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Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

Summary Background Long-term monitoring of white blood cell count is compulsory in patients taking clozapine, although the incidence of drug-induced agranulocytosis is lower than previously expected. The cost-effectiveness of this monitoring is unknown. We aimed to assess the cost-effectiveness of various strategies to monitor white blood cell count in adult patients with schizophrenia taking clozapine. Methods We assessed the cost-effectiveness of four strategies for monitoring white blood cell count (national strategies used in the UK, USA, and European countries, and a hypothetical 8-week strategy) compared with that of no monitoring. We used a semi-Markov model to do the cost–utility analysis from a health-care perspective with a 3-year time horizon, assuming a probability of 0·7% that a patient would develop agranulocytosis. Clinical and resource parameters were based on data from national registries of patients treated with clozapine, study cohorts, and a pharmacovigilance database; we derived estimates of health-related quality of life and mortality from the scientific literature. We assessed model uncertainty, including time horizon, with one-way and probabilistic sensitivity analyses. Findings Compared with no monitoring, all four monitoring strategies increased quality-adjusted survival by less than 1 day per patient; more than 5000 patients would need to be monitored to avoid one death. The incremental cost-effectiveness ratios (ICERs) were at least US$970 000 per quality-adjusted life-year gained for all four strategies compared with no monitoring. The ICERs were highest in the strategies with highest frequencies and longest durations of monitoring. The results remained robust in the one-way and probabilistic sensitivity analyses, suggesting that no monitoring had the highest probability of being cost effective. Interpretation Existing strategies for monitoring white blood cell count in patients taking clozapine, based on divergent national requirements, do not seem to be cost effective. This finding should be taken into account by public health authorities and policy makers in the revision of guidance for clozapine prescription. Funding University Hospitals of Geneva.

Liver resection is generally restricted to patients without clinically significant portal hypertension (Hepatic Venous Pressure Gradient - HVPG - ⩽10mmHg) and several teams perform transjugular HVPG measurements as part of the pre-operative work-up. The present study investigates whether a non-invasive Computed Tomography (CT)-based assessment could be as accurate as the invasive transjugular measurement.A cohort of patients with hepatocellular carcinoma (HCC) treated by resection (n=36) or transplantation (n=39) was selected (mean age: 61±9.2years, male/female ratio: 4/1). Pre-operative CTs were read by two independent investigators, and potential CT-based HVPG predictors were compared to the transjugular HVPG measurements. A validation was conducted on another cohort of 70 non-surgical patients.The invasive HVPG values were significantly correlated to liver/spleen volume ratio, spleen volume, platelet count, and peri-hepatic ascites (p0.001), which all showed high inter-observer agreements (intra-class correlation coefficients ⩾0.927, Kappa ⩾0.945). The presence of a HVPG10mmHg was best predicted by the liver/spleen volume ratio (AUC: 0.883 [0.805-0.960]) and the peri-hepatic ascites (p0.001). These two variables were combined into an accurate model for predicting HVPG10mmHg (AUC: 0.911 [0.847-0.975]), with sensitivity, specificity, and positive and negative predictive values of 92%, 79%, 91%, and 81%. The model was also accurate in the validation cohort with an AUC of 0.820 [0.719-0.921]. The computed formula was:The proposed CT-based model showed a high accuracy in the prediction of HVPG and, if further confirmed by prospective validation, could replace the invasive transjugular assessment in patients not requiring a biopsy of the non-tumoral liver.

© 2015 AASLD. © 2015 American Association for the Study of Liver Diseases. The demand for transplantable organs far outweighs the supply. Recently efforts have been made to increase the donor pool by adopting extended criteria for livers including those from hypernatremic donors. Currently there is no clear evidence that the use of organs from hypernatremic donors has detrimental effects on pediatric liver transplantation (LT) recipients. Our aim was to use the Scientific Registry of Transplant Recipients database to evaluate the effects of donor hypernatremia on 30 day outcomes in pediatric LT recipients. We performed an analysis of 2325 children who underwent whole or partial LT between 2005 and 2010. First we sought to determine a donor sodium threshold for increased mortality following pediatric LT. Second we examined rates of mortality and graft failure at 30 days after LT in patients receiving grafts from hypernatremic donors compared to patients receiving grafts from normonatremic donors. Hypernatremia was defined as a donor sodium level of =160 µmol/L. The primary outcome measure was mortality at 30 days after transplant. The secondary outcome measure was graft failure at 30 days after transplant. There was no threshold sodium level for increased 30 day mortality following pediatric LT. Mean recipient ages/weights Pediatric End Stage Liver Disease/Model for End Stage Liver Disease scores and mean cold and warm ischemia times were similar between the 2 study groups. There were no significant differences in mortality rates (3.9 versus 4.5; P=0.87) and graft failure rates (2.2 versus 1.9; P=1.00) in patients receiving grafts from hypernatremic donors compared to patients receiving grafts from normonatremic donors at 30 days after LT. In conclusion donor hypernatremia just before procurement does not appear to have negative effects on mortality and graft failure rates at 30 days following pediatric LT. Liver Transpl 21:1076 1081 2015.

