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1.  Prevention of ICU delirium and delirium-related outcome with haloperidol: a study protocol for a multicenter randomized controlled trial 
Trials  2013;14:400.
Background
Delirium is a frequent disorder in intensive care unit (ICU) patients with serious consequences. Therefore, preventive treatment for delirium may be beneficial. Worldwide, haloperidol is the first choice for pharmacological treatment of delirious patients. In daily clinical practice, a lower dose is sometimes used as prophylaxis. Some studies have shown the beneficial effects of prophylactic haloperidol on delirium incidence as well as on mortality, but evidence for effectiveness in ICU patients is limited. The primary objective of our study is to determine the effect of haloperidol prophylaxis on 28-day survival. Secondary objectives include the incidence of delirium and delirium-related outcome and the side effects of haloperidol prophylaxis.
Methods
This will be a multicenter three-armed randomized, double-blind, placebo-controlled, prophylactic intervention study in critically ill patients. We will include consecutive non-neurological ICU patients, aged ≥18 years with an expected ICU length of stay >1 day. To be able to demonstrate a 15% increase in 28-day survival time with a power of 80% and alpha of 0.05 in both intervention groups, a total of 2,145 patients will be randomized; 715 in each group. The anticipated mortality rate in the placebo group is 12%. The intervention groups will receive prophylactic treatment with intravenous haloperidol 1 mg/q8h or 2 mg/q8h, and patients in the control group will receive placebo (sodium chloride 0.9%), both for a maximum period of 28-days. In patients who develop delirium, study medication will be stopped and patients will subsequently receive open label treatment with a higher (therapeutic) dose of haloperidol. We will use descriptive summary statistics as well as Cox proportional hazard regression analyses, adjusted for covariates.
Discussion
This will be the first large-scale multicenter randomized controlled prevention study with haloperidol in ICU patients with a high risk of delirium, adequately powered to demonstrate an effect on 28-day survival.
Trial registration
Clinicaltrials.gov: NCT01785290.
EudraCT number: 2012-004012-66.
doi:10.1186/1745-6215-14-400
PMCID: PMC4222562  PMID: 24261644
Critically ill; Delirium; Haloperidol; Intensive care; Mortality; Prevention; Prophylaxis; Randomized trial
2.  MITEs in the promoters of effector genes allow prediction of novel virulence genes in Fusarium oxysporum 
BMC Genomics  2013;14:119.
Background
The plant-pathogenic fungus Fusarium oxysporum f.sp.lycopersici (Fol) has accessory, lineage-specific (LS) chromosomes that can be transferred horizontally between strains. A single LS chromosome in the Fol4287 reference strain harbors all known Fol effector genes. Transfer of this pathogenicity chromosome confers virulence to a previously non-pathogenic recipient strain. We hypothesize that expression and evolution of effector genes is influenced by their genomic context.
Results
To gain a better understanding of the genomic context of the effector genes, we manually curated the annotated genes on the pathogenicity chromosome and identified and classified transposable elements. Both retro- and DNA transposons are present with no particular overrepresented class. Retrotransposons appear evenly distributed over the chromosome, while DNA transposons tend to concentrate in large chromosomal subregions. In general, genes on the pathogenicity chromosome are dispersed within the repeat landscape. Effector genes are present within subregions enriched for DNA transposons. A miniature Impala (mimp) is always present in their promoters. Although promoter deletion studies of two effector gene loci did not reveal a direct function of the mimp for gene expression, we were able to use proximity to a mimp as a criterion to identify new effector gene candidates. Through xylem sap proteomics we confirmed that several of these candidates encode proteins secreted during plant infection.
Conclusions
Effector genes in Fol reside in characteristic subregions on a pathogenicity chromosome. Their genomic context allowed us to develop a method for the successful identification of novel effector genes. Since our approach is not based on effector gene similarity, but on unique genomic features, it can easily be extended to identify effector genes in Fo strains with different host specificities.
doi:10.1186/1471-2164-14-119
PMCID: PMC3599309  PMID: 23432788
3.  A survey of the current practice of the informed consent process in general surgery in the Netherlands 
Background
A properly conducted surgical informed consent process (SIC) allows patients to authorize an invasive procedure with full comprehension of relevant information including involved risks. Current practice of SIC may differ from the ideal situation. The aim of this study is to evaluate whether SIC practiced by Dutch general surgeons and residents is adequate with involvement of all required elements.
