Analysing the protection from respiratory tract infections and allergic diseases early in life by human milk components: the PRIMA birth cohort.

BACKGROUND: Many studies support the protective effect of breastfeeding on respiratory tract infections. Although infant formulas have been developed to provide adequate nutritional solutions, many components in human milk contributing to the protection of newborns and aiding immune development still need to be identified. In this paper we present the methodology of the "Protecting against Respiratory tract lnfections through human Milk Analysis" (PRIMA) cohort, which is an observational, prospective and multi-centre birth cohort aiming to identify novel functions of components in human milk that are protective against respiratory tract infections and allergic diseases early in life. METHODS: For the PRIMA human milk cohort we aim to recruit 1000 mother-child pairs in the first month postpartum. At one week, one, three, and six months after birth, fresh human milk samples will be collected and processed. In order to identify protective components, the level of pathogen specific antibodies, T cell composition, Human milk oligosaccharides, as well as extracellular vesicles (EVs) will be analysed, in the milk samples in relation to clinical data which are collected using two-weekly parental questionnaires. The primary outcome of this study is the number of parent-reported medically attended respiratory infections. Secondary outcomes that will be measured are physician diagnosed (respiratory) infections and allergies during the first year of life. DISCUSSION: The PRIMA human milk cohort will be a large prospective healthy birth cohort in which we will use an integrated, multidisciplinary approach to identify the longitudinal effect human milk components that play a role in preventing (respiratory) infections and allergies during the first year of life. Ultimately, we believe that this study will provide novel insights into immunomodulatory components in human milk. This may allow for optimizing formula feeding for all non-breastfed infants.

Estimation of treatment effects in short-term depression studies. An evaluation based on the ICH E9(R1) estimands framework.

Estimands aim to incorporate intercurrent events in design, data collection and estimation of treatment effects in clinical trials. Our aim was to understand what estimands may correspond to efficacy analyses commonly employed in clinical trials conducted before publication of ICH E9(R1). We re-analysed six clinical trials evaluating a new anti-depression treatment. We selected the following analysis methods-ANCOVA on complete cases, following last observation carried forward (LOCF) imputation and following multiple imputation; mixed-models for repeated measurements without imputation (MMRM), MMRM following LOCF imputation and following jump-to-reference imputation; and pattern-mixture mixed models. We included a principal stratum analysis based on the predicted subset of the study population who would not discontinue due to adverse events or lack of efficacy. We translated each analysis into the implicitly targeted estimand, and formulated corresponding clinical questions. We could map six estimands to analysis methods. The same analysis method could be mapped to more than one estimand. The major difference between estimands was the strategy for intercurrent events, with other attributes mostly the same across mapped estimands. The quantitative differences in MADRS10 population-level summaries between the estimands were 4-8 points. Not all six estimands had a clinically meaningful interpretation. Only a few analyses would target the same estimand, hence only few could be used as sensitivity analyses. The fact that an analysis could estimate different estimands emphasises the importance of prospectively defining the estimands targeting the primary objective of a trial. The fact that an estimand can be targeted by different analyses emphasises the importance of prespecifying precisely the estimator for the targeted estimand.

Inhibitor development in previously untreated patients with severe haemophilia: A comparison of included patients and outcomes between a clinical study and a registry-based study.

AIM: The aim of this study was to investigate whether a disease registry could serve as a suitable alternative to clinical studies to investigate safety of orphan drugs in children. METHODS: We used individual patient data from previously untreated patients (PUPs) with severe haemophilia A from the factor VIII (rAHF-PFM)-clinical study and the PedNet registry. The primary outcome was the patient characteristics at entry and the difference in inhibitor development between the clinical study and the registry-based study at 50 exposure days. RESULTS: Clinical study patients more often had a positive family history of inhibitors (31% vs 10%) and a high-risk F8 genotype (82% vs 63%). In the clinical study 41/55 (75%) and in the registry-based study 162/168 (96%) patients reached 50 exposure days. Inhibitors developed in 16 of the 41 patients in the clinical study (39%) vs 44 of the 162 patients in the registry-based study (27%); seven patients (7%) vs 28 patients (17%) had high-titre inhibitors. The risk of developing an inhibitor during the first 50 exposure days was similar (HR 1.04; 95% CI 0.56-1.94), when adjusted for family history of inhibitors, F8 gene mutation and intensive treatment at first exposure. CONCLUSION: In the registry-based study, patient numbers and completeness of follow-up were higher. The risk of developing an inhibitor to a single product was comparable. Although the sample size of this study was too small to conclude on differences in high- or low-titre inhibitors, this suggests that a registry could serve as a more suitable source for evaluation of high-titre inhibitors in the setting of factor VIII deficiency.