Objectives Obstetric work generates important subjective and objective mental stress and is perceived as a physically demanding activity by obstetricians. The aim of this study was to quantify physical and mental stress levels in obstetricians at work and during leisure activities to investigate their association with overall physical activity levels and professional experience. Study design 18 obstetricians at the maternity unit of the University of Geneva Hospitals were enrolled in a prospective observational study. Physical activity and stress levels were measured in two different activity sectors (delivery room and outpatient clinic) and outside work. Physical activity was assessed by questionnaire, visual analogue scale (VAS), and accelerometer. Mental stress levels were assessed by validated questionnaires, VAS, measurement of urine catecholamines and salivary cortisol, and night-time heart rate variability indices. Results Daily stress levels were higher at work compared to outside work (all, P = 0.002). Adrenalin ( P = 0.002) and dopamine ( P = 0.09) levels were elevated after a labour suite shift and a trend was observed for reduced heart rate variability during the night after this shift. The median average daily number of steps was 7132 (range, 5283–8649). Subjects reached a median of 32 min (range, 19–49 min) of moderate or higher intensity (≥1952 counts/min) daily physical activity. Conclusions Contrary to perception, obstetrics work is not physically demanding. It is, however, accompanied by important subjective and objective mental stress that may have a negative impact on health when combined with a lack of regular daily physical activity.

BACKGROUND: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapyinduced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy. METHODS: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n 5543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS). RESULTS: The proportions of patients in the 4 subgroups were comparable in both treatment arms (P 5.77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.722.0 months) according to toxicity subgroup (P 5.45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P

Introduction Measuring factor VIII (FVIII) activity can be challenging when it has been modified, such as when FVIII is pegylated to increase its circulating half-life. Use of a product-specific reference standard may help avoid this issue. Aim Evaluate the impact of using a product-specific reference standard for measuring the FVIII activity of BAX 855 – a pegylated FVIII – in eight of Switzerland's main laboratories. Methods Factor VIII-deficient plasma, spiked with five different concentrations of BAX 855, plus a control FVIII sample, was sent to the participating laboratories. They measured FVIII activity by using either with a one-stage (OSA) or the chromogenic assay (CA) against their local or a product-specific reference standard. Results When using a local reference standard, there was an overestimation of BAX 855 activity compared to the target concentrations, both with the OSA and CA. The use of a product-specific reference standard reduced this effect: mean recovery ranged from 127.7% to 213.5% using the OSA with local reference standards, compared to 110% to 183.8% with a product-specific reference standard, and from 146.3% to 182.4% using the CA with local reference standards compared to 72.7% to 103.7% with a product-specific reference standard. Conclusion In this in vitro study, the type of reference standard had a major impact on the measurement of BAX 855 activity. Evaluation was more accurate and precise when using a product-specific reference standard.

Background Inter-assay variability is a well-known problem in antiphospholipid antibody testing, due to the lack of standardization. Inter-lab reproducibility for a same assay is similarly important. Objectives Testing repeatability and reproducibility of HemosIL® AcuStar for anticardiolipin (aCL) and aβ2GPI IgG and IgM. Patients/Methods In this observational study, out of 420 samples from the thrombophilia centers of Ghent and Geneva, 100 samples were randomly selected and successively analyzed in three centers: Ghent (C1, in duplicate for repeatability evaluation), Geneva (C2) and Frankfurt (C3). Results Results from 99 samples were available, including 25 from patients with antiphospholipid syndrome (APS) and 74 from non-APS patients. The intra-center repeatability expressed as intra-class correlation coefficient (ICC) was higher than 0.99 for each parameter. Differences between two measurements rarely exceeded 1 U/ml for values below 100 U/ml, except for aβ2IgG where differences varied from -4 to 4 U/ml. The inter-centers ICC were higher than 0.99 except for aCL IgM (ICC = 0.961). These ICC remained high even when considering values below 100 U/ml (0.943, 0.964 and 0.977 for aCL IgG, aCL gM and aβ2GPI IgM, respectively), except for aβ2GPI IgG (ICC = 0.652). Qualitative comparison showed less than 5% of discordant classification between centers, with somewhat more discordant results for aβ2GPI IgG. Conclusions In terms of discriminating properties, The HemosIL® AcuStar has excellent intra-center repeatability and a good inter-center reproducibility for aCL IgG, aCL IgM and aβ2GPI IgM. Some concern may arise for aβ2GPI IgG. This article is protected by copyright. All rights reserved.