Methods
All members of the Dutch Society of Surgery received an online multiple choice questionnaire evaluating various aspects of SIC.
Results
A total of 453 questionnaires obtained from surgeons and residents representing >95% of all Dutch hospitals were eligible for analysis (response rate 30%). Knowledge on SIC was limited as only 55% was familiar with all three basic elements (‘assessment of preconditions’, ‘provision of information’ and ‘stage of consent’). Residents performance was inferior compared to surgeons regarding most aspects of daily practice of SIC. One in 6 surgeons (17%) had faced a SIC-related complaint in the previous five years possibly illustrating suboptimal SIC implementation in daily surgical practice.
Conclusions
The quality of the current SIC process is far from optimal in the Netherlands. Surgical residents require training aimed at improving awareness and skills. The SIC process is ideally supported using modern tools including web-based interactive programs. Improvement of the SIC process may enhance patient satisfaction and may possibly reduce the number of complaints.
doi:10.1186/1754-9493-7-4
PMCID: PMC3804026  PMID: 23336609
Informed consent; Surgery; Patient education; Questionnaire; Interactive tools; Training
4.  The measurement of urinary Δ1-piperideine-6-carboxylate, the alter ego of α-aminoadipic semialdehyde, in Antiquitin deficiency 
The assessment of urinary α-aminoadipic semialdehyde (α-AASA) has become the diagnostic laboratory test for pyridoxine dependent seizures (PDS). α-AASA is in spontaneous equilibrium with its cyclic form Δ1-piperideine-6-carboxylate (P6C); a molecule with a heterocyclic ring structure. Ongoing diagnostic screening and monitoring revealed that in some individuals with milder ALDH7A1 variants, and patients co-treated with a lysine restricted diet, α-AASA was only modestly increased. This prompted us to investigate the diagnostic power and added value of the assessment of urinary P6C compared to α-AASA. Urine samples were diluted to a creatinine content of 0.1 mmol/L, followed by the addition of 0.01 nmol [2H9]pipecolic acid as internal standard (IS) and 5 μL was injected onto a Waters C18 T3 HPLC column. Chromatography was performed using water/methanol 97/3 (v/v) including 0.03 % formic acid by volume with a flow rate of 150 μL/min and detection was accomplished in the multiple reaction monitoring mode: P6C m/z 128.1 > 82.1; [2H9]pipecolic acid m/z 139.1 > 93.1. Due to the dualistic nature of α-AASA/P6C, and the lack of a proper internal standard, the method is semi quantitative. The intra-assay CVs (n = 10) for two urine samples of proven PDS patients with only modest P6C increases were 4.7% and 8.1%, whereas their inter-assay CVs (n = 10) were 16 and 18% respectively. In all 40 urine samples from 35 individuals with proven PDS, we detected increased levels of P6C. Therefore, we conclude that the diagnostic power of the assessments of urinary P6C and α-AASA is comparable.
doi:10.1007/s10545-011-9443-0
PMCID: PMC3432202  PMID: 22249334
5.  A 50% higher prevalence of life-shortening chronic conditions among cancer patients with low socioeconomic status 
British Journal of Cancer  2010;103(11):1742-1748.
Background:
Comorbidity and socioeconomic status (SES) may be related among cancer patients.
Method:
Population-based cancer registry study among 72 153 patients diagnosed during 1997–2006.
Results:
Low SES patients had 50% higher risk of serious comorbidity than those with high SES. Prevalence was increased for each cancer site. Low SES cancer patients had significantly higher risk of also having cardiovascular disease, chronic obstructive pulmonary diseases, diabetes mellitus, cerebrovascular disease, tuberculosis, dementia, and gastrointestinal disease. One-year survival was significantly worse in lowest vs highest SES, partly explained by comorbidity.
Conclusion:
This illustrates the enormous heterogeneity of cancer patients and stresses the need for optimal treatment of cancer patients with a variety of concomitant chronic conditions.
doi:10.1038/sj.bjc.6605949
PMCID: PMC2994221  PMID: 20978508
socioeconomic status; comorbidity; chronic disease; survival
6.  Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium 
Nature  2010;464(7287):367-373.