Balloon catheter for induction of labor in women with one previous cesarean and an unfavorable cervix.

INTRODUCTION: When women with a previous cesarean section and an unfavorable cervix have an indication for delivery, the choice is to induce labor or to perform a cesarean section. This study aims to assess the effectiveness and safety of a balloon catheter as a method of induction of labor in women with one previous cesarean section and an unfavorable cervix compared with an elective repeat cesarean section. MATERIAL AND METHODS: We performed a prospective cohort study in 51 hospitals in the Netherlands on term women with one previous cesarean section, a live singleton fetus in cephalic position, an unfavorable cervix and an indication for delivery. We recorded obstetric, maternal and neonatal characteristics. We compared the outcome of women who were induced with a balloon catheter with the outcome of women who delivered by elective repeat cesarean section. Main outcomes were maternal and neonatal morbidity. Mode of delivery was a secondary outcome for women who were induced. Adjusted odds ratios (aOR) were calculated using logistic regression, adjusted for potential confounders. RESULTS: Analysis was performed on 993 women who were induced and 321 women who had a repeat cesarean section (August 2011 until September 2012). Among the women who were induced, 560 (56.4%) delivered vaginally and 11 (1.1%) sustained a uterine rupture. Composite adverse maternal outcome (uterine rupture, severe postpartum hemorrhage or postpartum infection) occurred in 73 (7.4%) in the balloon and 14 (4.5%) women in the repeat cesarean section group (aOR 1.58, 95% confidence interval [CI] 0.85-2.96). Composite adverse neonatal outcome (Apgar score <7 at 5 minutes or umbilical pH <7.10) occurred in 57 (5.7%) and 10 (3.2%) neonates, respectively (aOR 1.40, 95% CI 0.87-3.48). Women who were induced had a shorter postpartum admission time (2.0 vs 3.0 days (P < 0.0001)). CONCLUSIONS: In women with a previous cesarean section and a need for delivery, induction of labor with a balloon catheter does not result in a significant increase in adverse maternal and neonatal outcomes as compared with planned cesarean section.

The (cost) effectiveness of procedural sedation and analgesia versus general anaesthesia for hysteroscopic myomectomy, a multicentre randomised controlled trial: PROSECCO trial, a study protocol.

BACKGROUND: In women with abnormal uterine bleeding, fibroids are a frequent finding. In case of heavy menstrual bleeding and presence of submucosal type 0-1 fibroids, hysteroscopic resection is the treatment of first choice, as removal of these fibroids is highly effective. Hysteroscopic myomectomy is currently usually performed in the operating theatre. A considerable reduction in costs and a higher patient satisfaction are expected when procedural sedation and analgesia with propofol (PSA) in an outpatient setting is applied. However, both safety and effectiveness - including the necessity for re-intervention due to incomplete resection - have not yet been evaluated. METHODS: This study is a multicentre randomised controlled trial with a non-inferiority design and will be performed in the Netherlands. Women > 18 years with a maximum of 3 symptomatic type 0 or 1 submucosal fibroids with a maximum diameter of 3.5 cm are eligible to participate in the trial. After informed consent, 205 women will be randomised to either hysteroscopic myomectomy using procedural sedation and analgesia with propofol in an outpatient setting or hysteroscopic myomectomy using general anaesthesia in a clinical setting in the operating theatre. Primary outcome will be the percentage of complete resections, based on transvaginal ultrasonography 6 weeks postoperatively. Secondary outcomes are cost effectiveness, menstrual blood loss (Pictorial blood assessment chart), quality of life, pain, return to daily activities/work, hospitalization, (post) operative complications and re-interventions. Women will be followed up to one year after hysteroscopic myomectomy. DISCUSSION: This study may demonstrate comparable effectiveness of hysteroscopic myomectomy under procedural sedation and analgesia versus general anaesthesia in a safe and patient friendly environment, whilst achieving a significant cost reduction. TRIAL REGISTRATION: Dutch trial register, number NTR5357 . Registered 11th of August 2015.

Pharmacological pain relief and fear of childbirth in low risk women; secondary analysis of the RAVEL study.

