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Hydrofluoric acid (HF) is a ubiquitous industrial chemical that is particularly hazardous because of the potential for systemic effects and the induction of severe cutaneous necrosis after contact with the skin. Minimizing skin injury requires decontaminating the affected area promptly with an emergency rinsing solution. Few experimental studies have objectively characterized rinsing solutions such as Diphoterine (DP). Here we develop an ex vivo pigskin model to study and compare the efficacy of rinsing solutions as initial decontaminating agents to stop the progression of skin lesions after HF splashing. The pigskin model shows an immediate local response to HF at varying concentrations and exposure times. We then exposed the pigskin biopsies to 3.75% HF for 1 min and rinsed them with different solutions, including water, 0.9% NaCl solution (saline), 10% calcium gluconate (CaG), Hexafluorine (HXF), and DP. We found DP to be a more effective agent for decontaminating HF lesions than water, saline, and CaG. DP had a similar efficacy as HXF, an emergency rinsing solution used specifically for decontaminating HF-exposed skin. This study shows that skin exposed to HF must be treated quickly from the first minute of exposure., Competing Interests: Declaration of Competing Interest Dr. Legault and Dr. Pichette report research funding from Rio Tinto Aluminium and from LASEVE from University of Quebec at Chicoutimi, and they reported no biomedical financial interests or potential conflicts of interest. Mrs Bélanger, M.Sc. and Mr Gauthier, MD reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Belonging to the family of advanced therapy medicinal products, CAR-T cells have changed the management of hematological malignancies. These treatments are known to involve many actors in a complex process. The quotation of hospital stays associated with this therapeutic strategy is also unusual since there is currently no specific quotation. From November 2021 to May 2022, a study was conducted at the Nancy University Hospital to evaluate the organizational impact of CAR-T cell therapy on hospital actors and the budgetary impact of stays in care centers. Through this study, we have shown significant and variable organizational impacts: from 3.12% of an additional full-time equivalent for an administrative manager to 41.5% for a clinical research associate. These times, when compared to the hourly rates of the actors, generated high costs: 6582.81 € per patient, i.e. 15.60% of the total cost of hospitalization. Taking into account the current refund of hospital stays and the costs calculated above, the balance of an average hospital stay is a deficit of 674.10 € [±10,224.79] with a median of 1334.97 €. This study highlighted the workload generated by the management of these new therapies, as well as the fragile balance of financing hospital stays. To date, it seems necessary and even essential to adapt the quotations of the acts dedicated to CAR-T cells activity and to provide adequate funding through an adapted pricing system., (Copyright © 2023 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background Aims: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment for chemo-resistant hematological malignancies. Because of transport restriction imposed by the coronavirus disease 2019 pandemic, regulatory bodies and societies recommended graft cryopreservation before recipient conditioning. However, the freezing and thawing processes, including washing steps, might impair CD34+ cell recovery and viability, thereby impacting the recipient engraftment. Over 1 year (between March 2020 and May 2021), we aimed to analyze the results of frozen/thawed peripheral blood stem cell allografts in terms of stem cell quality and clinical outcomes., Methods: Transplant quality was evaluated by comparing total nucleated cells (TNCs), CD34+ cells and colony-forming unit-granulocyte/macrophage (CFU-GM)/kg numbers as well as TNC and CD34+ cell viabilities before and after thawing. Intrinsic biological parameters such as granulocyte, platelet and CD34+ cell concentrations were analyzed, as they might be responsible for a quality loss. The impact of the CD34+ cell richness of the graft on TNC and CD34 yields was evaluated by designing three groups of transplants based on their CD34 /kg value at collection: >8 × 10 6 /kg, between 6 and 8 × 10 6 /kg and <6 × 10 6 /kg. The consequences of cryopreservation were compared in the fresh and thawed group by evaluating the main transplant outcomes., Results: Over 1 year, 76 recipients were included in the study; 57 patients received a thawed and 19 patients a fresh allo-SCT. None received allo-SCT from a severe acute respiratory syndrome coronavirus 2-positive donor. The freezing of 57 transplants led to the storage of 309 bags, for a mean storage time (between freezing and thawing) of 14 days. For the fresh transplant group, only 41 bags were stored for potential future donor lymphocyte infusions. Regarding the graft characteristics at collection, median number of cryopreserved TNC and CD34+ cells/kg were greater than those for fresh infusions. After thawing, median yields were 74.0%, 69.0% and 48.0% for TNC, CD34+ cells and CFU-GM, respectively. The median TNC dose/kg obtained after thawing was 5.8 × 10 8 , with a median viability of 76%. The median CD34+ cells/kg was 5 × 10 6 , with a median viability of 87%. In the fresh transplant group, the median TNC/kg was 5.9 × 10 8 /kg, and the median CD34+ cells/kg and CFU-GM/kg were 6 × 10 6 /kg and 276.5 × 10 4 /kg, respectively. Sixty-one percent of the thawed transplants were out of specifications regarding the CD34+ cells/ kg requested cell dose (6 × 10 6 /kg) and 85% of them would have had this dose if their hematopoietic stem cell transplant had been infused fresh. Regarding fresh grafts, 15.8% contained less than 6 × 10 6 CD34+ cells /kg and came from peripheral blood stem cells that did not reach 6 × 10 6 CD34+ cells /kg at collection. Regarding the factor that impaired CD34 and TNC yield after thawing, no significant impact of the granulocyte count, the platelet count or the CD34+ cells concentration/µL was observed. However, grafts containing more than 8 × 10 6 /kg at collection showed a significantly lower TNC and CD34 yield., Conclusions: Transplant outcomes (engraftment, graft-versus-host disease, infections, relapse or death) were not significantly different between the two groups., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Modeling studies illustrate the potential for long-range transport of plastics into the Arctic, although the degree to which this occurs remains relatively undocumented. We utilised a teaching exercise at a UArctic summer school graduate course in Nuuk, Greenland to conduct a preliminary in-depth analysis of beach litter sources in the Nuup Kangerlua fjord. Students and instructors collected and analysed 1800 litter items weighing 200 kg from one location in the fjord and another at its mouth. The results suggest a predominance of local sources to macrolitter, rather than long-range transport from Europe. Fisheries-related items and rope were common. Packaging which could be identified was largely suspected to be products distributed in Greenland, and soft plastics, which rarely disperse far from its source, were also common. The results suggest local measures to reduce mismanaged waste and emissions from fisheries are important for reducing marine litter in West Greenland., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Over the last decade, fluctuations of retinoids (RETs), also known as vitamin A and derivatives, have proved to be useful biomarkers to assess the environmental chemical pressure on a wide variety of non-target vertebrates. This use of RET-based biomarkers is of particular interest in the non-target sentinel species Gammarus fossarum in which RETs were shown to influence crucial physiological functions. To study and probe this metabolism in this crustacean model, a UHPLC-MS/MS method was developed to 1) identify and 2) monitor several endogenous RETs in unexposed females throughout their reproductive cycle. Then, females were exposed in controlled conditions to exogenous all-trans retinoic acid (atRA) and citral (CIT), a RA synthesis inhibitor, to simulate an excess or deficiency in RA. Perturbation of vitamin A metabolism by pesticides was further studied in response to methoprene (MET), a juvenile hormone analog as well as glyphosate (GLY). The developed method allowed, for the first time in this model, the identification of RA metabolites (all-trans 4-oxo and 13-cis 4-oxo RA), RA isomers (all-trans and 13-cis RA) as well as retinaldehyde (RALD) isomers (all-trans, 11-cis, and 13-cis RALD) and showed two distinct phases in the reproductive cycle. Retinoic acid successfully increased the tissular concentration of both RA isomers and CIT proved to be efficient at perturbating the conversion from RALD to RA. Methoprene perturbed the ratios between RA isomers whereas GLY had no observed effects on the RET system of G. fossarum females. We were able to discriminate different dynamics of RET perturbations by morphogens (atRA or CIT) or MET which highlights the plausible mediation of RETs in MET-induced disorders. Ultimately, our study shows that RETs are influenced by exposure to MET and strengthen their potential to assess aquatic ecosystem chemical status., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint., Methods: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews., Results: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold., Conclusions: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period., (Copyright © 2022. Published by Elsevier Inc.)

