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How many gravitational-wave observations from double compact object mergers have we seen to date? This seemingly simple question surprisingly yields a somewhat ambiguous answer that depends on the chosen data-analysis pipeline, detection threshold, and other underlying assumptions. To illustrate this we provide visualizations of the number of existing detections from double compact object mergers by the end of the third observing run (O3) based on recent results from the literature. Additionally, we visualize the expected number of observations from future-generation detectors, highlighting the possibility of up to millions of detections per year by the time next-generation ground-based detectors like Cosmic Explorer and Einstein Telescope come online. We present a publicly available code that highlights the exponential growth in gravitational-wave observations in the coming decades and the exciting prospects of gravitational-wave (astro)physics. more...

Gravitational-wave detectors are now making it possible to investigate how the merger rate of binary black holes (BBHs) evolves with redshift. In this study, we examine whether the BBH merger rate of isolated binaries deviates from a scaled star formation rate density (SFRD)—a frequently used model in state-of-the-art research. To address this question, we conduct population synthesis simulations using COMPAS with a grid of stellar evolution models, calculate their cosmological merger rates, and compare them to a scaled SFRD. We find that our simulated rates deviate by factors up to 3.5 at z ∼ 0 and 5 at z ∼ 9 due to two main phenomena: (i) the formation efficiency of BBHs is an order of magnitude higher at low metallicities than at solar metallicity, and (ii) BBHs experience a wide range of delays (from a few megayears to many gigayears) between formation and merger. The deviations are similar when comparing to a delayed SFRD, and even larger (up to ∼10×) when comparing to SFRD-based models scaled to the local merger rate. Interestingly, our simulations find that the BBH delay time distribution is redshift dependent, increasing the complexity of the redshift distribution of mergers. We find similar results for simulated merger rates of black hole–neutron stars (BHNSs) and binary neutron stars (BNSs). We conclude that the rate of BBH, BHNS, and BNS mergers from the isolated channel can significantly deviate from a scaled SFRD, and that future measurements of the merger rate will provide insights into the formation pathways of gravitational-wave sources. more...

Gravitational-wave (GW) detectors are observing compact object mergers from increasingly far distances, revealing the redshift evolution of the binary black hole (BBH)—and soon the black hole–neutron star (BHNS) and binary neutron star (BNS)—merger rate. To help interpret these observations, we investigate the expected redshift evolution of the compact object merger rate from the isolated binary evolution channel. We present a publicly available catalog of compact object mergers and their accompanying cosmological merger rates from population synthesis simulations conducted with the COMPAS software. To explore the impact of uncertainties in stellar and binary evolution, our simulations use two-parameter grids of binary evolution models that vary the common-envelope efficiency with mass transfer accretion efficiency and supernova (SN) remnant mass prescription with SN natal kick velocity, respectively. We quantify the redshift evolution of our simulated merger rates using the local ( z ∼ 0) rate, the redshift at which the merger rate peaks, and the normalized differential rates (as a proxy for slope). We find that although the local rates span a range of ∼10 ^3 across our model variations, their redshift evolutions are remarkably similar for BBHs, BHNSs, and BNSs, with differentials typically within a factor 3 and peaks of z ≈ 1.2–2.4 across models. Furthermore, several trends in our simulated rates are correlated with the model parameters we explore. We conclude that future observations of the redshift evolution of the compact object merger rate can help constrain binary models for stellar evolution and GW formation channels. more...

BACKGROUND:First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first line fluoropyrimidine containing systemic therapy in patients with mCRC. METHODS:MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC. RESULTS:Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts. CONCLUSION:A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored. more...