BACKGROUND: Fear of childbirth may reduce the womens' pain tolerance during labour and may have impact on the mother-infant interaction. We aimed to assess (1) the association between fear of childbirth antepartum and subsequent request for pharmacological pain relief, and (2) the association between the used method of pain relief and experienced fear of childbirth as reported postpartum in low risk labouring women. METHODS: Secondary analysis of the RAVEL study, a randomised controlled trial comparing remifentanil patient controlled analgesia (PCA) and epidural analgesia to relieve labour pain. The RAVEL study included 409 pregnant women at low risk for obstetric complications at 18 midwifery practices and six hospitals in The Netherlands (NTR 3687). We measured fear of childbirth antepartum and experienced fear of childbirth reported postpartum, using the Wijma Delivery Expectancy/Experience Questionnaire. RESULTS: Women with fear of childbirth antepartum more frequently requested pain relief compared to women without fear of childbirth antepartum, but this association did not reach statistical significance (adjusted odds ratio (aOR2.0; 95% confidence interval (CI) 0.8-4.6). Women who received epidural analgesia more frequently reported fear of childbirth postpartum compared to women who did not receive epidural analgesia (aOR3.5; CI 1.5-8.2), while the association between remifentanil-PCA and fear of childbirth postpartum was not statistically significant (aOR1.7; CI 0.7-4.3). CONCLUSIONS: Women with fear of childbirth antepartum more frequently requested pain relief compared to women without fear of childbirth antepartum, but this association was not statistically significant. Women who received pharmacological pain relief more frequently reported that they had experienced fear of childbirth during labour compared to women who did not receive pain relief. Based on our data epidural analgesia with continuous infusion does not seem to be preferable over remifentanil-PCA as method of pain relief when considering fear of childbirth postpartum. TRIAL REGISTRATION: Netherlands Trial Register 3687 ; Register date: 5 Nov 2012.

Induction of labour at term with oral misoprostol versus a Foley catheter (PROBAAT-II): a multicentre randomised controlled non-inferiority trial.

BACKGROUND: Labour is induced in 20-30% of all pregnancies. In women with an unfavourable cervix, both oral misoprostol and Foley catheter are equally effective compared with dinoprostone in establishing vaginal birth, but each has a better safety profile. We did a trial to directly compare oral misoprostol with Foley catheter alone. METHODS: We did an open-label randomised non-inferiority trial in 29 hospitals in the Netherlands. Women with a term singleton pregnancy in cephalic presentation, an unfavourable cervix, intact membranes, and without a previous caesarean section who were scheduled for induction of labour were randomly allocated to cervical ripening with 50 µg oral misoprostol once every 4 h or to a 30 mL transcervical Foley catheter. The primary outcome was a composite of asphyxia (pH ≤7·05 or 5-min Apgar score <7) or post-partum haemorrhage (≥1000 mL). The non-inferiority margin was 5%. The trial is registered with the Netherlands Trial Register, NTR3466. FINDINGS: Between July, 2012, and October, 2013, we randomly assigned 932 women to oral misoprostol and 927 women to Foley catheter. The composite primary outcome occurred in 113 (12·2%) of 924 participants in the misoprostol group versus 106 (11·5%) of 921 in the Foley catheter group (adjusted relative risk 1·06, 90% CI 0·86-1·31). Caesarean section occurred in 155 (16·8%) women versus 185 (20·1%; relative risk 0·84, 95% CI 0·69-1·02, p=0·067). 27 adverse events were reported in the misoprostol group versus 25 in the Foley catheter group. None were directly related to the study procedure. INTERPRETATION: In women with an unfavourable cervix at term, induction of labour with oral misoprostol and Foley catheter has similar safety and effectiveness. FUNDING: FondsNutsOhra.

Vaginal prolapse repair with or without a midurethral sling in women with genital prolapse and occult stress urinary incontinence: a randomized trial.

