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1.  In-vivo T1 cardiovascular magnetic resonance study of diffuse myocardial fibrosis in hypertrophic cardiomyopathy 
Background
In hypertrophic cardiomyopathy (HCM), autopsy studies revealed both increased focal and diffuse deposition of collagen fibers. Late gadolinium enhancement imaging (LGE) detects focal fibrosis, but is unable to depict interstitial fibrosis. We hypothesized that with T1 mapping, which is employed to determine the myocardial extracellular volume fraction (ECV), can detect diffuse interstitial fibrosis in HCM patients.
Methods
T1 mapping with a modified Look-Locker Inversion Recovery (MOLLI) pulse sequence was used to calculate ECV in manifest HCM (n = 16) patients and in healthy controls (n = 14). ECV was determined in areas where focal fibrosis was excluded with LGE.
Results
The total group of HCM patients showed no significant changes in mean ECV values with respect to controls (0.26 ± 0.03 vs 0.26 ± 0.02, p = 0.83). Besides, ECV in LGE positive HCM patients was comparable with LGE negative HCM patients (0.27 ± 0.03 vs 0.25 ± 0.03, p = 0.12).
Conclusions
This study showed that HCM patients have a similar ECV (e.g. interstitial fibrosis) in myocardium without LGE as healthy controls. Therefore, the additional clinical value of T1 mapping in HCM seems limited, but future larger studies are needed to establish the clinical and prognostic potential of this new technique within HCM.
doi:10.1186/1532-429X-16-28
PMCID: PMC4026831  PMID: 24766828
T1 mapping; CMR; Diffuse fibrosis; HCM; Extracellular volume fraction
2.  SIMPLE: implementation of recommendations from international evidence-based guidelines on caesarean sections in the Netherlands. Protocol for a controlled before and after study 
Background
Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently.
Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives).
Methods
An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs.
Discussion
This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child.
Trial registration
http://www.clinicaltrials.gov: NCT01261676
doi:10.1186/1748-5908-8-3
PMCID: PMC3547819  PMID: 23281646
3.  Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909 
T-cells with specificity for antigens derived from Wilms-Tumor-gene(WT1), Proteinase3(Pr3), and mucin1(MUC1) have been demonstrated to lyse acute-myeloid-leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T-cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted-peptides and the PADRE or MUC1-helper-epitopes in combination with CpG7909 and MontanideISA51, 4 patients with AML and 5 with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T-cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+-T-cells was observed. An increase in PADRE-specific CD4+T-helper-cells was observed after vaccination but these appeared unable to produce IL2, and CD4+T-cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T-cell responses, our data allow to hypothesize that a vaccination with leukemia-associated-antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.
doi:10.1007/s00262-010-0929-7
PMCID: PMC3024516  PMID: 20963411
Vaccination; AML; MM; T cell; CpG; WT1
4.  Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909 
Cancer Immunology, Immunotherapy  2010;60(2):161-171.
T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.
Electronic supplementary material
The online version of this article (doi:10.1007/s00262-010-0929-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s00262-010-0929-7
PMCID: PMC3024516  PMID: 20963411
Vaccination; AML; MM; T cell; CpG; WT1
5.  Disproportionate Intrauterine Growth Intervention Trial At Term: DIGITAT 
Background
Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term.
Methods/design
The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm.
Discussion
This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term.
Trial registration
Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.
doi:10.1186/1471-2393-7-12
PMCID: PMC1933438  PMID: 17623077

Results 1-5 (5)