Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial.

BACKGROUND: Double-layer compared to single-layer closure of the uterus after a caesarean section (CS) leads to a thicker myometrial layer at the site of the CS scar, also called residual myometrium thickness (RMT). It possibly decreases the development of a niche, which is an interruption of the myometrium at the site of the uterine scar. Thin RMT and a niche are associated with gynaecological symptoms, obstetric complications in a subsequent pregnancy and delivery and possibly with subfertility. METHODS: Women undergoing a first CS regardless of the gestational age will be asked to participate in this multicentre, double blinded randomised controlled trial (RCT). They will be randomised to single-layer closure or double-layer closure of the uterine incision. Single-layer closure (control group) is performed with a continuous running, unlocked suture, with or without endometrial saving technique. Double-layer closure (intervention group) is performed with the first layer in a continuous unlocked suture including the endometrial layer and the second layer is also continuous unlocked and imbricates the first. The primary outcome is the reported number of days with postmenstrual spotting during one menstrual cycle nine months after CS. Secondary outcomes include surgical data, ultrasound evaluation at three months, menstrual pattern, dysmenorrhea, quality of life, and sexual function at nine months. Structured transvaginal ultrasound (TVUS) evaluation is performed to assess the uterine scar and if necessary saline infusion sonohysterography (SIS) or gel instillation sonohysterography (GIS) will be added to the examination. Women and ultrasound examiners will be blinded for allocation. Reproductive outcomes at three years follow-up including fertility, mode of delivery and complications in subsequent deliveries will be studied as well. Analyses will be performed by intention to treat. 2290 women have to be randomised to show a reduction of 15% in the mean number of spotting days. Additionally, a cost-effectiveness analysis will be performed from a societal perspective. DISCUSSION: This RCT will provide insight in the outcomes of single- compared to double-layer closure technique after CS, including postmenstrual spotting and subfertility in relation to niche development measured by ultrasound. TRIAL REGISTRATION: Dutch Trial Register ( NTR5480 ). Registered 29 October 2015.

Comparing induction of labour with oral misoprostol or Foley catheter at term: cost-effectiveness analysis of a randomised controlled multi-centre non-inferiority trial.

OBJECTIVE: To assess the costs of labour induction with oral misoprostol versus Foley catheter. DESIGN: Economic evaluation alongside a randomised controlled trial. SETTING: Obstetric departments of six tertiary and 23 secondary care hospitals in the Netherlands. POPULATION: Women with a viable term singleton pregnancy in cephalic presentation, intact membranes, an unfavourable cervix (Bishop score <6) without a previous caesarean section, were randomised for labour induction with oral misoprostol (n = 924) or Foley catheter (n = 921). METHODS: We performed economic analysis from a hospital perspective. We estimated direct medical costs associated with healthcare utilisation from randomisation until discharge. The robustness of our findings was evaluated in sensitivity analyses. MAIN OUTCOME MEASURES: Mean costs and differences were calculated per women induced with oral misoprostol or Foley catheter. RESULTS: Mean costs per woman in the oral misoprostol group and Foley catheter group were €4470 versus €4158, respectively [mean difference €312, 95% confidence interval (CI) -€508 to €1063]. Multiple sensitivity analyses did not change these conclusions. However, if cervical ripening for low-risk pregnancies in the Foley catheter group was carried out in an outpatient setting, with admittance to labour ward only at start of active labour, the difference would be €4470 versus €3489, respectively (mean difference €981, 95% CI €225-1817). CONCLUSIONS: Oral misoprostol and Foley catheter generate comparable costs. Cervical ripening outside labour ward with a Foley catheter could potentially save almost €1000 per woman. TWEETABLE ABSTRACT: Oral misoprostol or Foley catheter for induction of labour generates comparable costs.

NGS panel analysis in 24 ectopia lentis patients; a clinically relevant test with a high diagnostic yield.

BACKGROUND: Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. OBJECTIVE: The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. METHODS: A NGS gene panel was analysed in 24 patients with EL. RESULTS: A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. CONCLUSION: The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

Evaluation of extracorporeal shock wave therapy for refractory angina pectoris with quantitative analysis using cardiac magnetic resonance imaging: a short communication.