INTRODUCTION AND HYPOTHESIS: We compared pelvic organ prolapse (POP) repair with and without midurethral sling (MUS) in women with occult stress urinary incontinence (SUI). METHODS: This was a randomized trial conducted by a consortium of 13 teaching hospitals assessing a parallel cohort of continent women with symptomatic stage II or greater POP. Women with occult SUI were randomly assigned to vaginal prolapse repair with or without MUS. Women without occult SUI received POP surgery. Main outcomes were the absence of SUI at the 12-month follow-up based on the Urogenital Distress Inventory and the need for additional treatment for SUI. RESULTS: We evaluated 231 women, of whom 91 randomized as follows: 43 to POP surgery with and 47 without MUS. A greater number of women in the MUS group reported absence of SUI [86 % vs. 48 %; relative risk (RR) 1.79; 95 % confidence interval (CI) 1.29-2.48]. No women in the MUS group received additional treatment for postoperative SUI; six (13 %) in the control group had a secondary MUS. Women with occult SUI reported more urinary symptoms after POP surgery and more often underwent treatment for postoperative SUI than women without occult SUI. CONCLUSIONS: Women with occult SUI had a higher risk of reporting SUI after POP surgery compared with women without occult SUI. Adding a MUS to POP surgery reduced the risk of postoperative SUI and the need for its treatment in women with occult SUI. Of women with occult SUI undergoing POP-only surgery, 13 % needed additional MUS. We found no differences in global impression of improvement and quality of life.

A randomised comparison of single-incision versus traditional transobturator midurethral sling in women with stress urinary incontinence: results of a 24-month follow-up.

INTRODUCTION AND HYPOTHESIS: Midurethral sling procedures have become the principal surgical treatment for women with stress urinary incontinence (SUI). The 1-year results of this international trial comparing the efficacy and morbidity of a single-incision midurethral sling (SIMS; MiniArc) and a transobturator standard midurethral sling (SMUS; Monarc) showed that MiniArc is non-inferior regarding subjective cure and superior with regard to postoperative pain and recovery. The objective was to compare subjective and objective cure, morbidity and surgery-related discomfort following SIMS and transobturator SMUS up to a 24-month follow-up. METHODS: We carried out a non-blinded, randomised, controlled trial. Women with symptomatic SUI were eligible. Primary outcome was subjective cure, defined as an improvement on the Patient Global Impression of Improvement (PGI-I), at 12, 24 and 36 months. Secondary outcomes were objective cure based on the cough stress test, disease-specific quality of life questionnaires, surgical parameters and physical performance during recovery. Analysis was by intent to treat. Differences between the two groups regarding dichotomous variables were Chi-squared tested and presented as relative risks (RR) with corresponding 95 % confidence intervals. RESULTS: We randomised 97 women to MiniArc and 96 to Monarc. At the 24-month follow-up, subjective cure was 84 % following MiniArc and 89 % following Monarc (RR -5; 95% CI -0.17 to 0.06). Objective cure was 93 % following MiniArc and 94 % following Monarc (RR -1; 95% CI -0.10 to 0.07). Both procedures have low complication rates. CONCLUSIONS: At the 2-year follow-up, the non-prespecified analysis of this randomised trial showed that the MiniArc, a single-incision sling, had similar subjective and similar objective cure rates, although non-inferiority to Monarc for subjective cure could not be demonstrated.

Delivery-related risk factors for covert postpartum urinary retention after vaginal delivery.

INTRODUCTION AND HYPOTHESIS: Postpartum urinary retention (PUR) is a common consequence of bladder dysfunction after vaginal delivery. Patients with covert PUR are able to void spontaneously but have a postvoid residual bladder volume (PVRV) of ≥150 mL. Incomplete bladder emptying may predispose to bladder dysfunction at a later stage of life. The aim of this cross-sectional study was to identify independent delivery-related risk factors for covert PUR after vaginal delivery in order to identify women with an increased risk of covert PUR. METHODS: The PVRV of women who delivered vaginally was measured after the first spontaneous micturition with a portable bladder-scanning device. A PVRV of 150 mL or more was defined as covert PUR. Independent risk factors for covert PUR were identified in multivariate regression analysis. RESULTS: Of 745 included women, 347 (47%) were diagnosed with covert PUR (PVRV ≥150 mL), of whom 197 (26%) had a PVRV ≥250 mL (75th percentile) and 50 (7%) a PVRV ≥500 mL (95th percentile). In multivariate regression analysis, episiotomy (OR 1.7, 95% CI 1.02 - 2.71), epidural analgesia (OR 2.08, 95% CI 1.36 - 3.19) and birth weight (OR 1.03, 95% CI 1.01 - 1.06) were independent risk factors for covert PUR. Opioid analgesia during labour (OR 3.19, 95% CI 1.46 - 6.98), epidural analgesia (OR 3.54, 95% CI 1.64 - 7.64) and episiotomy (OR 3.72, 95% CI 1.71 - 8.08) were risk factors for PVRV ≥500 mL. CONCLUSIONS: Episiotomy, epidural analgesia and birth weight are risk factors for covert PUR. We suggest that the current cut-off values for covert PUR should be reevaluated when data on the clinical consequences of abnormal PVRV become available.