Neural differentiation of embryonic stem cells (ESC) is considered a promising model to perform in vitro testing for neuroactive and neurotoxic compounds. We studied the potential of a dual reporter murine ESC line to identify bioactive and/or toxic compounds. This line expressed firefly luciferase under the control of the neural cell-specific tubulin alpha promoter (TUBA1A), and renilla luciferase under the control of the ubiquitous translation elongation factor 1-alpha-1 (EEF1A1) promoter. During neural differentiation, TUBA1A activity increased, while EEF1A1 activity decreased. We first validated our test system using the known neurotoxin methyl mercury. This compound altered expression of both reporter genes, with ESC-derived neural precursors being affected at markedly lower concentrations than undifferentiated ESCs. Analysis of a library of 1040 bioactive compounds picked up 127 compounds with altered EEF1A1 and/or TUBA1A promoter activity, which were classified in 4 clusters. Cluster 1 (low EEF1A1 and TUBA1A) was the largest cluster, containing many cytostatic drugs, as well as known neurodevelopmental toxicants, psychotropic drugs and endocrine disruptors. Cluster 2 (high EEF1A1, stable TUBA1A) was limited to three sulfonamides. Cluster 3 (high EEF1A1 and TUBA1A) was small, but markedly enriched in neuroactive and neurotoxic compounds. Cluster 4 (stable EEF1A1, high TUBA1A) was heterogeneous, containing endocrine disruptors, neurotoxic and cytostatic drugs. The dual reporter gene assay described here might be a useful addition to in vitro drug testing panels. Our two-dimensional testing strategy provides information on complex response patterns, which could not be achieved by a single marker approach.

The antiplatelet clopidogrel and the proton pump inhibitor esomeprazole demonstrate a pharmacokinetic interaction through CYP2C19 that could translate into clinical inefficacy of clopidogrel. No medical consensus as to their coprescription has been reached, and different guidelines are available. We evaluated the prescribing practices at the Geneva University Hospitals (HUG) by measuring whether the coprescription was staggered as suggested by experts. We estimated the financial impact of different implementation guidelines. We used the HUG electronic patient records to follow the physicians' prescriptions and the administration by nurses from January 2013 to April 2014. We performed a time series analysis to assess 15 years of proton pump inhibitors (PPIs) and antiplatelet drug use. “Extra costs” were calculated assuming that clopidogrel or esomeprazole would replace prasugrel or ticagrelor and pantoprazole or ranitidine, respectively. Only 10.8% of the patient medical orders for the clopidogrel and esomeprazole coprescription specified to stagger the administration, 12.6% specified a concomitant coprescription, and 76.6% had no clear information. A high rate of 49.6% of the nurses staggered the clopidogrel and esomeprazole coprescription when no clear information was given. We found a statistically significant decrease in clopidogrel use after the publication of the OCLA (Omeprazole–CLopidogrel–Aspirin) study and a significant increase in the trend of esomeprazole. Alternative treatments to avoid this interaction are cost ineffective or offer therapeutic options of lesser quality. We observed a high rate of 56.2% of the clopidogrel and esomeprazole coprescription in our hospital and can therefore not ignore the PK/PD interaction. The most common prescription practice was to not specify the time frame of administration, which was translated by nurses in 49.6% of the cases to a scheduled staggered coprescription of clopidogrel and esomeprazole. As long as no consensus has been reached, the medical orders time frame information should be mandatory to allow a clear and harmonious staggering strategy.

Background. Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. Methods. We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. Results. Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27–1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72–2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35–2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57–2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91–1.64) did not achieve statistical significance. Conclusions. Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

Introduction The proportion of women engaged in clinical research has increased over time, but it is unclear if women and men contribute to the same extent during the conduct of research. Our objective were: –to describe the prevalence of women authors of original articles published in 2000 and 2015; –to compare the research contributions and author positions according to gender. Methods We conducted a repeated cross-sectional study among all original articles published in the Annals of Internal Medicine in 2000 and 2015. Participants were all authors listed on the byline of the original articles. The primary outcomes were 10 contributions listed at the end of the paper and included in the criteria of the International Committee of Medical Journal Editors (ICJME). Secondary outcomes were the author position on the byline (first, second, next-to-last and last compared to middle rank). The main exposures were the author gender and the year of publication (2000 or 2015). Other variables were the academic degrees mentioned by the author on the byline, the home institution, the country of affiliation, and the type of funding. We assessed the association and its evolution over time of the 10 specific contributions to research paper by using mixed effect logistic regression models (one per contribution) where the contribution was the dependent variable, the article was the random factor and the gender was the main fixed factor. In each model, we included the year and an interaction term between gender and year to assess change over time. We reassessed these associations after adjusting for academic degrees. To identify if gender was associated with a specific position on the article byline, we performed four conditional logistic regression models where each article defined a cluster, with author position (e.g. first vs. middle rank) as the dependent variable and gender the main predictor. We included year and an interaction term between year and gender to assess if there was a change over time of the associations between gender and author position. Then we adjusted the models for the 10 authors’ contributions to research. We built four models, comparing the first, second, next-to-last and last position to middle position. In these models, articles with four or less authors were excluded from the analyses. Results The proportion of women authors increased from 31.5% to 41.2% between 2000 and 2015 (P = 0.004). In 2000, women authors were less frequently involved than men in the conception and design (55.1% vs. 61.2%, P = 0.026), critical revision (70.4% vs. 80.7%, P = 0.001), final approval (80.7% vs. 85.8%, P = 0.038), and obtaining of funding (16.1% vs. 21.6%, P = 0.024). Women tended to be more involved than men in administration and logistics (35.0% vs. 26.0%, P = 0.019) and data collection (49.8% vs. 45.8%, P = 0.053), but they were similarly involved in the analysis and interpretation of data, drafting of the manuscript, provision of materials/patients, and statistical expertise. Women were less often last authors than men (9.0% vs. 15.5%, P = 0.016). These gender differences persisted in 2015. Conclusions The representation of women among authors of medical articles has increased notably between 2000 and 2015 but remained below 50%. Women's roles differed from those of men with no change over time. The study has some limitations with the use of a single journal and self-reported contributions. These differences may be due to justifiable reasons such as seniority, specific training and skills in research, or role preferences of the researchers. However, the possibility also exists that the academic research milieu perpetuates sexist attitudes and unequal treatment of researchers based solely on their gender. This requires further exploration, and justifies the continuation of local initiatives that promote women's involvement in research and ensure fair career opportunities, regardless of gender.