Chronic lymphocytic leukemia (CLL) is a low-grade B cell lymphoma with circulating cells, often revealed by hyperlymphocytosis. Its diagnosis and therapeutic indications (not systematic) have been defined in 2018. In fact, CLL can be separated in two entities differentiating themselves by their IGHV mutational status, but the search of other prognostic parameters like TP53 disruption is mandatory before treatment. Numerous genetic alterations and mutations exist in CLL. CLL cells are highly dependent from their b-cell receptor stimulation and from their microenvironment, which takes a central place in disease progression. Infections, dysimmune manifestations, cancers and Richter transformation are classic complications, and patients have poor vaccine response even without a treatment. Chemoimmunotherapy is being challenged by the new highly active drugs such as Bruton tyrosine-kinase inhibitors (ibrutinib, acalabrutinib) and by the association of venetoclax and anti-CD20. Future treatment strategies might integrate both new drugs and classical chemoimmunotherapy., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Asthma as a clinical entity manifests with a broad spectrum of disease severity. Unlike milder asthma, severe disease is poorly controlled by inhaled corticosteroids, the current standard of care. Transcriptomic data, along with patient characteristics and response to biologics show that though Type 2 (T2) immune response remains an integral feature of asthma, additional molecular and immunologic factors may play important roles in pathogenesis. Mechanisms of T2 development, cellular sources of T2 cytokines and their relationship to additional immune pathways concurrently activated may distinguish several different subphenotypes, and perhaps endotypes of asthma, with differential response to non-specific and targeted anti-inflammatory therapies. Recent data have also associated non-T2 cytokines derived from T cells, particularly IFN-γ, and epithelial mediators with severe asthma. These topics and their relationships to acute asthma exacerbations are discussed in this review., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Applying operando investigations is becoming essential for acquiring fundamental insights into the reaction mechanisms and phenomena at stake in batteries currently under development. The capability of a real-time characterization of the charge/discharge electrochemical pathways and the reactivity of the electrolyte is critical to decipher the underlying chemistries and improve the battery performance. Yet, adapting operando techniques for new chemistries such as metal-oxygen (i.e. metal-air) batteries introduces challenges in the cell design due notably to the requirements of an oxygen gas supply at the cathode. Herein a simple operando cell is presented with a two-compartment cylindrical cell design for NMR spectroscopy. The design is discussed and evaluated. Operando 7 Li static NMR characterization on a Li-O 2 battery was performed as a proof-of-concept. The productions of Li 2 O 2 , mossy Li/Li dendrites and other irreversible parasitic lithium compounds were captured in the charge/discharge processes, demonstrating the capability of tracking the evolution of the anodic and cathodic chemistry in metal-oxygen batteries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

The Wnt/β-catenin signaling pathway is critical for bone differentiation and regeneration. Tideglusib, a selective FDA approved glycogen synthase kinase-3β (GSK-3β) inhibitor, has been shown to promote dentine formation, but its effect on bone has not been examined. Our objective was to study the effect of localized Tideglusib administration on bone repair. Bone healing between Tideglusib treated and control mice was analysed at 7, 14 and 28 days postoperative (PO) with microCT, dynamic histomorphometry and immunohistology. There was a local downregulation of GSK-3β in Tideglusib animals, resulting in a significant increase in the amount of new bone formation with both enhanced cortical bone bridging and medullary bone deposition. The bone formation in the Tideglusib group was characterized by early osteoblast differentiation with down-regulation of GSK-3β at day 7 and 14, and higher accumulation of active β-catenin at day 14. Here, for the first time, we show a positive effect of Tideglusib on bone formation through the inactivation of GSK-3β. Furthermore, the findings suggest that Tideglusib does not interfere with precursor cell recruitment and commitment, contrary to other GSK-3β antagonists such as lithium chloride. Taken together, the results indicate that Tideglusib could be used directly at a fracture site during the initial intraoperative internal fixation without the need for further surgery, injection or drug delivery system. This FDA-approved drug may be useful in the future for the prevention of non-union in patients presenting with a high risk for fracture-healing., (Copyright © 2020. Published by Elsevier Ltd.)