Vaginal microcirculation: Non-invasive anatomical examination of the micro-vessel architecture, tortuosity and capillary density.

AIM: To describe the vaginal microcirculatory architecture and capillary density parameters using sidestream dark-field imaging (SDFI), and determine feasibility and reliability of this method. METHODS: In nine healthy female volunteers SDFI measurements were performed at two different time points in the luteal phase of the menstrual cycle. Non-invasive tissue micro-angioarchitecture and vaginal capillary density measurements were assessed independently by two observers. Agreement was expressed with mean differences between the measurements of both observers and the limits of agreement. Inter- and intra-observer agreement was quantified with the intra-class correlation coefficient (ICC). RESULTS: Vaginal microcirculatory assessment with the SDFI device was easy in use, painless and well accepted by the participants. Morphologically, the vaginal microcirculation revealed an array of single hairpin-shaped capillary loops distributed homogeneously across an imaged tissue segment. The intra-observer assessment of the capillary density measurements (comparing two measurement time points of one observer) showed good agreement with an ICC ranging from 0.62 to 0.85. The inter-observer assessments of the capillary density measurements (comparing assessments of two observers at one time point) revealed very good agreement, with small differences between observers and an ICC of more than 0.9. CONCLUSIONS: This is the first report on both microcirculatory architecture and quantitative microcirculatory parameters of the vagina with the use of SDFI. Micro-vessels of the vagina show a recognizable pattern in our study population of young, healthy women. SDFI gives a reproducible assessment of the vaginal microcirculation offering the researcher a wide field of applications.

Pregnant womens' concerns when invited to a randomized trial: a qualitative case control study.

BACKGROUND: Pregnant women were excluded from clinical trials until the 1990s, but the Food and Drug Administration nowadays allows--and even encourages--responsible inclusion of pregnant women in trials with adequate safety monitoring. Still, randomized trials in pregnant women face specific enrolment challenges. Previous studies have focused on barriers to trial participation in studies that had failed to recruit sufficient participants. Our aim was to identify barriers and motivators for participation in a range of clinical trials being conducted in the Netherlands, regardless of recruitment performance. METHODS: We performed a qualitative case control study in women who had been asked in 2010 to participate in one of eight clinical trials during pregnancy or shortly after giving birth. Both participants and non-participants of these clinical trials were invited for a face-to-face interview that addressed motives for participation and non-participation. We started the interview in an open fashion, asking the women for their main motive for participation or non-participation. When no new information emerged in this open part, we continued with a semi-structured interview, guided by a topic list. Transcripts of the interviews were analysed using a constant-comparative approach. Two researchers identified barriers and facilitators for participation, conjoined into main themes. RESULTS: Of 28 women invited for the interview, 21 agreed to be interviewed (12 participants and 9 non-participants). For 5 of the 12 participants, contribution to scientific research was their main motive, while 5 had participated because the intervention seemed favorable and was not available outside the trial. Key motives for non-participation (n = 9) were a negative association or a dislike of the intervention, either because it might do harm (n = 6) or for practical reasons (n = 3). Combining the open and topic list guided interviews we constructed seven main themes that influence the pregnant women's decision to participate: external influence, research and healthcare, perception own situation, study design, intervention, information and counselling, and uncertainty. CONCLUSIONS: Among seven main themes that influence pregnant women's decision to participate, uncertainty about scientific research or the intervention was reported to be of considerable importance. Measures should be taken to habituate pregnant women more to scientific research, and further evaluation of opt-out consent deserves attention.

Foley catheter versus vaginal misoprostol: randomized controlled trial (PROBAAT-M study) and systematic review and meta-analysis of literature.