AIMS: There is a continuing search for new treatment options in patients who suffer from refractory angina pectoris to improve quality of life. Several studies have recently demonstrated promising results by stimulating angiogenesis using extracorporeal shockwave therapy in these patients. The purpose of this study is to quantitatively analyse the effect of extracorporeal shockwave therapy on myocardial perfusion in patients with refractory angina pectoris. METHODS: We included 15 patients with NYHA class 3-4 of whom 8 patients underwent baseline and follow-up cardiac magnetic resonance imaging (CMR). All patients received 9 shockwave treatments of their ischaemic zone over a period of 3 months. RESULTS: Quantitative analysis of myocardial perfusion using CMR revealed no significant improvement of myocardial perfusion after treatment (0.80 ± 0.22 vs 0.76 ± 0.31; p = 0.42). However, the total group of 15 patients did experience a significant improvement in NYHA class (p = 0.034) and reduction of nitroglycerin use (p = 0.012). CONCLUSION: Although treatment with extracorporeal shockwave was associated with an improvement in NYHA class, we could not observe an improvement in myocardial ischaemic zone and perfusion with CMR. To unravel the exact mechanisms of shockwave treatment, more in vitro and animal studies as well as larger (placebo-controlled) studies are required.

Tumor necrosis factor blocking therapy and congestive heart failure in patients with inflammatory rheumatic disorders: a systematic review.

INTRODUCTION: Tumour necrosis factor (TNF) blocking therapy is an effective treatment for chronic inflammatory arthritis. As circulating TNF might induce or exacerbate the development of congestive heart failure (CHF), several trials have investigated the effect of TNF blocking therapy on CHF. However, due to inefficacy and even a risk of exacerbation of CHF, TNF blocking therapy has since then been contraindicated in patients with advanced CHF, New York Heart Association class III and IV. We review current knowledge on the pathophysiological mechanisms and safety of TNF blocking therapy in chronic inflammatory arthritis patients with regard to CHF. METHODS: A systematic search of the literature published up till December 2013 was conducted in MEDLINE, EMBASE and the Cochrane Library to identify all studies investigating the effect of TNF blocking therapy on the occurrence and risk of CHF in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). All articles reporting data on the prevalence or incidence of CHF during treatment with TNF blocking therapy in patients with in RA, AS or PsA were included. Also imaging studies and studies with biomarkers, investigating the effect of TNF blocking therapy on cardiac function were included. RESULTS: In total, 54 studies were included. Results from large prospective registries suggest that first, a potentially harmful effect of TNF blocking therapy on the incidence of CHF in older RA patients cannot be excluded and that no harmful effect was observed of TNF blocking therapy in other patients. Second, we found that TNF blocking therapy potentially improves several echocardiographic parameters of cardiac function in RA, AS and PsA, but due to small sample sizes, these results require validation in larger studies. Third, we found improvement in NT-proBNP levels after use of TNF blocking therapy in both RA and AS. CONCLUSION: Based on current literature, in patients with chronic inflammatory arthritis and concomitant symptomatic mild-tomoderate CHF (NYHA class I or II), treatment with TNF blocking therapy is not contraindicated. In chronic inflammatory arthritis patients with concomitant symptomatic moderate-to-severe CHF, NYHA class III-IV, treatment with TNF blocking therapy should be avoided if possible. Whenever, treatment with TNF-blocking therapy is considered in these patients consultation with a cardiologist is recommended before treatment is initiated.

Four-month metacarpal bone mineral density loss predicts radiological joint damage progression after 1†year in patients with early rheumatoid arthritis: exploratory analyses from the IMPROVED study.

AIM: To assess whether in early (rheumatoid) arthritis (RA) patients, metacarpal bone mineral density (BMD) loss after 4 months predicts radiological progression after 1 year of antirheumatic treatment. METHODS: Metacarpal BMD was measured 4 monthly during the first year by digital X-ray radiogrammetry (DXR-BMD) in patients participating in the IMPROVED study, a clinical trial in 610 patients with recent onset RA (2010 criteria) or undifferentiated arthritis, treated according to a remission (disease activity score<1.6) steered strategy. With Sharp/van der Heijde progression ≥0.5 points after 1 year (yes/no) as dependent variable, univariate and multivariate logistic regression analyses were performed. RESULTS: Of 428 patients with DXR-BMD results and progression scores available, 28 (7%) had radiological progression after 1 year. Independent predictors for radiological progression were presence of baseline erosions (OR (95% CI) 6.5 (1.7 to 25)) and early DXR-BMD loss (OR (95% CI) 1.5 (1.1 to 2.0)). In 366 (86%) patients without baseline erosions, early DXR-BMD loss was the only independent predictor of progression (OR (95% CI) 2.0 (1.4 to 2.9)). CONCLUSIONS: In early RA patients, metacarpal BMD loss after 4 months of treatment is an independent predictor of radiological progression after 1 year. In patients without baseline erosions, early metacarpal BMD loss is the main predictor of radiological progression.