The search for novel, more compliant vascular grafts for the replacement of blood vessels is ongoing, and predictive tools are needed to identify the most promising biomaterials. A simple analytical model was designed that enables the calculation of the ratio between the ultimate stress (σ ult ) and the elastic modulus (E). To reach both the compliance of small-diameter coronary arteries (0.0725%/mmHg) and a burst pressure of 2031 mmHg, a material with a minimum σ ult /E ratio of 1.78 is required. Based on this result and on data from the literature, random electrospun Polyurethane/Polycaprolactone (PU/PCL) tubular scaffolds were fabricated and compared to commercial ePTFE prostheses. PU/PCL grafts showed mechanical properties close to those of native arteries, with a circumferential elastic modulus of 4.8 MPa and a compliance of 0.036%/mmHg at physiological pressure range (80-120 mmHg) for a 145 μm-thick prosthesis. In contrast, commercial expanded polytetrafluoroethylene (ePTFE) grafts presented a high Young's modulus (17.4 MPa) and poor compliance of 0.0034%/mmHg. The electrospun PU/PCL did not however reach the target values as its σ ult /E ratio was lower than expected, at 1.54, well below the calculated threshold (1.78). The model tended to overestimate both the compliance and burst pressure, with the differences between the analytical and experimental results ranging between 13 and 34%, depending on the pressure range tested. This can be explained by the anisotropy of random electrospun PU/PCL and its slightly non-linear elastic behavior, in contrast to the hypotheses of our model. Impermeability tests showed that the electrospun scaffolds were impermeable to blood for all thicknesses above 50 μm. In conclusion, this analytical model allows to select materials with suitable mechanical properties for the design of small-diameter vascular grafts. The novel electrospun PU/PCL tubular scaffolds showed strongly improved compliance as compared to commercial ePTFE prostheses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Minimal residual disease (MRD) is widely used in oncohematology. In chronic lymphocytic leukemia (CLL), it can be measured by flow cytometry or polymerase chain reaction and is getting a greater place, owing to the dramatic therapeutic advances in the management this disease. As MRD decrease after chemoimmunotherapy is associated with improved progression free and overall survivals, its measure is now recommended as a surrogate marker for cytotoxic drugs licensures. This association is independent from treatment received and raises a few questions, such as sequential MRD measures to stop treatment in case of an early deep response and on the opposite, treatment continuation until reaching undetectable MRD (with the possible use of maintenance therapy). Furthermore, following MRD after a cytotoxic treatment could lead clinical trials investigators to propose pre-emptive treatments in case of MRD re-growth, to avoid overt relaspe. MRD re-growth kinetics and CD4 count after treatment completion can improve MRD-based survival predictions. On the other hand, BCR inhibitors do not lead to undetectable MRD, but their association with chemoimmunotherapy increases the proportion of patients reaching that goal. Moreover, BCL2 inhibitors do lead to deep response including in the relapse/refractory setting, giving to MRD a central place in currently investigated treatments evaluation., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background: Blood pressure (BP) readings taken in clinics are often higher than BP readings taken in a research setting. Recent guidelines and clinical trials have highlighted the necessity of using automated office blood pressure (AOBP) devices and standardizing measurement procedures. The goal of the present study was to compare AOBP vs manual BP measurement in both research and clinical environments in which operators and devices were the same and measurement procedures were standardized and optimal., Methods: Clinical manual BP and AOBP measurement estimates were gathered from a retrospective cohort of patients followed in a hypertension clinic. Research AOBP and manual BP measurement data were obtained from past research studies. Descriptive statistics and agreement analyses with Cohen kappa coefficients were developed. The AOBP/manual BP measurement gap between clinical and research follow-up was compared using an unpaired t test., Results: Two hundred eighty-eight patients were included in the clinical cohort, and 195 patients contributed to research-grade BP data. All patients had hypertension. AOBP averages were lower than manual measurement averages in both clinical (-3.6 ± 14.9 mm Hg / -3.0 ± 8.8 mm Hg) and research (-2.7 ± 10.0 / -2.4 ± 6.3 mm Hg) environments. The gap between measurement methods did not differ between research and clinical data. Cohen kappa coefficient was lower in the clinical context because of greater variability and more time between BP measurements (5.5 ± 2.9 months)., Conclusions: Manual BP readings were slightly higher than AOBP estimates. The difference was not influenced by the real-world context of clinical practice. Office nonautomated BP measurements may still be valuable if measurement procedures are well standardized and performed by trained nurses., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The determination of Shiga toxin (ST) subtypes can be an important element in the risk characterization of foodborne ST-producing Escherichia coli (STEC) isolates for making risk management decisions. ST subtyping methods include PCR techniques based on electrophoretic or pyrosequencing analysis of amplicons and in silico techniques based on whole genome sequence analysis using algorithms that can be readily incorporated into bioinformatics analysis pipelines for characterization of isolates by their genetic composition. The choice of technique will depend on the performance characteristics of the method and an individual laboratory's access to specialized equipment or personnel. We developed two whole genome sequence-based ST subtyping tools: (i) an in silico PCR algorithm requiring genome assembly to replicate a reference PCR-based method developed by the Statens Serum Institut (SSI) and (ii) an assembly-independent routine in which raw sequencing results are mapped to a database of known ST subtype sequence variants (V-Typer). These tools were evaluated alongside the SSI reference PCR method and a recently described PCR-based pyrosequencing technique. The V-Typer method results corresponded closely with the reference method in the analysis of 67 STEC cultures obtained from a World Health Organization National Reference Laboratory. In contrast, the in silico PCR method failed to detect ST subtypes in several cases, a result which we attribute to assembly-induced errors typically encountered with repetitive gene sequences. The V-Typer can be readily integrated into bioinformatics protocols used in the identification and characterization of foodborne STEC isolates.