Background Diaphragm dysfunction in mechanically ventilated patients is associated with poor outcome. Maximal inspiratory pressure (MIP) can be used to evaluate inspiratory muscle function. However, it is unclear whether respiratory weakness is independently associated with long-term mortality. The aim of this study was to determine if low MIP is independently associated with one-year mortality. Methods We conducted a prospective observational cohort study in an 18-bed ICU. Adults requiring at least 24 hours of mechanical ventilation with scheduled extubation and no evidence of pre-existing muscle weakness underwent MIP evaluation just before extubation. Patients were divided into two groups: low MIP (MIP ≤30 cmH2O) and high MIP (MIP >30 cmH2O). Mortality was recorded for one year after extubation. For the survival analysis, the effect of low MIP was assessed using the log-rank test. The independent effect of low MIP on post mechanical ventilation mortality was analyzed using a multivariable Cox regression model. Results One hundred and twenty-four patients underwent MIP evaluation (median age 66 years (25th–75th percentile 56–74), Simplified Acute Physiology Score (SAPS) 2 = 45 (33–57), duration of mechanical ventilation 7 days (4–10)). Fifty-four percent of patients had low MIP. One-year mortality was 31 % (95 % CI 0.21, 0.43) in the low MIP group and 7 % (95 % CI 0.02, 0.16) in the high MIP group. After adjustment for SAPS 2 score, body mass index and duration of mechanical ventilation, low MIP was independently associated with one-year mortality (hazard ratio 4.41, 95 % CI 1.5, 12.9, p = 0.007). Extubation failure was also associated with low MIP (relative risk 3.0, 95 % CI 1, -9.6; p = 0.03) but tracheostomy and ICU length of stay were not. Conclusion Low MIP is frequent in patients on mechanical ventilation and is an independent risk factor for long-term mortality in ICU patients requiring mechanical ventilation. MIP is easily evaluated at the patient’s bedside. Trial Registration This study was retrospectively registered in www.clinicaltrials.gov (NCT02363231) in February 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1418-y) contains supplementary material, which is available to authorized users.

Objectives To compare noninferiority margins defined in study protocols and trial registry records with margins reported in subsequent publications. Study Design and Setting Comparison of protocols of noninferiority trials submitted 2001 to 2005 to ethics committees in Switzerland and The Netherlands with corresponding publications and registry records. We searched MEDLINE via PubMed, the Cochrane Controlled Trials Register (Cochrane Library issue 01/2012), and Google Scholar in September 2013 to identify published reports, and the International Clinical Trials Registry Platform of the World Health Organization in March 2013 to identify registry records. Two readers recorded the noninferiority margin and other data using a standardized data-abstraction form. Results The margin was identical in study protocol and publication in 43 (80%) of 54 pairs of study protocols and articles. In the remaining pairs, reporting was inconsistent (five pairs, 9%), or the noninferiority margin was either not reported in the publication (five pairs, 9%) or not defined in the study protocol (one pair). The confidence interval or the exact P-value required to judge whether the result was compatible with noninferior, inferior, or superior efficacy was reported in 43 (80%) publications. Complete and consistent reporting of both noninferiority margin and confidence interval (or exact P-value) was present in 39 (72%) protocol-publication pairs. Twenty-nine trials (54%) were registered in trial registries, but only one registry record included the noninferiority margin. Conclusion The reporting of noninferiority margins was incomplete and inconsistent with study protocols in a substantial proportion of published trials, and margins were rarely reported in trial registries.