Assessment of left ventricular ejection fraction in patients eligible for ICD therapy: Discrepancy between cardiac magnetic resonance imaging and 2D echocardiography.

OBJECTIVE: Implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) have substantially improved the survival of patients with cardiomyopathy. Eligibility for this therapy requires a left ventricular ejection fraction (LVEF) <35 %. This is largely based on studies using echocardiography. Cardiac magnetic resonance imaging (CMR) is increasingly utilised for LVEF assessment, but several studies have shown differences between LVEF assessed by CMR and echocardiography. The present study compared LVEF assessment by CMR and echocardiography in a heart failure population and evaluated effects on eligibility for device therapy. METHODS: 152 patients (106 male, mean age 65.5 ± 9.9 years) referred for device therapy were included. During evaluation of eligibility they underwent both CMR and echocardiographic LVEF assessment. CMR volumes were computed from a stack of short-axis images. Echocardiographic volumes were computed using Simpson's biplane method. RESULTS: The study population demonstrated an underestimation of end-diastolic volume (EDV) and end-systolic volume (ESV) by echocardiography of 71 ± 53 ml (mean ± SD) and 70 ± 49 ml, respectively. This resulted in an overestimation of LVEF of 6.6 ± 8.3 % by echocardiography compared with CMR (echocardiographic LVEF 31.5 ± 8.7 % and CMR LVEF 24.9 ± 9.6 %). 28 % of patients had opposing outcomes of eligibility for cardiac device therapy depending on the imaging modality used. CONCLUSION: We found EDV and ESV to be underestimated by echocardiography, and LVEF assessed by CMR to be significantly smaller than by echocardiography. Applying an LVEF cut-off value of 35 %, CMR would significantly increase the number of patients eligible for device implantation. Therefore, LVEF cut-off values might need reassessment when using CMR.

Metacognitive group training for schizophrenia spectrum patients with delusions: a randomized controlled trial.

BACKGROUND: Metacognitive training (MCT) for patients with psychosis is a psychological group intervention that aims to educate patients about common cognitive biases underlying delusion formation and maintenance, and to highlight their negative consequences in daily functioning. METHOD: In this randomized controlled trial, 154 schizophrenia spectrum patients with delusions were randomly assigned to either MCT + treatment as usual (TAU) or TAU alone. Both groups were assessed at baseline, and again after 8 and 24 weeks. The trial was completed fully by 111 patients. Efficacy was measured with the Psychotic Symptom Rating Scales (PSYRATS) Delusions Rating Scale (DRS), and with specific secondary measures referring to persecutory ideas and ideas of social reference (the Green Paranoid Thoughts Scale, GPTS), cognitive insight (the Beck Cognitive Insight Scale, BCIS), subjective experiences of cognitive biases (the Davos Assessment of Cognitive Biases Scale, DACOBS) and metacognitive beliefs (the 30-item Metacognitions Questionnaire, MCQ-30). Economic analysis focused on the balance between societal costs and health outcomes (quality-adjusted life years, QALYs). RESULTS: Both conditions showed a decrease of delusions. MCT was not more efficacious in terms of reducing delusions, nor did it change subjective paranoid thinking and ideas of social reference, cognitive insight or subjective experience of cognitive biases and metacognitive beliefs. The results of the economic analysis were not in favour of MCT + TAU. CONCLUSIONS: In the present study, MCT did not affect delusion scores and self-reported cognitive insight, or subjective experience of cognitive biases and metacognitive beliefs. MCT was not cost-effective.

Predicting successful intended vaginal delivery after previous caesarean section: external validation of two predictive models in a Dutch nationwide registration-based cohort with a high intended vaginal delivery rate.