Genomic antimicrobial resistance (AMR) prediction tools have the potential to support foodborne illness outbreak investigations through their application in the analysis of bacterial genomes from causative strains. The AMR marker profile of a strain of interest, initially identified in outbreak-associated clinical samples, may serve as the basis for customization of selective enrichment media, facilitating its recovery from samples in a food safety investigation. Different possibilities for AMR analyses include the use of comprehensive AMR gene databases such as the Comprehensive Antibiotic Resistance Database, which can be mined with in-house bioinformatics alignment tools (e.g., Antimicrobial Resistance Marker Identifier), or publicly available tools based on clinically relevant acquired AMR gene databases (e.g., ResFinder). In combination with a previously reported pipeline (SigSeekr) designed to identify specific DNA sequences associated with a particular strain for its rapid identification by PCR, it should be possible to deploy custom recovery and identification tools for the efficient detection of priority pathogens such as Shiga toxigenic Escherichia coli (STEC) outbreak strains within the time frame of an active investigation. Using a laboratory STEC strain as a model, trimethoprim resistance identified by both Antimicrobial Resistance Marker Identifier and ResFinder was used as the basis for its selective recovery against a background of commensal E. coli bacteria in ground beef samples. Enrichment in modified tryptic soy broth containing trimethoprim greatly enhanced the recovery of low numbers of model strain cells inoculated in ground beef samples, as verified by the enumeration of colonies on plating media using a strain-specific PCR method to determine the recovery efficiency for the target strain. We discuss the relative merits of different AMR marker prediction tools for this purpose and describe how such tools can be utilized to good effect in a typical outbreak investigation scenario.

Control strains of bacterial pathogens such as Escherichia coli O157:H7 are commonly processed in parallel with test samples in food microbiology laboratories as a quality control measure to assure the satisfactory performance of materials used in the analytical procedure. Before positive findings can be reported for risk management purposes, analysts must have a means of verifying that pathogenic bacteria (e.g., E. coli O157:H7) recovered from test samples are not due to inadvertent contamination with the control strain routinely handled in the laboratory environment. Here, we report on the application of an in-house bioinformatic pipeline for the identification of unique genomic signature sequences in the development of specific oligonucleotide primers enabling the identification of a common positive control strain, E. coli O157:H7 (ATCC 35150), using a simple PCR procedure.

Non-O157 enterohemorrhagic Escherichia coli in priority serogroups O26, O45, O103, O111, O121, and O145 are increasingly recognized as important human pathogens. In the present study, a panel of monoclonal antibodies (MAbs) to the lipopolysaccharide O antigens of E. coli in serogroups O26, O45, O103, O111, O121, and O145 was produced. The specificity was evaluated by examining the reactivity of the MAbs with 50 E. coli strains and 42 non-E. coli bacteria, and several MAbs highly specific for E. coli strains in each of the six non-O157 priority serogroups were identified. The use of these highly specific MAbs may be of considerable value for determining whether an E. coli isolate belongs to one of the six priority non-O157 serogroups, for developing specific detection assays for these organisms, and for characterizing the lipopolysaccharide O antigens of isolates in these serogroups.

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors., (Copyright © 2014 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

A simple immunoenzymatic enterohemorrhagic Escherichia coli (EHEC) colony check (ECC) assay was developed for the presumptive identification of priority EHEC colonies isolated on plating media from enrichment broth cultures of foods. With this approach, lipopolysaccharide extracted from a colony is spotted on the grid of a polymyxin-coated polyester cloth strip, and bound E. coli serogroup O26, O45, O103, O111, O121, O145, and O157 antigens are subsequently detected by sequential reactions with a pool of commercially available peroxidase-conjugated goat antibodies and tetramethylbenzidine substrate solution. Each strip can accommodate up to 15 colonies, and test results are available within 30 min. Assay performance was verified using colonies from a total of 73 target EHEC isolates covering the range of designated priority serogroups (all of which were reactive), 41 nontarget E. coli isolates including several nontarget Shiga toxin-producing E. coli serogroups (all unreactive), and 33 non-E. coli strains (all unreactive except two bacterial strains possessing O-antigenic structures in common with those of the priority EHEC). The ECC assay was reactive with target colonies grown on several types of selective and nonselective plating media designed for their cultivation. These results support the use of the ECC assay for high-throughput screening of colonies isolated on plating media for detecting priority EHEC strains in foods.

A method has been developed for the detection in beef trim of priority Shiga toxin-producing E. coli (STEC) strains, defined as E. coli possessing the virulence factors stx1 and/or stx2 and intimin (eae), with O serogroups O26, O45, O103, O111, O121, O145, or O157. The method is based on recovery of the target bacteria by overnight enrichment in a broth optimized for recovery of O157 and non-O157 STEC, followed by screening using multiplex PCR techniques targeting (i) stx1, stx2, and eae (STE PCR) and (ii) gene sequences associated with the seven priority O serogroups (Poly O PCR), and then direct plating of broth samples positive in both STE and Poly O PCR onto Rainbow agar. Colonies on agar media were screened batchwise for STEC by the STE PCR, and presumptive isolates were characterized using a multiplex PCR and cloth-based hybridization array system targeting key virulence and O serogroup-specific markers. Using one representative strain of each priority O serogroup individually inoculated in beef trim samples, the method exhibited a limit of detection approaching 1 to 2 viable STEC cells per 65 g. None of the uninoculated trim samples produced positive results with either of the screening PCR procedures or on analysis of colonies recovered on plating media. STEC-negative samples were readily identified by screening PCR within 24 h, with a turnaround time of fewer than 4 days for confirmation of positives. The inclusivity and exclusivity characteristics of the screening PCR techniques were verified using a total of 65 different priority STEC strains: 24 nonpriority STEC, 15 non-STEC bacteria, and only those strains bearing the targeted characteristics produced screening PCR-positive results.