Purpose of Review: To review the role of innate immune cells in shaping the viral reservoir and maintenance of long-term viral control of spontaneous Elite and Viremic HIV controllers. Recent Findings: HIV controllers exhibit a smaller and transcriptionally suppressed viral reservoir. Different studies report that early responses from innate cells play a pivotal role in this reservoir configuration. NK cells, particularly those with cytotoxic activity and polyfunctional monocytes, have been linked to viral control, and DCs may contribute through early viral sensing and activation of adaptive responses. In some cases, cytotoxic NK cells appeared before HIV-specific CD8 + T cells, underscoring their importance in early viral suppression. Summary: Innate immune cells, including NK cells, monocytes, DCs, and γδ T-cells, are crucial in shaping the viral reservoir in HIV controllers. Early, robust innate responses may help to maintain long-term viral suppression and offer insights into potential therapeutic approaches. [ABSTRACT FROM AUTHOR] more...

Abstract Background Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. Methods Pregnant Sprague–Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. Results Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. Conclusions Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring. Graphical Abstract more...

Population inference of gravitational-wave catalogues is a useful tool to translate observations of black hole mergers into constraints on compact-binary formation. Different formation channels predict identifiable signatures in the astrophysical distributions of source parameters, such as masses and spins. One example within the scenario of isolated binary evolution is mass-ratio reversal: even assuming efficient core–envelope coupling in massive stars and tidal spin-up of the stellar companion by the first-born black hole, a compact binary with a lighter, non-spinning first-born black hole and a heavier, spinning second-born black hole can still form through mass transfer from the initially more to less massive progenitor. Using current LIGO/Virgo observations, we measure the fraction of sources in the underlying population with this mass–spin combination and interpret it as a constraint on the occurrence of mass-ratio reversal in massive binary stars. We modify commonly used population models by including negligible-spin subpopulations and, most crucially, non-identical component spin distributions. We do not find evidence for subpopulations of black holes with negligible spins and measure the fraction of massive binary stars undergoing mass-ratio reversal to be consistent with zero and |$\lt 32{{\ \rm per\ cent}}$| (⁠|$99{{\ \rm per\ cent}}$| confidence). The dimensionless spin peaks around 0.2–0.3 appear robust, however, and are yet to be explained by progenitor formation scenarios. [ABSTRACT FROM AUTHOR] more...

Making the most of the rapidly increasing population of gravitational-wave detections of black hole (BH) and neutron star (NS) mergers requires comparing observations with population synthesis predictions. In this work, we investigate the combined impact from the key uncertainties in population synthesis modelling of the isolated binary evolution channel: the physical processes in massive binary-star evolution and the star formation history as a function of metallicity, Z , and redshift z , |$\mathcal {S}(Z,z)$|⁠. Considering these uncertainties, we create 560 different publicly available model realizations and calculate the rate and distribution characteristics of detectable BHBH, BHNS, and NSNS mergers. We find that our stellar evolution and |$\mathcal {S}(Z,z)$| variations can combined impact the predicted intrinsic and detectable merger rates by factors in the range 102–104. We find that BHBH rates are dominantly impacted by |$\mathcal {S}(Z,z)$| variations, NSNS rates by stellar evolution variations and BHNS rates by both. We then consider the combined impact from all uncertainties considered in this work on the detectable mass distribution shapes (chirp mass, individual masses, and mass ratio). We find that the BHNS mass distributions are predominantly impacted by massive binary-star evolution changes. For BHBH and NSNS, we find that both uncertainties are important. We also find that the shape of the delay time and birth metallicity distributions are typically dominated by the choice of |$\mathcal {S}(Z,z)$| for BHBH, BHNS, and NSNS. We identify several examples of robust features in the mass distributions predicted by all 560 models, such that we expect more than 95 per cent of BHBH detections to contain a BH |$\gtrsim 8\, \rm {M}_{\odot }$| and have mass ratios ≲ 4. Our work demonstrates that it is essential to consider a wide range of allowed models to study double compact object merger rates and properties. Conversely, larger observed samples could allow us to decipher currently unconstrained stages of stellar and binary evolution. [ABSTRACT FROM AUTHOR] more...

