during the hospital stay and prediction of pharmacist's alerts overriding: a prospective analysis.

BACKGROUND: Drug prescribing errors are frequent in the hospital setting and pharmacists play an important role in detection of these errors. The objectives of this study are (1) to describe the drug prescribing errors rate during the patient's stay, (2) to find which characteristics for a prescribing error are the most predictive of their reproduction the next day despite pharmacist's alert (i.e. override the alert). METHODS: We prospectively collected all medication order lines and prescribing errors during 18 days in 7 medical wards' using computerized physician order entry. We described and modelled the errors rate according to the chronology of hospital stay. We performed a classification and regression tree analysis to find which characteristics of alerts were predictive of their overriding (i.e. prescribing error repeated). RESULTS: 12 533 order lines were reviewed, 117 errors (errors rate 0.9%) were observed and 51% of these errors occurred on the first day of the hospital stay. The risk of a prescribing error decreased over time. 52% of the alerts were overridden (i.e error uncorrected by prescribers on the following day. Drug omissions were the most frequently taken into account by prescribers. The classification and regression tree analysis showed that overriding pharmacist's alerts is first related to the ward of the prescriber and then to either Anatomical Therapeutic Chemical class of the drug or the type of error. CONCLUSIONS: Since 51% of prescribing errors occurred on the first day of stay, pharmacist should concentrate his analysis of drug prescriptions on this day. The difference of overriding behavior between wards and according drug Anatomical Therapeutic Chemical class or type of error could also guide the validation tasks and programming of electronic alerts.

A computerized handheld decision-support system to improve pulmonary embolism diagnosis: a randomized trial.

BACKGROUND: Testing for pulmonary embolism often differs from that recommended by evidence-based guidelines. OBJECTIVE: To assess the effectiveness of a handheld clinical decision-support system to improve the diagnostic work-up of suspected pulmonary embolism among patients in the emergency department. DESIGN: Cluster randomized trial. Assignment was by random-number table, providers were not blinded, and outcome assessment was automated. (ClinicalTrials.gov registration number: NCT00188032). SETTING: 20 emergency departments in France. PATIENTS: 1103 and 1768 consecutive outpatients with suspected pulmonary embolism. INTERVENTION: After a preintervention period involving 20 centers and 1103 patients, in which providers grew accustomed to inputting clinical data into handheld devices and investigators assessed baseline testing, emergency departments were randomly assigned to activation of a decision-support system on the devices (10 centers, 753 patients) or posters and pocket cards that showed validated diagnostic strategies (10 centers, 1015 patients). MEASUREMENTS: Appropriateness of diagnostic work-up, defined as any sequence of tests that yielded a posttest probability less than 5% or greater than 85% (primary outcome) or as strict adherence to guideline recommendations (secondary outcome); number of tests per patient (secondary outcome). RESULTS: The proportion of patients who received appropriate diagnostic work-ups was greater during the trial than in the preintervention period in both groups, but the increase was greater in the computer-based guidelines group (adjusted mean difference in increase, 19.3 percentage points favoring computer-based guidelines [95% CI, 2.9 to 35.6 percentage points]; P = 0.023). Among patients with appropriate work-ups, those in the computer-based guidelines group received slightly fewer tests than did patients in the paper guidelines group (mean tests per patient, 1.76 [SD, 0.98] vs. 2.25 [SD, 1.04]; P < 0.001). LIMITATION: The study was not designed to show a difference in the clinical outcomes of patients during follow-up. CONCLUSION: A handheld decision-support system improved diagnostic decision making for patients with suspected pulmonary embolism in the emergency department.

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.