Predicting dropout in fertility care: a longitudinal study on patient-centredness

Item does not contain fulltextSTUDY QUESTION: Are clinic factors, including patients' experiences with patient-centred care, associated with dropout in fertility care? SUMMARY ANSWER: Clinic factors, including patients' experiences with patient-centred care, are not related to dropout. WHAT IS KNOWN ALREADY: In fertility care, a significant proportion of patients do not achieve pregnancy because they discontinue treatment prematurely. Many studies have tried to identify factors predicting dropout, showing incompatible results. However, these studies mainly focus on factors at the treatment and patient level, while clinic factors have received little attention. STUDY DESIGN, SIZE, DURATION: This prospective, longitudinal study was nested within a large RCT, which aims to improve the level of patient-centredness of Dutch fertility care. Of the 1620 infertile women who were invited to participate, the baseline measurement of the study (T0) included 693 women who completed a questionnaire about their experiences with patient-centred fertility care. The follow-up of the patients was 1 year (T1). PARTICIPANTS/MATERIALS, SETTING, METHODS: All included women suffered from infertility and were undergoing treatment in one of the 32 Dutch clinics involved in the trial. Levels of patient-centredness were determined using the Patient-Centredness Questionnaire-Infertility (PCQ-Infertility) at T0. Meanwhile, a professionals' questionnaire was used to gather additional information on characteristics of the clinic (e.g. the number of patients per year or the presence of a fertility nurse). After 1 year, at T1 measurement, patients completed a questionnaire on their current status in fertility care, including their main reason for discontinuation if applicable. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 693 non-pregnant women completed the questionnaire set at T0 and 534 women (77.1%) provided consent for follow-up. At T1 measurement, 434 women (81.3%) completed the questionnaire and 153 of these women (35.2%) continued treatment while 76 women (17.5%) dropped out. Another 175 women (40.3%) had achieved pregnancy and 30 patients (7.9%) were advised to discontinue treatment for medical reasons. Neither levels of patient-centredness nor the additional clinic characteristics differed significantly between dropouts and compliers. However, patients who did not receive assisted reproduction treatment (ART; e.g. underwent intrauterine insemination, IUI) before they dropped out had significantly lower scores on the PCQ-Infertility subscale 'Respect for patients' values' than patients who continued their treatment [odds ratio (OR) 0.57; 95% confidence interval (CI) 0.34-0.95]. Patients who received ART and, subsequently, dropped out had higher scores on the PCQ-Infertility subscale 'Patient involvement' than those receiving non-ART (OR 2.39; 95% CI 1.02-5.59). LIMITATIONS, REASONS FOR CAUTION: We were not able to follow-up a significant proportion (ca. 19%) of the 1620 women who were invited for T0 measurement, which might have biased our results. We also excluded patients who were still in the diagnostic work-up stage and this might have influenced our results as it is known that patients dropout at this stage. As the PCQ-Infertility was validated in patients who were already undergoing treatment, we decided to focus on this patient group only. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide a better insight into those factors influencing dropout from the perspective of factors in the clinic itself. Although most clinic factors were not related to dropout, clinic factors might be of use when predicting dropout for specific patient groups, such as patients receiving ART and non-ART. Future research should involve an exploration of more specific predictors of dropout at the patient, treatment and clinic levels. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Merck Serono, the Netherlands. No competing interests declared

Feedback to professionals on patient-centered fertility care is insufficient for improvement: a mixed-method study

OBJECTIVE: To determine the effect of audits and feedback on the level of patient-centeredness in fertility care, and to obtain a more in-depth understanding of professionals' views on patient-centered care and achieving improvements. DESIGN: Mixed-method design, using semistructured in-depth interviews and patient questionnaires. SETTING: Fifteen Dutch fertility clinics. PATIENT(S): Women in infertility treatment (quantitative section) and fertility care professionals (qualitative section). INTERVENTION(S): Audit of the level of patient-centeredness of care, and feedback provided to clinics by a personalized paper-based feedback report. MAIN OUTCOME MEASURE(S): Quantitative section: the patient-reported differences in the level of patient-centered fertility care between 2009 and 2011 measured by the Patient-Centeredness Questionnaire-Infertility. Qualitative section: professionals views on improving patient-centered fertility care arranged into a Hibbard framework for behavioral change. RESULT(S): Multilevel regression analysis showed no statistically significant differences between the overall levels of patient-centeredness in 2009 and 2011. Qualitative research showed that professionals' urge to change and their ability to translate feedback were suboptimal to achieve behavioral change. CONCLUSION(S): Audits and feedback alone are not enough to improve the level of patient-centeredness in fertility care. Increasing professionals' desire to change and their ability to translate feedback about their performance into an optimal quality improvement strategy appear to be the key issues

FOXP3 can modulate TAL1 transcriptional activity through interaction with LMO2

© 2015 Macmillan Publishers Limited. All rights reserved.T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.VF and JvL were supported by a grant from the Dutch Arthritis Foundation (Rheumafonds), and BAC was supported by a fellowship from Fundação para a Ciência e a Tecnologia. This work was supported by grant from the Dutch Arthritis Foundation (Rheumafonds), and a fellowship from Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Utility of extrapolating human S1500+ genes to the whole transcriptome: tunicamycin case study