Gravitational-wave detections are enabling measurements of the rate of coalescences of binaries composed of two compact objects—neutron stars and/or black holes. The coalescence rate of binaries containing neutron stars is further constrained by electromagnetic observations, including Galactic radio binary pulsars and short gamma-ray bursts. Meanwhile, increasingly sophisticated models of compact objects merging through a variety of evolutionary channels produce a range of theoretically predicted rates. Rapid improvements in instrument sensitivity, along with plans for new and improved surveys, make this an opportune time to summarise the existing observational and theoretical knowledge of compact-binary coalescence rates. [ABSTRACT FROM AUTHOR] more...

Abstract Background Noonan syndrome spectrum disorders (NSSDs) constitute a group within the Rasopathies, and are one of the largest groups of syndromes with impact on multi-organ involvement known. The extreme variability of the clinical phenotype is, among others, due to the numerous different genes that are involved, and the differences in clinical presentation over the life span. We have studied the needs of patients and their relatives aiming to develop, evaluate and choose focus in research, medical care and policy to better meet their perspectives. Methods Using the participatory and interactive Dialogue method, 80 patients and relatives mentioned 53 different problems or needs (topics) that were categorized into eight themes. These themes and the topics within each theme, were subsequently prioritized by putting them in order of importance methodologically. Results The four highest prioritized themes were: (1) Physical problems (non-musculoskeletal related); (2) Social, emotional and behavioral problems; (3) Cognitive functioning and information processing; and (4) Problems related to the musculoskeletal system. Nineteen out of the 53 topics were physical problems. According to the total group of respondents, the top 3 prioritized topics within theme 1 were coagulation problems, heart problems, and feeding problems. Also data stratified by age groups, phenotype (NS and other NSSDs) and gender showed some remarkable results. For instance, feeding problems were prioritized as the most important topic of the highest prioritized theme, according to patients aged 0–12 years. Also feeding problems show a significant difference in its prioritization according to female patients (2) compared to male patients (7). On the other hand, heart problems were not mentioned in the top three prioritized topics in the youngest age groups, although heart problems are generally considered most important for patients with NSSD. Conclusions With our results we underline the importance of methodologically inventorying the needs of NSSD patients, not only at the group level, but to also focus on specific needs according to e.g. age, phenotype and gender. For instance, it is remarkable that both the current Clinical Guidelines and the Noonan Syndrome diagnostic criteria give little to no attention to feeding problems, though our results indicate that, to the youngest patients, these problems have top priority. A similar situation appears to apply to the clinical management of e.g. coagulation, neuropsychological and musculoskeletal problems (like physiotherapy or occupational therapy) and to a need for (educational) tools to support patients at school or at work. Our study may help to shape targeted (clinical) management, research and policy inside and outside medical (research) institutes and shed light on the complex phenotypes of NSSDs, the families’ and patients’ perspectives on the everyday consequences of the many different problems, as well as their needs. more...

Novae are some of the most commonly detected optical transients and have the potential to provide valuable information about binary evolution. Binary population synthesis codes have emerged as the most effective tool for modelling populations of binary systems, but such codes have traditionally employed greatly simplified nova physics, precluding detailed study. In this work, we implement a model treating H and He novae as individual events into the binary population synthesis code binary_c. This treatment of novae represents a significant improvement on the 'averaging' treatment currently employed in modern population synthesis codes. We discuss the evolutionary pathways leading to these phenomena and present nova event rates and distributions of several important physical parameters. Most novae are produced on massive white dwarfs, with approximately 70 and 55 per cent of nova events occurring on O/Ne white dwarfs for H and He novae, respectively. Only 15 per cent of H-nova systems undergo a common-envelope phase, but these systems are responsible for the majority of H nova events. All He-accreting He-nova systems are considered post-common-envelope systems, and almost all will merge with their donor star in a gravitational-wave-driven inspiral. We estimate the current annual rate of novae in M31 (Andromeda) to be approximately 41 ± 4 for H novae, underpredicting the current observational estimate of |$65^{+15}_{-16}$|⁠ , and 0.14 ± 0.015 for He novae. When varying common-envelope parameters, the H nova rate varies between 20 and 80 events per year. [ABSTRACT FROM AUTHOR] more...