INTRODUCTION: Patients undergoing immunosuppressive therapy are at increased risk of infection. Community-acquired pneumonia and invasive pneumococcal disease account for substantial morbidity and mortality in this population and may be prevented by vaccination. Ideally, immunization to pneumococcal antigens should take place before the start of immunosuppressive treatment. Often, however, the treatment cannot be delayed. Little is known about the efficacy of pneumococcal vaccines during immunosuppressive treatment. The objectives of this study were to determine the percentage of vaccine-naïve, immunosuppressed adults with inflammatory diseases seroprotected against Streptococcus pneumoniae and to assess factors associated with the immunogenicity, clinical impact and safety of 23-valent pneumococcal polysaccharide vaccine (PPV) in seronegative subjects. METHODS: This observational study included patients 18 years of age and older who were receiving prednisone ≥20 mg/day or other immunosuppressive drugs. Exclusion criteria were PPV administration in the previous 5 years, intravenous immunoglobulins and pregnancy. Serum immunoglobulin G (IgG) antibody levels against six pneumococcal serotypes were measured. Seropositivity was defined as IgG of 0.5 μg/ml or greater for at least four of six serotypes. Seronegative patients received PPV, and seropositive patients were included as a comparison group. Vaccine response and tolerance were assessed after 4-8 weeks. Disease activity was evaluated on the basis of the Physician Global Assessment scores. Serology was repeated after 1 year, and information on any kind of infection needing medical attention was collected. Outcomes were the proportion of seropositivity and infections between vaccinated and unvaccinated patients. RESULTS: Of 201 included patients, 35 received high-dose corticosteroids and 181 were given immunosuppressive drugs. Baseline seronegativity in 60 (30 %) patients was associated with corticotherapy and lower total IgG. After PPV, disease activity remained unchanged or decreased in 81 % of patients, and 87 % became seropositive. After 1 year, 67 % of vaccinated compared with 90 % of observed patients were seropositive (p < 0.001), whereas the rate of infections did not differ between groups. Those still taking prednisone ≥10 mg/day tended to have poorer serological responses and had significantly more infections. CONCLUSIONS: PPV was safe and moderately effective based on serological response. Seropositivity to pneumococcal antigens significantly reduced the risk of infections. Sustained high-dose corticosteroids were associated with poor vaccine response and more infections.

Managing bleeding in patients receiving P2Y12 inhibitors is challenging. Few data are available regarding the efficacy of platelet transfusion in patients treated with prasugrel or ticagrelor. The aim of this study was to evaluate the minimal amount of platelet supplementation (in terms of ratio of non-inhibited platelets to inhibited platelets) necessary to restore platelet reactivity in platelet-rich plasma (PRP) of patients treated with aspirin and a prasugrel or ticagrelor loading dose for an acute coronary syndrome. PRP samples from patients were mixed ex vivo with increasing proportions of pooled PRP from healthy volunteers. Platelet reactivity was challenged with adenosine diphosphate (ADP), arachidonic acid, collagen or thrombin receptor activating peptide using light transmission aggregometry. The primary endpoint was the proportion of patient samples recovering an ADP-induced maximal aggregation (ADP-Aggmax) value above 40%. In patients treated with prasugrel (n = 32), ADP-Aggmax increased progressively with supplements of pooled PRP, with an average increase of 7.9% (95% CI [7.1; 8.8], p

Fig 1 is incorrect in the published article. Please view the correct Fig 1 and its legend here. Fig 1 The decision tree represents both strategies: “ECG screening” at hospital admission versus “No ECG screening”.

Purpose This study included all patients treated at the University Hospital of Geneva for a first episode of uncomplicated diverticulitis. Risks of recurrence and treatment failure were evaluated by comparing the results between short-course and long-course intravenous (IV) antibiotic therapy groups. Methods The records of all patients hospitalized at our facility from January 2007 to February 2012 for a first episode of uncomplicated diverticulitis (Hinchey Ia), as confirmed by computed tomography, were prospectively collected. We published an auxiliary analysis from this registered study at Clinicaltrials.gov (identifier number: NCT01015378). Two groups of patients were considered: one received a short-course IV antibiotic arm (ceftriaxone and metronidazole) for up to 5 days (followed by 5 days of oral antibiotics); the other received a long-course IV arm between days 5 and 10. The primary outcome was the recurrence-free survival time. Results Follow-up was completed for 256 patients-50% men and 50% women, with a median age of 56 years (range, 24-85 years). The average follow-up was 50 months (range, 19-89 months). Of the 256 patients included in the study, 46 patients received a short-course IV antibiotic treatment and 210 received a long-course treatment. The recurrence-free survivals were very similar between the two groups, which was supported by a log rank test (P = 0.772). Four treatment failures, all in the long-course IV antibiotic treatment group, occurred. Conclusion Treatment of diverticulitis with a short IV antibiotic treatment is possible and does not modify the recurrence rate in patients with uncomplicated diverticulitis.

Introduction The aim of the study was to assess whether adults admitted to hospitals with both Intensive Care Units (ICU) and Intermediate Care Units (IMCU) have lower in-hospital mortality than those admitted to ICUs without an IMCU. Methods An observational multinational cohort study performed on patients admitted to participating ICUs during a four-week period. IMCU was defined as any physically and administratively independent unit open 24 hours a day, seven days a week providing a level of care lower than an ICU but higher than a ward. Characteristics of hospitals, ICUs and patients admitted to study ICUs were recorded. The main outcome was all-cause in-hospital mortality until hospital discharge (censored at 90 days). Results One hundred and sixty-seven ICUs from 17 European countries enrolled 5,834 patients. Overall, 1,113 (19.1%) patients died in the ICU and 1,397 died in hospital, with a total of 1,397 (23.9%) deaths. The illness severity was higher for patients in ICUs with an IMCU (median Simplified Acute Physiology Score (SAPS) II: 37) than for patients in ICUs without an IMCU (median SAPS II: 29, P