A cloth-based hybridization array system (CHAS) was developed for the identification of foodborne colony isolates of seven priority enterohemorrhagic Escherichia coli (EHEC-7) serogroups targeted by U. S. food inspection programs. Gene sequences associated with intimin; Shiga-like toxins 1 and 2; and the antigenic markers O26, O45, O103, O111, O121, O145, and O157 were amplified in a multiplex PCR incorporating a digoxigenin label, and detected by hybridization of the PCR products with an array of specific oligonucleotide probes immobilized on a polyester cloth support, with subsequent immunoenzymatic assay of the captured amplicons. The EHEC-7 CHAS exhibited 100 % inclusivity and 100 % exclusivity characteristics with respect to detection of the various markers among 89 different E. coli strains, with various marker gene profiles and 15 different strains of non-E. coli bacteria.

Background: Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce., Patients and Methods: All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study., Results: Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX., Conclusions: This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

At Cape Vera (Devon Island, Nunavut, Canada), a seabird colony of northern fulmars (Fulmarus glacialis) congregates and releases nutrients through the deposition of guano to the coastal terrestrial environment, thus creating nutrient-fertilized habitats important to insects, birds, and mammals. Here we determined whether mercury was similarly enriched in various terrestrial food web components in this High Arctic coastal ecosystem due to seabird inputs. Stable isotopes (delta(15)N, delta(13)C) were used to identify trophic linkages and possible routes of contaminant transfer in the food web. Values of delta(15)N were significantly higher in lichens and certain plants collected closer to the bird colony, demonstrating a gradient of seabird influence, and were higher at Cape Vera than our reference site at Cape Herschel, on eastern Ellesmere Island, an area relatively unaffected by seabirds. In contrast, delta(13)C showed little variation among terrestrial species, suggesting minimal influence by seabirds. Concentrations of total mercury (THg) in primary producers and phyto/zooplankton were not significantly correlated with distance from the seabird colony or delta(15)N values, and were similar to other taxa from the High Arctic. Our results provide novel data on THg in several Arctic taxa where concentrations have not been reported previously. Moreover, the analyses indicate that delta(15)N is significantly enriched in the adjacent environment by guano fertilization, but our study was unable to show an enrichment of THg and delta(13)C in the terrestrial food web near the seabird colony.

In the honeybee, the conditioning of the proboscis extension response using tactile antennal stimulations is well suited for studying the side-specificity of learning including the possible bilateral transfer of memory traces in the brain, and the role of inhibitory networks. A tactile stimulus was presented to one antenna in association with a sucrose reward to the proboscis. The other antenna was either not stimulated (A+/0 training), stimulated with a non-reinforced tactile stimulus B (A+/B- training) or stimulated with B reinforced with sucrose to the proboscis (A+/B+ training). Memory tests performed 3 and 24h after training showed in all situations that a tactile stimulus learnt on one side was only retrieved ipsilaterally, indicating no bilateral transfer of information. In all these groups, we investigated the effect of the phenylpyrazole insecticide fipronil by applying a sublethal dose (0.5 ng/bee) on the thorax 15 min before training. This treatment decreased acquisition success and the subsequent memory performances were lowered but the distribution of responses to the tactile stimuli between sides was not affected. These results underline the role of the inhibitory networks targeted by fipronil on tactile learning and memory processes.

Nalidixic acid-resistant (NalR) mutants of Salmonella enterica serovar Berta and Escherichia coli O157:H7 were derived from wild-type laboratory cultures to serve as distinguishable control strains for routine use in food microbiology testing programs. The prevalence of the NalR phenotype among different bacteria was verified using panels of related and unrelated strains with the ability to grow vigorously on plating media containing nalidixic acid, being restricted to the NalR mutants. The NalR phenotype was stable in both mutant strains over several generations in the absence of selective pressure and enabled their differentiation from wild-type bacteria on the basis of their ability to grow on plating media containing nalidixic acid. A similar approach for the development of a distinguishable Listeria monocytogenes control strain was not possible due to the inherent resistance of this organism to nalidixic acid. Instead, an L. monocytogenes isolate with rare genotypic and serologic features was identified as a possible candidate to serve as a unique and distinguishable positive control strain.

Many problems concerned with the production and the purification of recombinant proteins must be addressed prior to launching an industrial production process. Among these problems, attention is focused on low-level expression that complicates the purification step and can jeopardise the process. The expression of a membrane protein, rP30, of Toxoplasma gondii in the yeast Schizosaccharomyces pombe led to a secretion of only 0.5 microg ml(-1). In order to obtain a sufficient quantity for biochemical characterization and evaluation in vitro diagnostic test development, strategies for both production and purification had to be optimized. First, the influence of four nitrogen sources (three peptones and yeast extract) on the growth rate, but also on the separation between the protein and the components of the fermentation broth was assessed. Second, batch and fed-batch fermentations were compared in terms of final biomass and rP30 concentrations. Third, three different protocols that included fixed and expanded bed ion exchange chromatography were compared for processing a large volume of feedstock. By using the most appropriate strategies, i.e. fed-batch fermentation, capture on EBA cation exchanger and affinity chromatography polishing, a purification factor of 1778 and a yield of 49% were achieved. These performances allowed a 12.5-fold increase for the overall rP30 process productivity.

Osteopontin (OPN) is expressed in numerous carcinomas and plays a role in tumour development, invasion and metastasis. This study examines by immunohistochemistry the expression of OPN in normal salivary gland tissue and three types of salivary gland tumour: pleomorphic adenoma (PA), adenoid cystic carcinoma (ACC) and polymorphous low grade adenocarcinoma (PLGA). PAs and PLGAs demonstrated higher levels of OPN than normal salivary gland tissue, while ACC, although showing a trend towards increased OPN, was not significantly different. The results of this study indicate that OPN expression is present in normal salivary gland tissue, and is increased in certain salivary gland tumours, but further investigation is necessary to clarify its role.