Fusarium species are among the most important phytopathogenic and toxigenic fungi. To understand the molecular underpinnings of pathogenicity in the genus Fusarium, we compared the genomes of three phenotypically diverse species: Fusarium graminearum, Fusarium verticillioides and Fusarium oxysporum f. sp. lycopersici. Our analysis revealed lineage-specific (LS) genomic regions in F. oxysporum that include four entire chromosomes and account for more than one-quarter of the genome. LS regions are rich in transposons and genes with distinct evolutionary profiles but related to pathogenicity, indicative of horizontal acquisition. Experimentally, we demonstrate the transfer of two LS chromosomes between strains of F. oxysporum, converting a non-pathogenic strain into a pathogen. Transfer of LS chromosomes between otherwise genetically isolated strains explains the polyphyletic origin of host specificity and the emergence of new pathogenic lineages in F. oxysporum. These findings put the evolution of fungal pathogenicity into a new perspective.
doi:10.1038/nature08850
PMCID: PMC3048781  PMID: 20237561
7.  Reducing errors in health care: cost-effectiveness of multidisciplinary team training in obstetric emergencies (TOSTI study); a randomised controlled trial 
Background
There are many avoidable deaths in hospitals because the care team is not well attuned. Training in emergency situations is generally followed on an individual basis. In practice, however, hospital patients are treated by a team composed of various disciplines. To prevent communication errors, it is important to focus the training on the team as a whole, rather than on the individual. Team training appears to be important in contributing toward preventing these errors. Obstetrics lends itself to multidisciplinary team training. It is a field in which nurses, midwives, obstetricians and paediatricians work together and where decisions must be made and actions must be carried out under extreme time pressure.
It is attractive to belief that multidisciplinary team training will reduce the number of errors in obstetrics. The other side of the medal is that many hospitals are buying expensive patient simulators without proper evaluation of the training method. In the Netherlands many hospitals have 1,000 or less annual deliveries. In our small country it might therefore be more cost-effective to train obstetric teams in medical simulation centres with well trained personnel, high fidelity patient simulators, and well defined training programmes.
Methods/design
The aim of the present study is to evaluate the cost-effectiveness of multidisciplinary team training in a medical simulation centre in the Netherlands to reduce the number of medical errors in obstetric emergency situations. We plan a multicentre randomised study with the centre as unit of analysis. Obstetric departments will be randomly assigned to receive multidisciplinary team training in a medical simulation centre or to a control arm without any team training.
The composite measure of poor perinatal and maternal outcome in the non training group was thought to be 15%, on the basis of data obtained from the National Dutch Perinatal Registry and the guidelines of the Dutch Society of Obstetrics and Gynaecology (NVOG). We anticipated that multidisciplinary team training would reduce this risk to 5%. A sample size of 24 centres with a cluster size of each at least 200 deliveries, each 12 centres per group, was needed for 80% power and a 5% type 1 error probability (two-sided). We assumed an Intraclass Correlation Coefficient (ICC) value of maximum 0.08.
The analysis will be performed according to the intention-to-treat principle and stratified for teaching or non-teaching hospitals.
Primary outcome is the number of obstetric complications throughout the first year period after the intervention. If multidisciplinary team training appears to be effective a cost-effective analysis will be performed.
Discussion
If multidisciplinary team training appears to be cost-effective, this training should be implemented in extra training for gynaecologists.
Trial Registration
The protocol is registered in the clinical trial register number NTR1859
doi:10.1186/1471-2393-10-59
PMCID: PMC2964561  PMID: 20932293
8.  Surgeons Underestimate Their Patients’ Desire for Preoperative Information 
World Journal of Surgery  2008;32(6):964-970.
Background
Provision of adequate patient information may contribute to a “satisfying” surgical treatment. The patient’s views on successful transfer of information concerning operative characteristics may not be in concert with the surgeon’s. The aim of the present study was to determine opinions of both surgeons and patients about issues of surgical information.
Methods
A group of surgeons (n = 24) and surgical patients (n = 125) responded to a questionnaire that included 80 topics involving domains of information on disease, physical examination, preoperative period, anesthesia, operation, postoperative period, self care, and general hospital issues. Both groups were asked for their opinion on what they considered important and useful preoperative information for patients. Questions were scored with a visual analog scale. The reliability of the questionnaire was calculated with Cronbach’s alpha. Differences in opinions between surgeons and patients were analyzed with Student’s t-test.
Results
The Cronbach’s alpha of the questionnaire was high (0.91), indicating its high reliability. Patients scored significantly higher (p < 0.001) in most domains, including preoperative period, anaesthesia, operation, postoperative period, self care, and general hospital information. Women demonstrated a significantly higher need for information than men did. These findings were independent of patient age or complexity of operation. In contrast, surgeons thought that their patients desired more extensive information on cause, effect, and prognosis of the disease itself (p < 0.001).