The TempO-Seq S1500+ platform(s), now available for human, mouse, rat, and zebrafish, measures a discrete number of genes that are representative of biological and pathway co-regulation across the entire genome in a given species. While measurement of these genes alone provides a direct assessment of gene expression activity, extrapolating expression values to the whole transcriptome (~26 000 genes in humans) can estimate measurements of non-measured genes of interest and increases the power of pathway analysis algorithms by using a larger background gene expression space. Here, we use data from primary hepatocytes of 54 donors that were treated with the endoplasmic reticulum (ER) stress inducer tunicamycin and then measured on the human S1500+ platform containing ~3000 representative genes. Measurements for the S1500+ genes were then used to extrapolate expression values for the remaining human transcriptome. As a case study of the improved downstream analysis achieved by extrapolation, the "measured only" and "whole transcriptome" (measured + extrapolated) gene sets were compared. Extrapolation increased the number of significant genes by 49%, bringing to the forefront many that are known to be associated with tunicamycin exposure. The extrapolation procedure also correctly identified established tunicamycin-related functional pathways reflected by coordinated changes in interrelated genes while maintaining the sample variability observed from the "measured only" genes. Extrapolation improved the gene- and pathway-level biological interpretations for a variety of downstream applications, including differential expression analysis, gene set enrichment pathway analysis, DAVID keyword analysis, Ingenuity Pathway Analysis, and NextBio correlated compound analysis. The extrapolated data highlight the role of metabolism/metabolic pathways, the ER, immune response, and the unfolded protein response, each of which are key activities associated with tunicamycin exposure that were unrepresented or underrepresented in one or more of the analyses of the original "measured only" dataset. Furthermore, the inclusion of the extrapolated genes raised "tunicamycin" from third to first upstream regulator in Ingenuity Pathway Analysis and from sixth to second most correlated compound in NextBio analysis. Therefore, our case study suggests an approach to extend and enhance data from the S1500+ platform for improved insight into biological mechanisms and functional outcomes of diseases, drugs, and other perturbations.Toxicolog

Oil-based versus water-based contrast media for hysterosalpingography in infertile women of advanced age, with ovulation disorders or a high risk for tubal pathology:study protocol of a randomized controlled trial (H2Oil2 study)

BACKGROUND: In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. METHODS: We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. DISCUSSION: This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as 'H2Oil2' (reference number NL7925, https://www.trialregister.nl/trial/7925 )

Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds

Drug-induced liver injury (DILI) has become a major problem for patients and for clinicians, academics and the pharmaceutical industry. To date, existing hepatotoxicity test systems are only poorly predictive and the underlying mechanisms are still unclear. One of the factors known to amplify hepatotoxicity is the tumor necrosis factor alpha (TNFα), especially due to its synergy with commonly used drugs such as diclofenac. However, the exact mechanism of how diclofenac in combination with TNFα induces liver injury remains elusive. Here, we combined time-resolved immunoblotting and live-cell imaging data of HepG2 cells and primary human hepatocytes (PHH) with dynamic pathway modeling using ordinary differential equations (ODEs) to describe the complex structure of TNFα-induced NFκB signal transduction and integrated the perturbations of the pathway caused by diclofenac. The resulting mathematical model was used to systematically identify parameters affected by diclofenac. These analyses showed that more than one regulatory module of TNFα-induced NFκB signal transduction is affected by diclofenac, suggesting that hepatotoxicity is the integrated consequence of multiple changes in hepatocytes and that multiple factors define toxicity thresholds. Applying our mathematical modeling approach to other DILI-causing compounds representing different putative DILI mechanism classes enabled us to quantify their impact on pathway activation, highlighting the potential of the dynamic pathway model as a quantitative tool for the analysis of DILI compounds.Toxicolog

The effectiveness of immediate versus delayed tubal flushing with oil-based contrast in women with unexplained infertility (H2Oil-timing study): study protocol of a randomized controlled trial

Abstract Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography leads to significantly more live births as compared to tubal flushing with water-based contrast during hysterosalpingography. However, it is unknown whether incorporating tubal flushing with oil-based contrast in the initial fertility work-up results to a reduced time to conception leading to live birth when compared to delayed tubal flushing that is performed six months after the initial fertility work-up. We also aim to evaluate the effectiveness of tubal flushing with oil-based contrast during hysterosalpingography versus no tubal flushing in the first six months of the study. Methods This study will be an investigator-initiated, open-label, international, multicenter, randomized controlled trial with a planned economic analysis alongside the study. Infertile women between 18 and 39 years of age, who have an ovulatory cycle, who are at low risk for tubal pathology and have been advised expectant management for at least six months (based on the Hunault prediction score) will be included in this study. Eligible women will be randomly allocated (1:1) to immediate tubal flushing (intervention) versus delayed tubal flushing (control group) by using web-based block randomization stratified per study center. The primary outcome is time to conception leading to live birth with conception within twelve months after randomization. We assess the cumulative conception rate at six and twelve months as two co-primary outcomes. Secondary outcomes include ongoing pregnancy rate, live birth rate, miscarriage rate, ectopic pregnancy rate, number of complications, procedural pain score and cost-effectiveness. To demonstrate or refute a shorter time to pregnancy of three months with a power of 90%, a sample size of 554 women is calculated. Discussion The H2Oil-timing study will provide insight into whether tubal flushing with oil-based contrast during hysterosalpingography should be incorporated in the initial fertility work-up in women with unexplained infertility as a therapeutic procedure. If this multicenter RCT shows that tubal flushing with oil-based contrast incorporated in the initial fertility work-up reduces time to conception and is a cost-effective strategy, the results may lead to adjustments of (inter)national guidelines and change clinical practice. Trial registration number The study was retrospectively registered in International Clinical Trials Registry Platform (Main ID: EUCTR2018-004153-24-NL)