The HemosIL AcuStar antiphospholipid assay (Instrumentation Laboratory, Bedford, MA, USA) is a fully automated assay using chemiluminescent technology for the detection of anticardiolipin and anti-beta2 glycoprotein-1 antibodies. This assay showed excellent agreement between results of different laboratories. The cutoff values to define positivity were calculated in 250 healthy blood bank donors but were associated with large confidence intervals (CIs).The objective of this study was to more precisely determine the cutoff values of the HemosIL AcuStar antiphospholipid assay by increasing the number of healthy blood bank donors through a multicenter study and by applying a normalization procedure of the distribution of each antibody.Five laboratories participated to this study, allowing the inclusion of 626 samples. We used a Box-Cox power transformation method to normalize the distribution and calculate the 99th percentile and the corresponding 95%CI for each antibody.The revised cutoff values were overall lower than those initially calculated with more stringent CIs and yielded a 4.2% increase in sensitivity with a 2.7% decrease in specificity regarding thrombotic events or obstetric complications.We provide refined cutoff values for the detection of anticardiolipin and anti-beta2 glycoprotein-1 antibodies with the HemosIL AcuStar Antiphospholipid assay that should be preferred for routine use.

Introduction Point of care devices (POCT) are used for coagulation evaluation in adults. Reduced blood volumes and the direct use of whole blood allow studies when venous puncture is difficult, such as in newborns. Elimination of sample transport is attractive for use in emergencies and intensive care. Objective To prospectively compare neonatal coagulation parameters measured by the GEM®PCL POCT versus a central laboratory. Materials and Methods Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) were performed on whole cord blood (POCT) and plasma (central laboratory) collected from consecutive newborns at Geneva University Hospitals. Agreement was assessed with a Bland & Altman plot and intra-class correlation coefficient (ICC) in 213 newborns cord blood; intra-assay variability (repeatability) was assessed using ICC and coefficient of variation (CV). Results 189 samples were available for the agreement analysis, 24 were excluded for technical problems. The 95% limits of agreements in the Bland & Altman plot ranged from -5.6 to 11.6 and from -39.6 to 11.6 seconds for the PT and aPTT, respectively. The ICC between the two methods was 0.28 (CI 95% 0.06 to 0.47) for PT and 0.20 (CI 95% -0.06 to 0.42) for aPTT. Repeatability (ICC) on the 43 eligible samples was 0.46 (CI 95% 0.19 to 0.67) for PT and 0.52 (CI 95% 0.26 to 0.71) for aPTT. The CV was 10.6% and 12% for PT and aPTT, respectively. Conclusions In newborn cord blood, PT and aPTT measurements with the GEM®PCL POCT had poor agreement with the central laboratory and poor repeatability.

Importance Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. Objective To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. Design, Setting, and Participants A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. Interventions Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. Main Outcomes and Measures The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. Results At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). Conclusions and Relevance In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. Trial Registration clinicaltrials.gov Identifier:NCT00413946

Combined liver-kidney transplantation (CLKT) in children is uncommon and outcomes have not been well defined. Using the Scientific Registry of Transplant Recipients, data were analyzed on 152 primary pediatric CLKTs performed from October 1987 to February 2011, to determine their outcome in the largest series reported to date. Patient survival was 86.8%, 82.1% and 78.9% at 1, 5 and 10 years, liver graft survival was 81.9%, 76.5% and 72.6%, and kidney graft survival was 83.4%, 76.5% and 66.8%. By way of comparison, the Registry was queried for pediatric patient survival following isolated liver transplantation (LT) during the same time frame: 86.7%, 81.2% and 77.4% and following isolated kidney transplant (KT): 98.2%, 95.4% and 90% at 1, 5 and 10 years. In patients having undergone CLKT, primary hyperoxaluria was associated with reduced patient (p = 0.01), liver graft (p = 0.01) and kidney graft survival (p = 0.01). Furthermore, graft outcome following CLKT improved over the past decade (p = 0.04 for liver, p = 0.02 for kidney), but this did not translate into improved patient outcome (p = 0.2). All in all, our results confirmed that survival following LT was less than following KT, and that CLKT offered similar patient survival to isolated LT.

Neuropsychiatric fluctuations in Parkinson's disease (PD) are frequent and disabling. One way to investigate them is to assess the ability to inhibit distractive emotional information by a modified emotional Stroop (ES) task. We compared non-depressed, non-demented PD patients with healthy controls. During an acute levodopa challenge, patients performed a modified ES task during functional MRI and a neuropsychological assessment including Visual Analog Mood (VAMS) and Apathy scales. Ten patients and 12 controls completed the study. The VAMS scores were significantly improved by the acute intake of levodopa (p = 0.02), as was the apathy score (p = 0.03). Negative ES task (i.e. fearful facial expressions with the words “happy” or “fear” written across them), induced a lengthening of the mean reaction time during the incongruent trials compared with the congruent trials in controls (relative difference = 2.7%, p < 0.001) and in ON patients (relative difference = 5.9%, p < 0.001), but not in OFF patients (relative difference = 1.7%, p = 0.28). Controls and ON patients displayed greater activation than OFF patients within the right pregenual anterior cingulate cortex (pACC), an area specifically involved in emotional conflict resolution (p < 0.001 and p < 0.008 respectively, k > 5 uncorrected). No difference in the activation of the pACC was found between controls and ON patients, suggesting a normalization of the activation following levodopa administration. These results suggest that emotional conflict processes could be dopamine-dependent. Pregenual ACC hypoactivation could be directly due to the degeneration of dopaminergic mesocorticolimbic pathway. Our results propose that neuropsychiatric fluctuations in PD patients could be partially explained by pACC hypoactivation and that adjustments of dopaminergic medication might be helpful for their treatment.