This study examined the utility of the recently published MMSE-2:SV in detecting cognitive impairment. We used receiver operating characteristics to test the discriminative power of the MMSE-2:SV for distinguishing between older adults without mild cognitive impairment (MCI) or dementia (n=67) and patients with MCI (n=76) or dementia (n=79). The results show that the MMSE-2:SV had excellent discriminative ability in distinguishing older controls from patients with dementia, with cut-off scores of 26 and 27 (max=30) yielding appropriate sensitivity (0.810 and 0.924, respectively) and specificity (0.940 and 0.806). Discriminative power was close to good in distinguishing between older controls and patients with MCI. Here, however, no optimal cut-off point could be determined. Even though this study shows good sensitivity and adequate specificity for the MMSE-2:SV in discriminating individuals without MCI or dementia from those with dementia, its validity is limited for identifying patients with MCI. [ABSTRACT FROM AUTHOR] more...

Gravitational-wave observations of double compact object (DCO) mergers are providing new insights into the physics of massive stars and the evolution of binary systems. Making the most of expected near-future observations for understanding stellar physics will rely on comparisons with binary population synthesis models. However, the vast majority of simulated binaries never produce DCOs, which makes calculating such populations computationally inefficient. We present an importance sampling algorithm, stroopwafel , that improves the computational efficiency of population studies of rare events, by focusing the simulation around regions of the initial parameter space found to produce outputs of interest. We implement the algorithm in the binary population synthesis code compas , and compare the efficiency of our implementation to the standard method of Monte Carlo sampling from the birth probability distributions. stroopwafel finds ∼25–200 times more DCO mergers than the standard sampling method with the same simulation size, and so speeds up simulations by up to two orders of magnitude. Finding more DCO mergers automatically maps the parameter space with far higher resolution than when using the traditional sampling. This increase in efficiency also leads to a decrease of a factor of ∼3–10 in statistical sampling uncertainty for the predictions from the simulations. This is particularly notable for the distribution functions of observable quantities such as the black hole and neutron star chirp mass distribution, including in the tails of the distribution functions where predictions using standard sampling can be dominated by sampling noise. [ABSTRACT FROM AUTHOR] more...

We investigate the impact of uncertainty in the metallicity-specific star formation rate over cosmic time on predictions of the rates and masses of double compact object mergers observable through gravitational waves. We find that this uncertainty can change the predicted detectable merger rate by more than an order of magnitude, comparable to contributions from uncertain physical assumptions regarding binary evolution, such as mass transfer efficiency or supernova kicks. We statistically compare the results produced by the COMPAS population synthesis suite against a catalogue of gravitational-wave detections from the first two Advanced LIGO and Virgo observing runs. We find that the rate and chirp mass of observed binary black hole mergers can be well matched under our default evolutionary model with a star formation metallicity spread of 0.39 dex around a mean metallicity 〈 Z 〉 that scales with redshift z as 〈 Z 〉 = 0.035 × 10−0.23 z , assuming a star formation rate of |$0.01 \times (1+z)^{2.77} / (1+((1+z)/2.9)^{4.7}) \, \rm {M}_\odot$|  Mpc−3 yr−1. Intriguingly, this default model predicts that 80 per cent of the approximately one binary black hole merger per day that will be detectable at design sensitivity will have formed through isolated binary evolution with only dynamically stable mass transfer, i.e. without experiencing a common-envelope event. [ABSTRACT FROM AUTHOR] more...

