Does the effectiveness of IUI in couples with unexplained subfertility depend on their prognosis of natural conception? A replication of the H2Oil study

Study question Can we replicate the finding that the benefit of IUI-ovarian stimulation (IUI-OS) compared to expectant management for couples with unexplained subfertility depends on the prognosis of natural conception?Summary answer The estimated benefit of IUI-OS did not depend on the prognosis of natural conception but did depend on when treatment was started after diagnosis, with starting IUI-OS later yielding a larger absolute and relative benefit of treatment.What is known already IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials (RCTs) compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found different results. In a previous study (a Dutch national cohort), it was found that the benefit of IUI-OS compared to expectant management seemed dependent on the prognosis of natural conception, but this finding warrants replication. Study design size durationWe conducted a secondary analysis of the H2Oil study (n = 1119), a multicentre RCT that evaluated the effect of oil-based contrast versus water-based contrast during hysterosalpingography (HSG). Couples were randomized before HSG and followed up for 3-5 years. We selected couples with unexplained subfertility who received HSG and had follow-up or pregnancy data available. Follow-up was censored at the start of IVF, after the last IUI cycle or at last contact and was truncated at a maximum of 18 months after the fertility workup.Participants/materials setting methodsThe endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month the ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.Main results and the role of chanceData from 975 couples were available. There were 587 couples who received at least one IUI-OS cycle within 18 months after HSG of whom 221 conceived leading to an ongoing pregnancy (rate: 0.74 per couple per year over a median follow-up for IUI of 5 months). The median period between HSG and starting IUI-OS was 4 months. Out of 388 untreated couples, 299 conceived naturally (rate: 0.56 per couple per year over a median follow-up of 4 months). After creating our mimicked trial datasets, starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.50 (95% CI: 1.19-1.89) compared to expectant management. We did not find strong evidence that the effect of treatment was modified by a couple's prognosis of achieving natural conception (Akaike's Information Criterion (AIC) decreased by 1 point). The effect of treatment was dependent on when couples started IUI-OS (AIC decreased by more than 2 points). The patterns of estimated absolute chances over time for couples with increasingly better prognoses were different from the previous study but the finding that starting later yields a larger benefit of treatment was similar. We found IUI-OS increased the absolute chance of pregnancy by at least 5% compared to expectant management. The absolute chance of pregnancy after IUI-OS seems less variable between couples and starting times of treatment than the absolute chance after expectant management.Limitations reasons for cautionThis is a secondary analysis, as the H2Oil trial was not designed with this research question in mind. Owing to sample size restrictions, it remained difficult to distinguish between the ranges of prognoses in which true benefit was found.Wider implications of the findingsWe replicated the finding that starting IUI-OS later after diagnosis yields a larger absolute and relative benefit of treatment. We did not replicate the dependency of the effect of IUI-OS on the prognosis of natural conception and could not identify clear thresholds for the prognosis of natural conception when IUI-OS was and/or was not effective. Because many of these couples still have good chances of natural conception at the time of diagnosis, we suggest clinicians should advise couples to delay the start of IUI-OS for several months to avoid unnecessary treatment. Study funding/competing interestsThe H2Oil study (NTR 3270) was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The follow-up study (NTR 6577) was also an investigator-initiated study with funding by Guerbet, France. The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by an Investigator grant (GNT1176437) from the Australian National Health and Medical Research Council (NHMRC). K.D. reports receiving travel and speaker fees from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. V.M. reports receiving travel- and speaker fees as well as research grants from Guerbet.R. van Eekelen, K. Rosielle, N. van Welie, K. Dreyer, M. van Wely, M. van Wely ... et al

Self-Control of Traffic Lights and Vehicle Flows in Urban Road Networks

Based on fluid-dynamic and many-particle (car-following) simulations of traffic flows in (urban) networks, we study the problem of coordinating incompatible traffic flows at intersections. Inspired by the observation of self-organized oscillations of pedestrian flows at bottlenecks [D. Helbing and P. Moln\'ar, Phys. Eev. E 51 (1995) 4282--4286], we propose a self-organization approach to traffic light control. The problem can be treated as multi-agent problem with interactions between vehicles and traffic lights. Specifically, our approach assumes a priority-based control of traffic lights by the vehicle flows themselves, taking into account short-sighted anticipation of vehicle flows and platoons. The considered local interactions lead to emergent coordination patterns such as ``green waves'' and achieve an efficient, decentralized traffic light control. While the proposed self-control adapts flexibly to local flow conditions and often leads to non-cyclical switching patterns with changing service sequences of different traffic flows, an almost periodic service may evolve under certain conditions and suggests the existence of a spontaneous synchronization of traffic lights despite the varying delays due to variable vehicle queues and travel times. The self-organized traffic light control is based on an optimization and a stabilization rule, each of which performs poorly at high utilizations of the road network, while their proper combination reaches a superior performance. The result is a considerable reduction not only in the average travel times, but also of their variation. Similar control approaches could be applied to the coordination of logistic and production processes