OBJECTIVES: To assess effectiveness and safety of Foley catheter versus vaginal misoprostol for term induction of labor. STUDY DESIGN: This trial randomly allocated women with singleton term pregnancy to 30-mL Foley catheter or 25-µg vaginal misoprostol tablets. Primary outcome was cesarean delivery rate. Secondary outcomes were maternal and neonatal morbidity and time to birth. Additionally, a systematic review was conducted. RESULTS: Fifty-six women were allocated to Foley catheter, 64 to vaginal misoprostol tablets. Cesarean delivery rates did not differ significantly (25% Foley versus 17% misoprostol; relative risk [RR] 1.46, 95% confidence interval [CI] 0.72 to 2.94), with more cesarean deliveries due to failure to progress in the Foley group (14% versus 3%; RR 4.57, 95% CI 1.01 to 20.64). Maternal and neonatal outcomes were comparable. Time from induction to birth was longer in the Foley catheter group (36 hours versus 25 hours; p < 0.001). Meta-analysis showed no difference in cesarean delivery rate and reduced vaginal instrumental deliveries and hyperstimulation in the Foley catheter group. Other outcomes were not different. CONCLUSION: Our trial and meta-analysis showed no difference in cesarean delivery rates and less hyperstimulation with fetal heart rate changes and vaginal instrumental deliveries when using Foley catheter, thereby supporting potential advantages of the Foley catheter over misoprostol as ripening agent.

Potential improvement of pregnancy outcome through prenatal small for gestational age detection. [correction].

OBJECTIVE: To assess differences in mode of delivery and pregnancy outcome between prenatally detected and nonprenatally detected small for gestational age (SGA) neonates born at term. STUDY DESIGN: We performed a retrospective multicenter cohort study. All singleton infants, born SGA in cephalic position between 36(0/7) and 41(0/7) weeks gestation, were classified as either prenatally detected SGA or nonprenatally detected SGA. With propensity score matching we created groups with comparable baseline characteristics. We compared these groups for composite adverse perinatal outcome, labor induction, and cesarean section rates. RESULTS: We included 718 SGA infants, of whom 555 (77%) were not prenatally detected. Composite adverse neonatal outcome did not differ statistically significant between the matched prenatally detected and the nonprenatally detected group (5.5 vs. 7.4%, odds ratio [OR] 0.74, 95% confidence interval [CI]: 0.30-1.8). However, perinatal mortality only occurred in the nonprenatally detected group (1.8% [3/163] in the matched cohort, 1.3% [7/555] in the complete cohort). In the propensity matched prenatally detected SGA group both induction of labor (57 vs. 9%, OR 14.0, 95% CI: 7.4-26.2) and cesarean sections (20 vs. 8%, OR 2.9, 95% CI: 1.5-5.8) were more often performed compared with the nonprenatally detected SGA group. CONCLUSION: Prenatal SGA detection at term allows timely induction of labor and cesarean sections thus potentially preventing stillbirth.

Does recruitment for multicenter clinical trials improve dissemination and timely implementation of their results? A survey study from the Netherlands.

BACKGROUND RESULTS: from clinical trials are often slowly implemented. We studied whether participation in multicenter clinical trials improves reported dissemination, convincement, and subsequent implementation of its results. METHODS: We sent a web-based questionnaire to gynecologists, residents, nurses, and midwives in all obstetrics and gynecology departments in the Netherlands. For nine trials in perinatology, reproductive medicine, and gynecologic oncology, we asked the respondents whether they had knowledge of the results, were convinced by the results, and what percentage of their patients were treated according to the results of these trials. We compared the level of knowledge, convincement, and reported implementation of results in practice for the nine trials for respondents who worked in hospitals that had recruited for a trial with respondents who worked in a hospital that had not recruited for that trial. The reported implementation was restricted to six trials that showed decisive results. Results We analyzed 202 questionnaires from 83 departments in obstetrics and gynecology in the Netherlands (93% of all departments). The percentage of respondents who had worked in a hospital that recruited for a specific study varied between 8% and 71% per study and was 28% on average. The relative risk (RR) for knowledge of the study result for respondents who had worked in a recruiting hospital was for all studies positive and varied between 1.1 and 3.3 (pooled RR: 1.8, 95% confidence interval (CI): 1.7-1.9). In general, health-care workers were convinced of trial results, independent of whether they had worked in a hospital that recruited for a trial or not (pooled RR: 1.02, 95% CI: 0.99-1.05). Reported implementation of trial's results, that is, less than 20% were treated with unfavorable treatment according to study results, was better in hospitals that had recruited for those trials (pooled RR: 1.1, 95% CI: 1.02-1.19). CONCLUSION: Participation in these multicenter clinical trials was associated with better knowledge about the trial's results, with a minor improvement of the reported implementation of the study results.