Advanced maternal age (≥35 years) is associated with an increased risk of pregnancy complications such as fetal growth restriction and preeclampsia. We previously demonstrated poor pregnancy outcomes (reduced fetal body weight), altered vascular function, and increased expression of endoplasmic reticulum (ER) stress markers (phospho-eIF2α and CHOP) in mesenteric arteries from a rat model of advanced maternal age. Further, treatment of aged dams during pregnancy with an ER stress inhibitor, tauroursodeoxycholic acid (TUDCA) increased fetal body weight (both male and female), tended to improve uterine artery function, and reduced expression of phospho-eIF2α and CHOP in systemic arteries. Placental ER stress has been linked to poor pregnancy outcomes in complicated pregnancies but whether placental ER stress is evident in advanced maternal age is not known. In addition, sex-specific changes in the placental labyrinth and junctional zones from male and female offspring in advanced maternal age have not been investigated. Therefore, the current study aimed to investigate the effect of TUDCA intervention on placental ER stress. We hypothesize that placental ER stress is increased in a rat model of advanced maternal age that is alleviated by TUDCA intervention for both sexes. Placental ER stress markers (GRP78, phospho-eIF2α, ATF-4, CHOP, ATF-6α, and sXBP-1) were quantified by Western blot in placentas from male and female offspring; the labyrinth and junction zones were analyzed separately. In the placental labyrinth zone from male offspring, only GRP78 (p = 0.007) was increased in aged dams compared to young dams; TUDCA treatment reduced the placental expression of GRP78 in aged dams (p = 0.003). In addition, TUDCA reduced the levels of phospho-eIF2α (p = 0.021), ATF-4 (p = 0.016), and CHOP (p = 0.012) in aged dams but no effect was observed in young TUDCA-treated dams. In the placental labyrinth zone from female offspring, an increased level of phospho-eIF2α (p = 0.005) was observed in aged dams compared to young dams, and TUDCA treatment had no effect in both young and aged groups. In the placental junctional zone from male and female offspring, no changes in the expression of GRP78, phospho-eIF2α, ATF-4, CHOP, and ATF-6α was observed with or without TUDCA treatment in both young and aged groups, however, a reduced expression of sXBP-1 protein was observed in from both male (p = 0.001) and female (p = 0.031) placentas from aged-TUDCA treated dams compared to aged control. In conclusion, our data highlight the complexity and sex-specificity of ER stress responses in advanced maternal age with TUDCA treatment maintaining ER stress proteins to basal levels and improving fetal growth in both male and female offspring. more...

Background: First line chemotherapy is effective in 75 to 80% of patients with metastatic colorectal cancer (mCRC). We studied whether microRNA (miR) expression profiles can predict treatment outcome for first line fluoropyrimidine containing systemic therapy in patients with mCRC. Methods: MiR expression levels were determined by next generation sequencing from snap frozen tumor samples of 88 patients with mCRC. Predictive miRs were selected with penalized logistic regression and posterior forward selection. The prediction co-efficients of the miRs were re-estimated and validated by real-time quantitative PCR in an independent cohort of 81 patients with mCRC. Results: Expression levels of miR-17-5p, miR-20a-5p, miR-30a-5p, miR-92a-3p, miR-92b-3p and miR-98-5p in combination with age, tumor differentiation, adjuvant therapy and type of systemic treatment, were predictive for clinical benefit in the training cohort with an AUC of 0.78. In the validation cohort the addition of the six miR signature to the four clinicopathological factors demonstrated a significant increased AUC for predicting treatment response versus those with stable disease (SD) from 0.79 to 0.90. The increase for predicting treatment response versus progressive disease (PD) and for patients with SD versus those with PD was not significant. in the validation cohort. MiR-17-5p, miR-20a-5p and miR-92a-3p were significantly upregulated in patients with treatment response in both the training and validation cohorts. Conclusion: A six miR expression signature was identified that predicted treatment response to fluoropyrimidine containing first line systemic treatment in patients with mCRC when combined with four clinicopathological factors. Independent validation demonstrated added predictive value of this miR-signature for predicting treatment response versus SD. However, added predicted value for separating patients with PD could not be validated. The clinical relevance of the identified miRs for predicting treatment response has to be further explored. [ABSTRACT FROM AUTHOR] more...