Phase behaviour experiments employing PCB (Aroclor 1242)/alcohol/water systems were conducted with ethanol (EtOH) and n-propanol (nPA). Both exhibited an affinity for the aqueous phase within the entire two-phase region. As much as 88% by volume (88% vol.) EtOH and 80% vol. nPA were necessary to achieve full miscibility of the PCB in the aqueous phase. DNAPL-water interfacial tension (IFT) was reduced from 38.9 dyn/cm to 4.7 dyn/cm and 2.4 dyn/cm with 80% vol. EtOH and 76% vol. nPA. The addition of alcohol brought about 41% and 54% reductions in DNAPL viscosity at maximal concentrations of EtOH and nPA. Density of the PCB-DNAPL was relatively unaffected by the presence of alcohol. A series of seven experiments were conducted where successive slugs of nPA and xanthan gum polymer solutions were injected into a fractured shale sample. A 30% vol. nPA solution injected under a hydraulic gradient of 0.36 allowed enhanced PCB removal primarily through reduction of IFT and resulted in 72% DNAPL recovery. Several pore volumes of alcohol solution were necessary to displace all the potentially mobile non-wetting phase since the high-viscosity DNAPL was mobilized at a lower flow rate than the overall fluid velocity, illustrating non-piston displacement. The injection of a 95% vol. nPA alcohol solution, theoretically at a sufficient concentration to produce fully miscible displacement of the residual DNAPL at equilibrium, resulted in non-equilibrium partitioning of the PCB into the flushing solution, likely due to the high fluid velocities in the fracture. The injection of 200 pore volumes of 95% vol. nPA solution resulted in 94% DNAPL recovery. Alcohol floods operated below the miscibility envelope appear to be a valuable source zone remedial alternative where the objective is to reduce DNAPL mobility to zero, but it should be noted that DNAPL mobility is increased during the application of the technology and steps may need to be taken to prevent unwanted vertical mobilization.

Toxoplasma gondii, the intracellular parasite responsible for toxoplasmosis infects more than one-third of the world population and can be life-threatening for fetuses and immunocompromised patients. The surface protein SAG1 is an important immune target, which provides a strong immune response against the invasive tachyzoite while the other forms of the parasite, devoid of SAG1 at their surface, are multiplying. In addition to this role as a "hot spot" decoy, SAG1 is predicted to act as an adhesin during host-cell attachment through its binding to proteoglycans. To begin to understand the relationships between SAG1 epitopes and the ligand-binding site, we have solved the crystal structure of the monomeric form of T.gondii SAG1 complexed to a Fab derived from a monoclonal antibody raised against tachyzoite particles. This antibody competes strongly with human Toxoplasma-specific sera, suggesting that its epitope is part of an immunodominant region present on the surface of SAG1. The structure reveals that this conformational epitope, located within the SAG1 N-terminal domain, does not overlap with the proposed ligand-binding pocket. This study provides the first structural description of the monomeric form of SAG1, and significant insights into its dual role of adhesin and immune target during parasite infection.

Objectives: The authors had for aim to show that preventing the diffusion of multidrug-resistant organism (MRO) is possible thanks to the coordination of recommended preventive actions and the implementation of a sensible anti-infective prescription policy. They also wanted to highlight the role played by the nursing care staff in enforcing recommendations., Method: We compared the results of two health care facilities having both implemented the same strategy aimed at preventing cross-transmission and prescribing anti-infective drugs., Results: Audits reported a very variable enforcement of recommendations. The results obtained from microbiological monitoring confirmed the essential impact of protocol enactment by every team, on the control of MRO diffusion. The antibiotherapy specialist has a key role in the suggested strategy, allowing a significant decrease in the number of anti-infective prescriptions and a more rational use., Conclusion: The collaboration of a hygiene specialist with an antibiotherapy specialist has proved operational in the fight against MRO diffusion, as long as the competences of both specialists are acknowledged and their cross-disciplinary activities accepted. For the entire staff, enacting a corporate culture is a crucial asset.

Fipronil is a phenylpyrazole insecticide introduced for pest control, but it can also affect non-target insects such as honeybees. In insects, fipronil is known to block GABA receptors and to inhibit ionotropic glutamate-gated chloride channels, but the behavioral effects of low doses are not yet fully understood. We have studied the effect of sublethal doses of fipronil on the behavior of the honeybee (Apis mellifera) under controlled laboratory conditions. The drug was either administered orally or applied topically on the thorax. A significant reduction of sucrose sensitivity was observed for the dose of 1 ng/bee 1 h after a thoracic application. No significant effect on sucrose sensitivity was obtained with acute oral treatment. A lower dose of fipronil (0.5 ng/bee applied topically) impaired the olfactory learning of the honeybees. By contrast, locomotor activity was not affected. Our results suggest a particular vulnerability of the olfactory memory processes and sucrose perception to sublethal doses of fipronil in the honeybee.

A simple cloth-based hybridization array system was developed for the characterization of Clostridium botulinum isolates based on the botulinum neurotoxin serotype. Bacterial isolates were subjected to a multiplex PCR incorporating digoxigenin-dUTP and primers targeting the four botulinum neurotoxin gene serotypes (A, B, E, and F) predominantly involved in human illness, followed by hybridization of the amplicons with an array of toxin gene-specific oligonucleotide probes immobilized on polyester cloth and subsequent immunoenzymatic assay of the bound digoxigenin label. This system provided sensitive and specific detection of the different botulinum neurotoxin gene markers in a variety of C. botulinum strains, exhibiting the expected patterns of reactivity with a panel of target and nontarget organisms.

Oocytes collected by laparoscopic ovum pick-up (LOPU) were successfully used to produce transgenic goats by pronuclear microinjection of in vitro zygotes. Estrus cycles of 109 donor goats were synchronized using intravaginal sponges impregnated with 60 mg of medroxyprogesterone acetate and treatment with 70 mg NIH-FSH-P1 and 300 IU eCG to stimulate follicular development. Follicles were aspirated under laparoscopic observation. In vitro maturation (IVM) of oocytes was performed in M199 supplemented with hormones, kanamycin and 10% estrus goat serum. Following IVM, oocytes were cocultured with capacitated semen in TALP supplemented with 20% estrus goat serum for 15-20 h. The resulting zygotes were microinjected with a linear DNA fragment. In total, 3293 follicles were aspirated (15.7+/-9 follicles aspirated per donor) and 2823 oocytes were recovered (13.4+/-8 oocytes per donor). A total of 1366 zygotes were microinjected and transferred into 219 recipient goats by midventral laparotomy (average 6.2 embryos per recipient). A total of 150 kids were born, of which 9 (6 M: 3 F) were confirmed to be transgenic by PCR and Southern blotting analyses. These results demonstrate that acceptable transgenesis rates can be obtained in goats by DNA microinjection of in vitro produced zygotes.