Induction of labour with a Foley catheter or oral misoprostol at term: the PROBAAT-II study, a multicentre randomised controlled trial.

BACKGROUND: Induction of labour is a common obstetric procedure. At present, different methods are used for induction of labour in women with an unfavourable cervix. Recently, we showed that in term women with an unfavorable cervix the use of a Foley catheter in comparison with vaginal Prostaglandin E2 gel, results in a comparable vaginal delivery rate. A meta-analysis on the subject indicated lower rates of hyperstimulation, and probably as a sequel fewer cases of postpartum haemorrhage. Misoprostol (PgE1) is another type of prostaglandin frequently used for labour induction, recommended by the international federation of gynaecology and obstetrics (FIGO). Misoprostol can be administered by vaginal, rectal and oral route. There is evidence that oral administration results in less asphyxia and hyperstimulation than vaginal administration. At present, valid comparisons between oral misoprostol and Foley catheter are lacking. Therefore, we propose a randomised controlled trial comparing Foley catheter to oral misoprostol in order to assess safety and cost-effectiveness. METHODS/DESIGN: We plan a multicentre, randomised, controlled, open-label clinical trial among term pregnant women with a vital singleton in cephalic presentation, unfavorable cervix, intact membranes and an indication for induction of labour. After informed consent, women will be randomly allocated by a webbased randomisation system to transcervical Foley catheter or oral misoprostol (50 mcg every 4 hours). The primary outcome will be a composite of complications of uterine hyperstimulation, i.e. post partum haemorrhage and asphyxia. Secondary outcomes are mode of delivery, maternal and neonatal morbidity, costs and women's preference. Serious adverse events such as severe maternal or neonatal morbitity or mortality will be monitored and reported to an independent data safety monitory board. With a sample size of 1860 women we will be able to demonstrate a 5% non-inferiority of the Foley catheter as compared to misoprostol for the composite outcome. DISCUSSION: Worldwide, various methods are being used for labour induction. Results of the proposed trial will contribute to the answer which method of induction of labour is most safe, cost-effective, and patient friendly and will help to construct evidence based guidelines. TRIAL REGISTRATION: The Netherlands Trial Register NTR3466.

How to confidently teach EBM on foot: development and evaluation of a web-based e-learning course.

BACKGROUND: Scarcity of well-trained clinical tutors is a key constraint in integrating teaching of evidence-based medicine (EBM) into clinical activities. OBJECTIVES: We developed a web-based educational course for clinical trainers to confidently teach EBM principles in everyday practice. Its e-learning modules defined the learning objectives and incorporated video clips of practical and effective EBM teaching methods for exploiting educational opportunities in six different clinical settings. METHODS: We evaluated the course with clinical tutors in different specialties across six European countries using a questionnaire to capture learning achievement against preset objectives. RESULTS: Among 56 tutors, 47 participants (84%) improved their scores from baseline. The mean pre-course score was 69.2 (SD=10.4), which increased to 77.3 (SD=11.7) postcourse (p<0.0001). The effect size was moderate with a Cohen's d of 0.73. CONCLUSIONS: An e-learning approach incorporating videos of applied EBM teaching and learning based on real clinical scenarios in the workplace can be useful in facilitating EBM teaching on foot. It can be integrated in the continuing professional development programmes for clinical trainers.

Tools to assess evidence-based practice behaviour among healthcare professionals.

OBJECTIVE: To identify and compare tools to assess Evidence-Based Practice (EBP) behaviour among healthcare professionals. DESIGN: Systematic review. DATA SOURCES: MEDLINE, EMBASE, Cochrane Library, PsychInfo and CINAHL up to July 2011. STUDY SELECTION: Titles, abstracts and eligible full text articles were screened by two reviewers independently. DATA EXTRACTION: Relevant data were extracted by one reviewer and checked by a second reviewer. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: original studies among all healthcare professionals that described the development or use of EBP behaviour assessment tools. RESULTS: Of 19 310 identified articles, 172 studies were included. We identified 117 questionnaires, 10 interviews or focus groups, nine observational studies, 27 chart evaluations and nine studies used a combination of methods. Psychometric properties of the questionnaires used were reported in about half of the studies, in seven studies that assess a single EBM step and in six studies that assess a combination of EBM steps. One of these assessed all five steps of EBP. CONCLUSIONS: Valid and reliable EBP behaviour assessment tools are available. However, only one questionnaire validly assessed all five EBP steps, covering the entire concept of EBP.