OBJECTIVE: To externally validate two models from the USA (entry-to-care [ETC] and close-to-delivery [CTD]) that predict successful intended vaginal birth after caesarean (VBAC) for the Dutch population. DESIGN: A nationwide registration-based cohort study. SETTING: Seventeen hospitals in the Netherlands. POPULATION: Seven hundred and sixty-three pregnant women, each with one previous caesarean section and a viable singleton cephalic pregnancy without a contraindication for an intended VBAC. METHODS: The ETC model comprises the variables maternal age, prepregnancy body mass index (BMI), ethnicity, previous vaginal delivery, previous VBAC and previous nonprogressive labour. The CTD model replaces prepregnancy BMI with third-trimester BMI and adds estimated gestational age at delivery, hypertensive disease of pregnancy, cervical examination and induction of labour. We included consecutive medical records of eligible women who delivered in 2010. For validation, individual probabilities of women who had an intended VBAC were calculated. MAIN OUTCOME MEASURES: Discriminative performance was assessed with the area under the curve (AUC) of the receiver operating characteristic and predictive performance was assessed with calibration plots and the Hosmer-Lemeshow (H-L) statistic. RESULTS: Five hundred and fifteen (67%) of the 763 women had an intended VBAC; 72% of these (371) had an actual VBAC. The AUCs of the ETC and CTD models were 68% (95% CI 63-72%) and 72% (95% CI 67-76%), respectively. The H-L statistic showed a P-value of 0.167 for the ETC model and P = 0.356 for the CTD model, indicating no lack of fit. CONCLUSION: External validation of two predictive models developed in the USA revealed an adequate performance within the Dutch population.

A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: the IMPROVED study.

OBJECTIVES: To assess which treatment strategy is most effective in inducing remission in early (rheumatoid) arthritis. METHODS: 610 patients with early rheumatoid arthritis (RA 2010 criteria) or undifferentiated arthritis (UA) started treatment with methotrexate (MTX) and a tapered high dose of prednisone. Patients in early remission (Disease Activity Score <1.6 after 4 months) tapered prednisone to zero and those with persistent remission after 8 months, tapered and stopped MTX. Patients not in early remission were randomised to receive either MTX plus hydroxychloroquine plus sulfasalazine plus low-dose prednisone (arm 1) or to MTX plus adalimumab (ADA) (arm 2). If remission was present after 8 months both arms tapered to MTX monotherapy; if not, arm 1 changed to MTX plus ADA and arm 2 increased the dose of ADA. Remission rates and functional and radiological outcomes were compared between arms and between patients with RA and those with UA. RESULTS: 375/610 (61%) patients achieved early remission. After 1 year 68% of those were in remission and 32% in drug-free remission. Of the randomised patients, 25% in arm 1 and 41% in arm 2 achieved remission at year 1 (p<0.01). Outcomes were comparable between patients with RA and those with UA. CONCLUSIONS: Initial MTX and prednisone resulted in early remission in 61% of patients with early (rheumatoid) arthritis. Of those, 68% were in remission and 32% were in drug-free remission after 1 year. In patients not in early remission, earlier introduction of ADA resulted in more remission at year 1 than first treating with disease-modifying antirheumatic drug combination therapy plus prednisone.

Vaginal birth after a caesarean section: the development of a Western European population-based prediction model for deliveries at term.

OBJECTIVE: To develop and internally validate a model that predicts the outcome of an intended vaginal birth after caesarean (VBAC) for a Western European population that can be used to personalise counselling for deliveries at term. DESIGN: Registration-based retrospective cohort study. SETTING: Five university teaching hospitals, seven non-university teaching hospitals, and five non-university non-teaching hospitals in the Netherlands. POPULATION: A cohort of 515 women with a history of one caesarean section and a viable singleton pregnancy, without a contraindication for intended VBAC, who delivered at term. METHODS: Potential predictors for a vaginal delivery after caesarean section were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN OUTCOME MEASURES: Predictors for VBAC. For model validation, the area under the receiver operating characteristic curve (AUC) for discriminative capacity and calibration-per-risk-quantile for accuracy were calculated. RESULTS: A total of 371 out of 515 women had a VBAC (72%). Variables included in the model were: estimated fetal weight greater than the 90(th) percentile in the third trimester; previous non-progressive labour; previous vaginal delivery; induction of labour; pre-pregnancy body mass index; and ethnicity. The AUC was 71% (95% confidence interval, 95% CI = 69-73%), indicating a good discriminative ability. The calibration plot shows that the predicted probabilities are well calibrated, especially from 65% up, which accounts for 77% of the total study population. CONCLUSION: We developed an appropriate Western European population-based prediction model that is aimed to personalise counselling for term deliveries.