Hepatitis B virus core protein (HBc) is an important serology marker of hepatitis B infection and patient follow-up. It is an M, 21,000 protein, which has the intrinsic capacity to self-assemble as a capsid-like particle. The hepatitis B core protein has been expressed in Escherichia coli and Pichia pastoris (three different constructions) in order to select a HBc recombinant antigen suitable for serodiagnosis requirements with a cost effective downstream strategy. The expression and purification of the different forms of recombinant HBc have been described. For the last step, ultracentrifugation and size-exclusion chromatography were compared. The morphology of these capsids was observed using an electron microscope. Our data shows that HBc antigen is produced in large quantities in E. coli but some contaminants remained which were associated with the E. coli HBc protein after ultracentrifugation or size-exclusion chromatography. The ultracentrifugation enables a higher purity of HBc antigen to be obtained than size-exclusion chromatography but the latter enables a higher recovery rate. P. pastoris enables the expression and extraction of a highly purified HBc antigen suitable for diagnostic purposes.

Purpose: Drug-induced hypersensitivity syndrome (DIHS) is an acute and severe drug reaction. Manifestations include severe skin lesions, fever, nodal enlargement, blood eosinophilia and multisystemic involvement. The severe systemic manifestations of DIHS are responsible for a 10% mortality rate. The pertinence of corticosteroid therapy is discussed., Methods: The authors report eight retrospective cases of DIHS obtained from the PMSI (Programme de Médicalisatiopn des Systèmes d'Information) between November 1991 and November 1998., Results: The series consisted of five male and three female patients (mean age: 52.6 years; range: 23-83 years). The interval between the introduction of the drug and the onset of the reaction varied from two to eight weeks. Due to severe systemic manifestations, three patients were given corticosteroid therapy. Healing of skin and systemic disorders resolved with a mean delay of 4.4 weeks (range: 1 to 56 weeks)., Conclusion: DIHS can be a diagnostic trap, as there are no diagnostic criteria for DIHS. Only the association of multiple arguments such as the time to the occurrence of symptoms, clinical similarity to many infectious illnesses, hypereosinophilia, atypical lymphocytosis, etc. may help guide diagnosis. DIHS can also be a therapeutic trap, as prompt withdrawal of the offending drug is essential to minimize morbidity. Although still controversial in the literature, the pertinence of corticosteroid therapy may be discussed in case of severe systemic effects. Patch testing can be a valuable tool to determine the responsibility of a drug; however it proves to be useful only when positive.

Purpose: Alpha, beta or gamma interferon (INF) are cytokines produced by cells in response to antigenic stimulation. They are used to treat various hepatic, hematological, oncological and neurological diseases. Cutaneous reactions (rash, alopecia, labial herpes, erythema, or induration at the site of injection, and more rarely cutaneous necrosis) represent 5 to 12% of side-effects observed in patients receiving INF. The authors report six cases of local cutaneous reactions to alpha INF, five of which corresponded to cutaneous necrosis. This makes them question the relevance of INF reintroduction., Methods: The study included 5 male and 1 female patients (mean age: 59.1 years; range: 42 to 74 years old). Three patients had chronic hepatitis C, while three others presented a blood disease., Results: Cutaneous necrosis occurred after 1 to 10 months of treatment. The mean time to healing was 16.2 weeks. Reintroduction of the drug including injection in other sites did not lead to recurrence of necrosis in five out of the six cases., Conclusion: INF-induced cutaneous necrosis does not depend on the type of INF, the site of injection, the dose and may occur 2 months to 9 years after treatment implementation. The exact mechanisms involved in cutaneous necrosis remain unknown. Morbidity is due to a very long time to healing (4 to 6 months). Futhermore, healing sometimes requires prior surgery. Physicians should be aware of the potential occurrence of erythema in patients treated by INF, as it is the first sign of necrosis. The site of injection should then be modified. In case of necrosis, risk factors for thrombophilia, factors reducing microcirculation (DHE, beta-blockers, cigarette smoking) should be investigated. INF injections should be cautiously reintroduced in other sites with the help of a nurse in case of self-injections prior to the occurrence of necrosis. Regarding self-injections patients' training should be emphasized.

One-trial conditioning of the proboscis extension reflex (PER) in honeybees was used to examine the qualitative effects of two muscarinic antagonists, atropine and pirenzepine, on the acquisition and retrieval of memory following intracranial injection. The main result of this study is that atropine, at a relatively high concentration of 10(-2) M, impairs memory retrieval but not acquisition of memory after a single olfactory conditioning trial (at this concentration, there is no effect of atropine on the sensorimotor components of the PER). This result is in agreement with the effects of scopolamine, reported in a previously published article. Pirenzepine, at the same concentration as atropine, had no effect on either acquisition or retrieval of memory. These results suggest that blockade of muscarinic-like receptors, except those that bind to pirenzepine, induces solely an impairment of memory retrieval.

The industrial production of recombinant proteins requires control of both fermentation and purification steps. For the serodiagnosis of toxoplasmosis, the main antigen is a membrane protein of 30 kDa (P30). The P30 gene was cloned and expressed in Schizosaccharomyces pombe at 0.7 microg/ml in culture medium. Batch fermentation was optimized by the specific choice of peptones, which enabled optimum growth and protein expression without reducing the efficacy of the purification step. Analytical purification was then carried out using cation-exchange chromatography. For larger volumes, scaling up was performed on expanded mode by using a Streamline system (Pharmacia). This purification step allowed us to obtain a 67.5% recovery with a purification factor greater than 27-fold. Expanded bed adsorption technology is a convenient and effective technique for protein capture directly from feedstock, and the eluted fraction is ready for a second affinity chromatography step. This second step is performed with a yield of 40% and provides a final purification factor of 2000-fold.