BACKGROUND: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic nephrotic syndrome (INS). We have evaluated the reliability of urinary neutrophil-gelatinase-associated lipocalin (uNGAL), urinary alpha1-microglobulin (uα1M) and urinary N-acetyl-beta-D-glucosaminidase (uβNAG) as markers for differentiating MCD from FSGS. We have also evaluated whether these proteins are associated to INS relapses or to glomerular filtration rate (GFR). METHODS: The patient cohort comprised 35 children with MCD and nine with FSGS; 19 healthy age-matched children were included in the study as controls. Of the 35 patients, 28 were in remission (21 MCD, 7 FSGS) and 16 were in relapse (14 MCD, 2 FSGS). The prognostic accuracies of these proteins were assessed by receiver operating characteristic (ROC) curve analyses. RESULTS: The level of uNGAL, indexed or not to urinary creatinine (uCreat), was significantly different between children with INS and healthy children (p = 0.02), between healthy children and those with FSGS (p = 0.007) and between children with MCD and those with FSGS (p = 0.01). It was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cut-off value of 17 ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 0.77 and specificity of 0.78. uβNAG was not significantly different in patients with MCD and those with FSGS (p = 0.86). Only uα1M, indexed or not to uCreat, was significantly (p

Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy.Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS).The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively.Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.

e8 Volume 37 Number 8S ElECTroCardiographiC SCrEENiNg for drug-iNduCEd loNg qT To rEduCE SuddEN CardiaC dEaTh iN pSyChiaTriC paTiENTS: a CoST-EffECTiVENESS aNalySiS Antoine Poncet; Baris Gencer; Marc Blondon; Marianne Gex-Fabry; Christophe Combescure; Dipen Shah; Peter J. Schwartz; Marie Besson; and Francois R. Girardin Department of Health and Community Medicine, University Hospitals and University of Geneva, rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; Department of Internal Medicine, University Hospitals and University of Geneva, rue GabriellePerret-Gentil 4, 1205 Geneva, Switzerland; Department of Psychiatry, University Hospitals and University of Geneva, 2 chemin du Petit-Bel-Air, 1225 Chene-Bourg, Switzerland; Center for Cardiac Arrhythmias of Genetic Origin, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Anesthesiology, Intensive Care, and Clinical Pharmacology, University Hospitals and University of Geneva, rue GabriellePerret-Gentil 4, 1205 Geneva, Switzerland; and Medical Directorate, University Hospitals and University of Geneva, rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland Background: Sudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) triggered by psychotropic medication is common and predisposes to torsades-de-pointes (TdP) and subsequent mortality. We estimated the cost-effectiveness of electrocardiographic screening to detect drug-induced LQT in psychiatric inpatients. Material and Methods: We built a decision analytic model based on a decision tree to evaluate the cost-effectiveness and utility of LQT screening from a health care perspective. LQT proportion parameters were derived from an in-hospital cross-sectional study. We performed experts’ elicitation to estimate the risk of TdP, given the extent of QT prolongation. A TdP reduction of 65% after LQT detection was based on positive drug dechallenge rate and through adequate treatment and electrolyte adjustments. The base-case model uncertainty was assessed with one-way and probabilistic sensitivity analyses. Finally, the TdP-related mortality and TdP avoidance parameters were varied in a 2-way sensitivity analysis to assess their effect on the incremental cost-effectiveness ratio (ICER). Results: In the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95% CI, 3144–82,498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50,000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT. Conclusions: In psychiatric hospitals, performing systematic ECG screening at admission helps reduce the number of sudden cardiac deaths in a cost-effective fashion.

Purpose: Our objectives were to assess the quality of PET images and coregistered anatomic images obtained with PET/MR, to evaluate the detection of focal uptake and SUV, and to compare these findings with those of PET/CT in patients with head and neck tumours. Methods: The study group comprised 32 consecutive patients with malignant head and neck tumours who underwent whole-body 18F-FDG PET/MR and PET/CT. PET images were reconstructed using the attenuation correction sequence for PET/MR and CT for PET/CT. Two experienced observers evaluated the anonymized data. They evaluated image and fusion quality, lesion conspicuity, anatomic location, number and size of categorized (benign versus assumed malignant) lesions with focal uptake. Region of interest (ROI) analysis was performed to determine SUVs of lesions and organs for both modalities. Statistical analysis considered data clustering due to multiple lesions per patient. Results: PET/MR coregistration and image fusion was feasible in all patients. The analysis included 66 malignant lesions (tumours, metastatic lymph nodes and distant metastases), 136 benign lesions and 470 organ ROIs. There was no statistically significant difference between PET/MR and PET/CT regarding rating scores for image quality, fusion quality, lesion conspicuity or anatomic location, number of detected lesions and number of patients with and without malignant lesions. A high correlation was observed for SUVmean and SUVmax measured on PET/MR and PET/CT for malignant lesions, benign lesions and organs (ρ = 0.787 to 0.877, p