Expression and Regulation of the Fkbp5 Gene in the Adult Mouse Brain

BACKGROUND: Chronic stress has been found to be a major risk factor for various human pathologies. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, which is tightly regulated via, among others, the glucocorticoid receptor (GR). The activity of the GR is modulated by a variety of proteins, including the co-chaperone FK506 binding protein 51 (FKBP5). Although FKBP5 has been associated with risk for affective disorders and has been implicated in GR sensitivity, previous studies focused mainly on peripheral blood, while information about basal distribution and induction in the central nervous system are sparse. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we describe the basal expression pattern of Fkbp5 mRNA in the brain of adult male mice and show the induction of Fkbp5 mRNA via dexamethasone treatment or different stress paradigms. We could show that Fkbp5 is often, but not exclusively, expressed in regions also known for GR expression, for example the hippocampus. Furthermore, we were able to induce Fkbp5 expression via dexamethasone in the CA1 and DG subregions of the hippocampus, the paraventricular nucleus (PVN) and the central amygdala (CeA). Increase of Fkbp5 mRNA was also found after restrained stress and 24 hours of food deprivation in the PVN and the CeA, while in the hippocampus only food deprivation caused an increase in Fkbp5 mRNA. CONCLUSIONS/SIGNIFICANCE: Interestingly, regions with a low basal expression showed higher increase in Fkbp5 mRNA following induction than regions with high basal expression, supporting the hypothesis that GR sensitivity is, at least partly, mediated via Fkbp5. In addition, this also supports the use of Fkbp5 gene expression as a marker for GR sensitivity. In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain

Modelling of Short-Term Interactions Between Concrete Support and the Excavated Damage Zone Around Galleries Drilled in Callovo–Oxfordian Claystone

peer reviewedProduction of energy from nuclear power plants generates high-level radioactive nuclear waste, harmful during dozens of thousand years. Deep geological disposal of nuclear waste represents the most reliable solutions for its safe isolation. Confinement of radioactive wastes relies on the multi-barrier concept in which isolation is provided by a series of engineered (canister, backfill) and natural (host rock) barriers. Few underground research laboratories have been built all over the world to test and validate storage solutions. The underground drilling process of disposal drifts may generate cracks, fractures/strain localisation in shear bands within the rock surrounding the gallery especially in argillaceous rocks. These degradations affect the hydro-mechanical properties of the material, such as permeability, e.g. creating a preferential flow path for radionuclide migration. Hydraulic conductivity increase within this zone must remain limited to preserve the natural barrier. In addition galleries are currently reinforced by different types of concrete supports such as shotcrete and/or prefab elements. Their purpose is twofold: avoiding partial collapse of the tunnel during drilling operations and limiting convergence of the surrounding rock. Properties of both concrete and rock mass are time dependent, due to shotcrete hydration and hydromechanical couplings within the host rock. By the use of a hydro-mechanical coupled Finite Element Code with a Second Gradient regularization, this paper aims at investigating and predicting support and rock interactions (convergence, stress field). The effect of shotcrete hydration evolution, spraying time and use of compressible wedges is studied in order to determine their relative influence

Parental obesity and risk factors for cardiovascular disease among their offspring in mid-life: findings from the 1958 British Birth Cohort Study

Background:Few studies have investigated whether parental adiposity is associated with offspring cardiovascular health or the underlying pathways. Studying these associations may help to illuminate the paradox of increasing prevalence of obesity and declining trends in cardiovascular disease (CVD) mortality, which may be partially explained by beneficial adaptations to an obesogenic environment among people exposed to such environments from younger ages.Objective:To investigate associations between parental body mass index (BMI) and risk factors for CVD among their offspring in mid-life and to test whether associations of offspring BMI with CVD risk factors were modified by parental BMI.Methods:Data from parents and offspring in the 1958 British birth cohort were used (N=9328). Parental BMI was assessed when offspring were aged 11 years; offspring BMI, waist circumference and CVD risk factors (lipid levels, blood pressure, glycosylated haemoglobin (HbA1c) and inflammatory and haemostatic markers) were measured at 44-45 years.Results:Higher parental BMI was associated with less favourable levels of offspring risk factors for CVD. Most associations were maintained after adjustment for offspring lifestyle and socioeconomic factors but were largely abolished or reversed after adjustment for offspring adiposity. For some CVD risk factors, there was evidence of effect modification; the association between higher BMI and an adverse lipid profile among offspring was weaker if maternal BMI had been higher. Conversely, offspring BMI was more strongly associated with HbA1c if parental BMI had been higher.Conclusions:Intergenerational influences may be important in conferring the effect of high BMI on CVD risk among offspring

How personality diversity influences team performance in student software engineering teams

Contains fulltext : 195377.pdf (Publisher’s version ) (Open Access)ICTAS: 2018 Conference on Information Communications Technology and Society, 8-9 March 2018 Durban, South Africa. Proceeding