C1-inhibitor is a proteinase inhibitor in the serpin family. It is an important inhibitor of complement C1, plasma kallikrein, and factor XIIa, and as such is involved in regulating inflammatory pathways. Studies on the plasma-derived protein are hampered by the relative ease with which the protein converts to an inactive state on storage, under mild denaturing conditions, or by incubating in some unfavorable buffers. This inactivation is caused by formation of soluble polymers which can be visualized on native electrophoresis. In order to facilitate studies on both the plasma-derived protein and recombinant variants planned for the future, it was necessary to devise a method for the rapid reactivation of the polymers in high yield. It was found that nonionic detergents did not dissociate the polymers, but they were readily dissociated in 0.1% SDS. Treatment with 0.1% SDS followed by rapid removal of the SDS and refolding on an FPLC Superose 6 column allowed for recovery of about 15% of the protein in the active monomeric form. Eighty-five percent eluted as a range of higher order polymers. Using 8 M urea as the denaturant a 25% yield of active monomer was recovered. However, with 6 M guanidine hydrochloride as the denaturant, the yield of active monomer was almost 50%. The remaining material was not present as a range of polymeric species but was probably a dimer. Therefore this method is a useful technique to facilitate studies on C1-inhibitor. Moreover, the ability to produce monomer, dimer, and polymer forms of C1-inhibitor is useful for studies investigating the conformational changes which have occurred in the different forms.

Study Objective: To compare the hypnotic effects of a bedtime dose of zolpidem, triazolam, and placebo., Design: "Double-blind, randomized, placebo- and active-controlled, parallel-group" trial., Setting: Six Canadian hospitals., Patients: 357 patients (aged 19 to 71 years) hospitalized the night before a surgical procedure., Interventions: At bedtime, each patient received either zolpidem 10 mg, triazolam 0.25 mg, or placebo, and was allowed to sleep for a maximum of 8 hours., Measurements: Outcome measures were subjective in nature and included a morning questionnaire, visual analog scales, and observation forms by study personnel. All continuous variables were analyzed by analysis of variance. All categorical data were compared using the Cochran-Mantel-Haenszel (CMH) test, and the percentage of patients asleep was compared using a CMH chi-square analysis. When significant overall treatment effects were observed, pairwise comparisons were undertaken. Compared with the placebo group, the following parameters were significantly (p < 0.001) different in the zolpidem and triazolam groups: sleep latency was shorter, total sleep time was longer, patients fell asleep more easily, and the number of patients awake 2 hours after drug administration was lower. There were no differences between any groups in next-morning somnolence or ability to concentrate. Both drugs were well tolerated, with adverse event incidence rates nearly identical to placebo., Conclusions: In patients suffering from transient insomnia, a single dose of zolpidem 10 mg was as effective as triazolam 0.25 mg, and both were more effective than placebo and were well tolerated.

Study Objectives: To determine the cumulated incidence and the density of incidence of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS) in critically ill children; to distinguish patients with primary from those with secondary MODS., Design: Prospective cohort study., Setting: Pediatric ICU of a university hospital., Patients: One thousand fifty-eight consecutive hospital admissions., Interventions: None., Measurements and Results: SIRS occurred in 82% (n=869) of hospital admissions, 23% (n=245) had sepsis, 4% (n=46) had severe sepsis, 2% (n=25) had septic shock; 16% (n=168) had primary MODS and 2% (n=23) had secondary MODS; 6% (n=68) of the study population died. The pediatric risk of mortality (PRISM) scores on the first day of admission to pediatric ICU were as follows: 3.9 +/- 3.6 (no SIRS), 7.0 +/- 7.0 (SIRS), 9.5 +/- 8.3 (sepsis), 8.8 +/- 7.8 (severe sepsis), 21.8 +/- 15.8 (septic shock); differences among groups (p=0.0001), all orthogonal comparisons, were significant (p<0.05), except for patients with severe sepsis. The observed mortality for the whole study population was also different according to the underlying diagnostic category (p=0.0001; p<0.05 for patients with SIRS and those with septic shock, compared with all groups). Among, patients with MODS, the difference in mortality between groups did not reach significance (p=0.057). Children with secondary MODS had a longer duration of organ dysfunction (p<0.0001), a longer stay in pediatric ICU after MODS diagnosis (p<0.0001), and a higher risk of mortality (odds ratio, 6.5 [2.7 to 15.9], p<0.0001) than patients with primary MODS., Conclusions: SIRS and sepsis occur frequently in critically ill children. The presence of SIRS, sepsis, or septic shock is associated with a distinct risk of mortality among critically ill children admitted to the pediatric ICU; more data are needed concerning children with MODS. Secondary MODS is much less common than primary MODS, but it is associated with an increased morbidity and mortality; we speculate that distinct pathophysiologic mechanisms are involved in these two conditions.

Patients admitted to intensive care units frequently develop stress ulcers, erosive gastritis and complications such as upper gastrointestinal bleeding. Stress-related upper gastrointestinal bleeding (UGIB) has been of particular concern to many practitioners working in intensive care units and has led to the treatment of most if not all patients admitted to these units with antacids, H2 receptor antagonists or sucralfate in order to protect the gastric mucosa. It is considered that the 3 aforementioned medications are effective in decreasing the overall incidence of UGIB, but it has not been demonstrated that they are efficacious in reducing the incidence of clinically significant UGIB, ie cases that are complicated by anemia, hemorrhagic shock, or death. In addition, the cost and complications resulting from prophylaxis should be taken into consideration, which raises further questions about the systematic use of these agents. This article reviews the current literature on this subject; the authors propose a conservative use of prophylaxis, and that these agents be prescribed in a selective manner to the patients at the greatest risk of developing UGIB.