Repurposed drug studies on the primary prevention of SARS-CoV-2 infection during the pandemic: systematic review and meta-analysis.

OBJECTIVE: Current evidence on the effectiveness of SARS-CoV-2 prophylaxis is inconclusive. We aimed to systematically evaluate published studies on repurposed drugs for the prevention of laboratory-confirmed SARS-CoV-2 infection and/or COVID-19 among healthy adults. DESIGN: Systematic review. ELIGIBILITY: Quantitative experimental and observational intervention studies that evaluated the effectiveness of repurposed drugs for the primary prevention of SARS-CoV-2 infection and/or COVID-19 disease. DATA SOURCE: PubMed and Embase (1 January 2020-28 September 2022). RISK OF BIAS: Cochrane Risk of Bias 2.0 and Risk of Bias in Non-Randomised Studies of Interventions tools were applied to assess the quality of studies. DATA ANALYSIS: Meta-analyses for each eligible drug were performed if ≥2 similar study designs were available. RESULTS: In all, 65 (25 trials, 40 observational) and 29 publications were eligible for review and meta-analyses, respectively. Most studies pertained to hydroxychloroquine (32), ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB) (11), statin (8), and ivermectin (8). In trials, hydroxychloroquine prophylaxis reduced laboratory-confirmed SARS-CoV-2 infection (risk ratio: 0.82 (95% CI 0.74 to 0.90), I2=48%), a result largely driven by one clinical trial (weight: 60.5%). Such beneficial effects were not observed in observational studies, nor for prognostic clinical outcomes. Ivermectin did not significantly reduce the risk of SARS-CoV-2 infection (RR: 0.35 (95% CI 0.10 to 1.26), I2=96%) and findings for clinical outcomes were inconsistent. Neither ACEi or ARB were beneficial in reducing SARS-CoV-2 infection. Most of the evidence from clinical trials was of moderate quality and of lower quality in observational studies. CONCLUSIONS: Results from our analysis are insufficient to support an evidence-based repurposed drug policy for SARS-CoV-2 prophylaxis because of inconsistency. In the view of scarce supportive evidence on repurposing drugs for COVID-19, alternative strategies such as immunisation of vulnerable people are warranted to prevent the future waves of infection. PROSPERO REGISTRATION NUMBER: CRD42021292797.

Community Use of Repurposed Drugs Before and During COVID-19 Pandemic in the Netherlands: An Interrupted Time-Series Analysis.

Background: Repurposing registered drugs could reduce coronavirus disease (COVID-19) burden before novel drugs are authorized. Little is known about how the pandemic and imposed restrictions changed their dispensing. We aimed to investigate the impact of COVID-19 pandemic on repurposed drugs dispensing in the Netherlands. Methods: We performed interrupted time-series study using University of Groningen prescription database IADB.nl to evaluate dispensing trends of 24 repurposed drugs before (2017-February 2020) and after (March 2020-2021) the pandemic' start. Primary outcomes were monthly prevalence and incidence rates. An autoregressive integrated moving average model assessed the effect of pandemic and stringency index (measuring strictness of government's restriction policies). Results: Annual number of IADB.nl population ranged from 919,697 to 952,400. Generally, dispensing of common long-term-used drugs was not significantly affected by pandemic. The prevalence of antibacterials (-4.20 users per 1000 people), antivirals (-0.04), corticosteroids (-1.29), prednisolone (-1.32), calcium channel blocker (-0.41), and diuretics (-1.29) was lower than expected after the pandemic's start, while the prevalence of ivermectin (0.07), sulfonylureas (0.15), sodium-glucose co-transporter-2 (SGLT2) inhibitor (0.17), and anticoagulants (1.95) was higher than expected. The pandemic was associated with statistically significant decreases in the incidence of antibacterials (-1.21), corticosteroids (-0.60), prednisolone (-0.64) and anticoagulants (-0.02), and increases in ivermectin (0.02), aggregated antidiabetic drugs (0.13), and SGLT2 inhibitors (0.06). These trends were positively associated with pandemic and negatively associated with stringency index. Conclusion: Dispensing of most drugs was not significantly associated with pandemic and government's response. Despite some statistically significant disruptions, these were not necessarily clinically relevant due to small absolute differences observed.