Involving women in personalised decision-making on mode of delivery after caesarean section: the development and pilot testing of a patient decision aid.

OBJECTIVE: To develop a patient decision aid (PtDA) for mode of delivery after caesarean section that integrates personalised prediction of vaginal birth after caesarean (VBAC) with the elicitation of patient preferences and evidence-based information. DESIGN: A PtDA was developed and pilot tested using the International Patients Decision Aid Standards (IPDAS) criteria. SETTING: Obstetric health care in the Netherlands. POPULATION: A multidisciplinary steering group, an expert panel, and 25 future users of the PtDA, i.e. women with a previous caesarean section. METHODS: The development consisted of a construction phase (definition of scope and purpose, and selection of content, framework, and format) and a pilot testing phase by interview. The process was supervised by a multidisciplinary steering group. MAIN OUTCOME MEASURES: Usability, clarity, and relevance. RESULTS: The construction phase resulted in a booklet including unbiased balanced information on mode of birth after caesarean section, a preference elicitation exercise, and tailored risk information, including a prediction model for successful VBAC. During pilot testing, visualisation of risks and clarity formed the main basis for revisions. Pilot testing showed the availability of tailored structured information to be the main factor involving women in decision-making. The PtDA meets 39 out of 50 IPDAS criteria (78%): 23 out of 23 criteria for content (100%) and 16 out of 20 criteria for the development process (80%). Criteria for effectiveness (n = 7) were not evaluated. CONCLUSIONS: An evidence-based PtDA was developed, with the probability of successful VBAC and the availability of structured information as key items. It is likely that the PtDA enhances the quality of decision-making on mode of birth after caesarean section.

The relationship between disease activity and depressive symptoms severity and optimism--results from the IMPROVED study.

To assess depressive symptoms severity and dispositional optimism in patients with recent onset arthritis both before and after 4 months treatment. Two hundred twenty-two patients with recent onset RA and undifferentiated arthritis in the IMPROVED study filled out the Beck Depression Inventory (BDI-II) to assess depressive symptoms severity and the Life Orientation Test Revised (LOT-R) to measure optimism before and after 4 months of treatment. All patients were treated with methotrexate 25 mg/week and prednisone 60 mg/day (tapered to 7.5 mg/day in 7 weeks). Linear regression analysis was used to assess the association between the disease activity score (DAS) and its components (tender joint count, general well-being measured with a visual analogue scale (VAS), swollen joint count, and erythrocyte sedimentation rate) with the BDI-II an LOT-R scores. In general, depressive symptoms were mild. The DAS was an independent predictor of depressive symptoms scores both at baseline and after 4 months follow-up, in particular tender joint count and VAS global health. Disease activity was not associated with the level of optimism. Nevertheless, patients who achieved clinical remission improved significantly more in both depression score and optimism score than patients who did not. Patients with early arthritis report improvement in depressive symptoms and optimism with improvement in disease activity and achieving clinical remission. Depression scores are associated with pain and unwell being but not with swollen joint counts and inflammatory parameters.

Drug therapy in undifferentiated arthritis: a systematic literature review.

Undifferentiated arthritis (UA) is defined as an inflammatory oligoarthritis or polyarthritis in which no definitive diagnosis can be made. We performed a literature review to assess the efficacy of various drug therapies in patients with UA. The literature search was conducted using electronic databases Pubmed, EMBASE and MEDLINE in adults with UA or early arthritis (not fulfilling the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis). Drug therapy consisted of disease modifying antirheumatic drugs (DMARDs), biological agents and oral, intramuscular or intra-articular corticosteroids. Nine publications on eight randomised controlled trials (RCTs), two publications on two uncontrolled open-label trials and seven publications on three cohort studies were included. Temporary treatment with methotrexate (MTX), abatacept and intramuscular corticosteroids were demonstrated in RCTs with 12 months to 5 years follow-up to be more effective than placebo in suppressing disease activity or radiological progression. One study suggests that DMARD combination therapy is, at least after 4 months, superior to MTX monotherapy in patients with UA at high risk of developing persistent arthritis. The open-label uncontrolled trials and cohort studies also suggested that early treatment may provide immediate suppression of inflammation. The long-term benefit of early treatment in UA remains unclear. In conclusion, patients with UA benefit from early treatment with MTX. Combining multiple DMARDs or DMARDs with corticosteroids and biological agents may be even more beneficial. However, which treatment may provide the best results or may alter the disease course has still to be determined. More RCTs with longer follow-up time are needed.

Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial.

OBJECTIVE: To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians' decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. DESIGN: A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. METHODS: Data were analysed using logistic regression modelling. MAIN OUTCOME MEASURES: The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. RESULTS: The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. CONCLUSION: Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

Identification of biomarkers for tuberculosis disease using a novel dual-color RT-MLPA assay.

Owing to our lack of understanding of the factors that constitute protective immunity during natural infection with Mycobacterium tuberculosis (Mtb), there is an urgent need to identify host biomarkers that predict long-term outcome of infection in the absence of therapy. Moreover, the identification of host biomarkers that predict (in)adequate response to tuberculosis (TB) treatment would similarly be a major step forward. To identify/monitor multi-component host biomarker signatures at the transcriptomic level in large human cohort studies, we have developed and validated a dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) method, permitting rapid and accurate expression profiling of as many as 60-80 transcripts in a single reaction. dcRT-MLPA is sensitive, highly reproducible, high-throughput, has an extensive dynamic range and is as quantitative as QPCR. We have used dcRT-MLPA to characterize the human immune response to Mtb in several cohort studies in two genetically and geographically diverse populations. A biomarker signature was identified that is strongly associated with active TB disease, and was profoundly distinct from that associated with treated TB disease, latent infection or uninfected controls, demonstrating the discriminating power of our biomarker signature. Identified biomarkers included apoptosis-related genes and T-cell/B-cell markers, suggesting important contributions of adaptive immunity to TB pathogenesis.

Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT).

OBJECTIVE: To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term. DESIGN: Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT)). SETTING: Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008. PARTICIPANTS: Pregnant women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected intrauterine growth restriction. INTERVENTIONS: Induction of labour or expectant monitoring. MAIN OUTCOME MEASURES: The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means. RESULTS: 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference -9.9 days, 95% CI -11.3 to -8.6) and weighed 130 g less (mean difference -130 g, 95% CI -188 g to -71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference -0.8%, 95% CI -4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI -5.0% to 5.6%). CONCLUSIONS: In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN10363217.

An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre-eclampsia at term (HYPITAT trial).

OBJECTIVE: To assess the economic consequences of labour induction compared with expectant monitoring in women with gestational hypertension or pre-eclampsia at term. DESIGN: An economic analysis alongside the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: Women diagnosed with gestational hypertension or pre-eclampsia between 36(+0) and 41(+0) weeks of gestation, randomly allocated to either induction of labour or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a societal perspective during a 1-year time horizon. MAIN OUTCOME MEASURES: One-year costs were estimated and health outcomes were expressed as the prevalence of poor maternal outcome defined as either maternal complications or progression to severe disease. RESULTS: The average costs of induction of labour (n = 377) were €7077 versus €7908 for expectant monitoring (n = 379), with an average difference of -€831 (95% CI -€1561 to -€144). This 11% difference predominantly originated from the antepartum period: per woman costs were €1259 for induction versus €2700 for expectant monitoring. During delivery, more costs were generated following induction (€2190) compared with expectant monitoring (€1210). No substantial differences were found in the postpartum, follow-up and for non-medical costs. CONCLUSION: In women with gestational hypertension or mild pre-eclampsia at term, induction of labour is less costly than expectant monitoring because of differences in resource use in the antepartum period. As the trial already demonstrated that induction of labour results in less progression to severe disease without resulting in a higher caesarean section rate, both clinical and economic consequences are in favour of induction of labour in these women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

Rise in maternal mortality in the Netherlands.

OBJECTIVE: To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality. SETTING: Nationwide in the Netherlands. POPULATION: 2,557,208 live births. METHODS: Data analysis of all maternal deaths in the period 1993-2005. MAIN OUTCOME MEASURES: Maternal mortality. RESULTS: The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%). CONCLUSIONS: Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.