Conclusion
Surgeons generally underestimate their patients’ desire for receiving extensive information prior to a surgical procedure of any complexity. Surgeons should develop strategies to bridge this informational mismatch.
doi:10.1007/s00268-008-9581-1
PMCID: PMC2386849  PMID: 18408963
9.  Suppression of Plant Resistance Gene-Based Immunity by a Fungal Effector 
PLoS Pathogens  2008;4(5):e1000061.
The innate immune system of plants consists of two layers. The first layer, called basal resistance, governs recognition of conserved microbial molecules and fends off most attempted invasions. The second layer is based on Resistance (R) genes that mediate recognition of effectors, proteins secreted by pathogens to suppress or evade basal resistance. Here, we show that a plant-pathogenic fungus secretes an effector that can both trigger and suppress R gene-based immunity. This effector, Avr1, is secreted by the xylem-invading fungus Fusarium oxysporum f.sp. lycopersici (Fol) and triggers disease resistance when the host plant, tomato, carries a matching R gene (I or I-1). At the same time, Avr1 suppresses the protective effect of two other R genes, I-2 and I-3. Based on these observations, we tentatively reconstruct the evolutionary arms race that has taken place between tomato R genes and effectors of Fol. This molecular analysis has revealed a hitherto unpredicted strategy for durable disease control based on resistance gene combinations.
Author Summary
In agriculture, the most environmentally friendly way to combat plant diseases is to make use of the innate immune system of plants, for instance by crossing into crop varieties polymorphic resistance genes that occur in natural populations of the crop plant or its close relatives. Plant pathogens, however, have co-evolved with their host plants and have developed ways to overcome the immune system. To effectively make use of components of the plant immune system, it is therefore important to understand the co-evolution of plants and their pathogens at the molecular level. For the interaction between a fungal pathogen and tomato, this paper presents a breakthrough in this respect. A small protein secreted by some strains of the fungus Fusarium oxysporum was found to suppress the activity of two disease resistance genes of tomato. However, a third resistance gene specifically targets this suppressor protein and renders the plant fully resistant against fungal strains that produce it. With this insight, together with knowledge of the genetic variation in the pathogen population, a combination of resistance genes is suggested that is expected to confer durable resistance in tomato against Fusarium wilt disease.
doi:10.1371/journal.ppat.1000061
PMCID: PMC2330162  PMID: 18464895
11.  Comorbidity has negligible impact on treatment and complications but influences survival in breast cancer patients 
British Journal of Cancer  2004;90(12):2332-2337.
doi:10.1038/sj.bjc.6601844
PMCID: PMC2409529  PMID: 15162155
comorbidity; complications; treatment; prognosis; elderly and breast cancer
12.  Obesity and other health determinants across Europe: The EURALIM Project 
STUDY OBJECTIVE—EURALIM (EURope ALIMentation), a European collaborative study, aimed to determine and describe the extent to which European data on risk factor distributions from different populations could be pooled and harmonised in a common database for international comparisons.
SETTING—Seven independent population-based surveys from six European countries (France, Italy, Northern Ireland/United Kingdom, Spain, Switzerland, the Netherlands). 
METHODS—Data for 18 381 women and 12 908 men aged 40-59 were pooled in a common database. Central statistical analyses on major cardiovascular risk factors were conducted with careful consideration of methodological issues, including differences in study designs, data assessment tools, and analytic techniques used.
MAIN RESULTS—Because of the detected variability among methods used, direct comparisons of risk factor distributions and prevalences between studies were problematic. None the less, comparisons of within population contrasts by sex, age group, and other health determinants were considered to be meaningful and apt, as illustrated here for obesity. Results were targeted and disseminated to both the general public and public health professionals and framed in the context of a European information campaign.
CONCLUSIONS—International and national comparisons between existing locally run studies are feasible and useful, but harmonisation methods need improvement. Development of an international risk factor surveillance programme based on decentralised data collection is warranted. In the meantime, risk factor contrasts across populations can be used as a basis for targeting needed public health intervention programmes.


Keywords: comparative study; obesity; risk factor surveillance
doi:10.1136/jech.54.6.424
PMCID: PMC1731700  PMID: 10818117

Results 1-12 (12)