Background Currently, there is inadequate evidence on which to base clinical management of neurotoxic snakebite envenoming, especially in the choice of initial antivenom dosage. This randomised controlled trial compared the effectiveness and safety of high versus low initial antivenom dosage in victims of neurotoxic envenoming. Methodology/ Principal findings This was a balanced, randomised, double-blind trial that was conducted in three health care centers located in the Terai plains of Nepal. Participants received either low (two vials) or high (10 vials) initial dosage of Indian polyvalent antivenom. The primary composite outcome consisted of death, the need for assisted ventilation and worsening/recurrence of neurotoxicity. Hourly evaluations followed antivenom treatment. Between April 2011 and October 2012, 157 snakebite victims were enrolled, of which 154 were analysed (76 in the low and 78 in the high initial dose group). Sixty-seven (43·5%) participants met the primary outcome definition. The proportions were similar in the low (37 or 48.7%) vs. high (30 or 38.5%) initial dose group (difference = 10·2%, 95%CI [-6·7 to 27·1], p = 0·264). The mean number of vials used was similar between treatment groups. Overall, patients bitten by kraits did worse than those bitten by cobras. The occurrence of treatment-related adverse events did not differ among treatment groups. A total of 19 serious adverse events occurred, including seven attributed to antivenom. Conclusions This first robust trial investigating antivenom dosage for neurotoxic snakebite envenoming shows that the antivenom currently used in Nepal performs poorly. Although the high initial dose regimen is not more effective than the low initial dose, it offers the practical advantage of being a single dose, while not incurring higher consumption or enhanced risk of adverse reaction. The development of new and more effective antivenoms that better target the species responsible for bites in the region will help improve future patients’ outcomes. Trial registration The study was registered on clinicaltrials.gov (NCT01284855) (GJ 5/1), Author summary Snakebite is an important medical problem in tropical regions, including in Nepal where tens of thousands of people are bitten every year. Snakebite can result in life-threatening envenoming and correct identification of the biting species is crucial for doctors to choose appropriate treatment and anticipate complications. This paper compares two different doses of antivenom for the treatment of neurotoxic snakebite envenoming. Out of 157 snakebite victims presenting to one of the study centers, 78 received a low initial dose and 79 received a high initial dose. The proportion of patients who either died, needed breathing support or additional doses of antivenom were the same in the two groups. Overall, patients bitten by kraits did worse than those bitten by cobras. The occurrence of adverse reactions was comparable among those received low or high initial dose respectively. This study is the first to use a rigorous and robust method for comparing doses of antivenom in snakebite victims in South Asia. Although the high initial dose was not more effective than the low initial dose, it offers the practical advantage of being simpler to administer and was as safe as the low initial dose. The development of new and more effective antivenoms that better target the species responsible for bites in the region will help improve future patients’ outcomes.

Introduction Severity assessment and site-of-care decisions for patients with community-acquired pneumonia (CAP) are pivotal for patients' safety and adequate allocation of resources. Late admission to the intensive care unit (ICU) has been associated with increased mortality in CAP. We aimed to review and meta-analyze systematically the performance of clinical prediction rules to identify CAP patients requiring ICU admission or intensive treatment. Methods We systematically searched Medline, Embase, and the Cochrane Controlled Trials registry for clinical trials evaluating the performance of prognostic rules to predict the need for ICU admission, intensive treatment, or the occurrence of early mortality in patients with CAP. Results Sufficient data were available to perform a meta-analysis on eight scores: PSI, CURB-65, CRB-65, CURB, ATS 2001, ATS/IDSA 2007, SCAP score, and SMART-COP. The estimated AUC of PSI and CURB-65 scores to predict ICU admission was 0.69. Among scores proposed for prediction of ICU admission, ATS-2001 and ATS/IDSA 2007 scores had better operative characteristics, with a sensitivity of 70% (CI, 61 to 77) and 84% (48 to 97) and a specificity of 90% (CI, 82 to 95) and 78% (46 to 93), but their clinical utility is limited by the use of major criteria. ATS/IDSA 2007 minor criteria have good specificity (91% CI, 84 to 95) and moderate sensitivity (57% CI, 46 to 68). SMART-COP and SCAP score have good sensitivity (79% CI, 69 to 97, and 94% CI, 88 to 97) and moderate specificity (64% CI, 30 to 66, and 46% CI, 27 to 66). Major differences in populations, prognostic factor measurement, and outcome definition limit comparison. Our analysis also highlights a high degree of heterogeneity among the studies. Conclusions New severity scores for predicting the need for ICU or intensive treatment in patients with CAP, such as ATS/IDSA 2007 minor criteria, SCAP score, and SMART-COP, have better discriminative performances compared with PSI and CURB-65. High negative predictive value is the most consistent finding among the different prediction rules. These rules should be considered an aid to clinical judgment to guide ICU admission in CAP patients.