BackgroundThe full potential of eHealth technologies to support self-management and disease management for patients with chronic diseases is not being reached. A possible explanation for these lacking results is that during the development process, insufficient attention is paid to the needs, wishes, and context of the prospective end users. To overcome such issues, the user-centered design practice of creating personas is widely accepted to ensure the fit between a technology and the target group or end users throughout all phases of development. ObjectiveIn this study, we integrate several approaches to persona development into the Persona Approach Twente to attain a more holistic and structured approach that aligns with the iterative process of eHealth development. MethodsIn 3 steps, a secondary analysis was carried out on different parts of the data set using the Partitioning Around Medoids clustering method. First, we used health-related electronic patient record data only. Second, we added person-related data that were gathered through interviews and questionnaires. Third, we added log data. ResultsIn the first step, 2 clusters were found, with average silhouette widths of 0.12 and 0.27. In the second step, again 2 clusters were found, with average silhouette widths of 0.08 and 0.12. In the third step, 3 clusters were identified, with average silhouette widths of 0.09, 0.12, and 0.04. ConclusionsThe Persona Approach Twente is applicable for mixed types of data and allows alignment of this user-centered design method to the iterative approach of eHealth development. A variety of characteristics can be used that stretches beyond (standardized) medical and demographic measurements. Challenges lie in data quality and fitness for (quantitative) clustering. more...

Abstract Background Personal health records (PHRs) provide the opportunity for self-management support, enhancing communication between patients and caregivers, and maintaining and/or improving the quality of chronic disease management. Their implementation is a multi-level and complex process, requiring a holistic approach that takes into account the technology, its users and the context of implementation. The aim of this research is to evaluate the fidelity of a PHR in chronic care (the degree to which it was implemented as intended) in order to explain the found effects. Methods A convergent parallel mixed methods design was used, where qualitative and quantitative data were collected in parallel, analyzed separately, and finally merged. Log data of 536 users were used to gain insight into the actual long-term use of the PHR (the dose). Focus group meetings among caregivers (n = 13) were conducted to assess program differentiation (or intended use). Interviews with caregivers (n = 28) and usability tests with potential end-users (n = 13) of the PHR were used to understand the responsiveness and the differences and similarities between the intended and actual use of the PHR. Results The results of the focus groups showed that services for coaching are strongly associated with monitoring health values and education. However, the PHR was not used that way during the study period. In the interviews, caregivers indicated that they were ignorant on how to deploy the PHR in current working routines. Therefore, they find it difficult to motivate their patients in using the PHR. Participants in the usability study indicate that they would value a PHR in the future, given that the usability will be improved and that the caregivers will use it in daily practice as well. Conclusions In this study, actual use of the PHRs by patients was influenced by the responsiveness of caregivers. This responsiveness is likely to be strongly influenced by the perceived support when defining the differentiation and delivery of the PHR. A mixed-methods approach to understand intervention fidelity was of added value in providing explanations for the found effects that could not be revealed by solely focusing on the effectiveness of the technology in an experimental trial. more...

Prenatal hypoxia predisposes the offspring to the development of cardiovascular (CV) dysfunction in adult life. Using a rat model, we assessed the effect of prenatal hypoxia on vasoconstrictive and vasodilative mechanisms in left anterior descending coronary arteries of 4- and 9.5-month-old offspring. Endothelium-dependent relaxation to methylcholine and vasoconstriction responses to endothelin-1 (ET-1) were assessed by wire myography. Prenatal hypoxia impaired endothelium-dependent vasodilation in 4- and 9.5-month-old offspring. Inhibition of nitric oxide (NO) synthase prevented coronary artery relaxation in all groups. Inhibition of prostaglandin H synthase (PGHS) improved relaxation in prenatally hypoxic males and tended to improve vasorelaxation in females, suggesting that impaired vasodilation was mediated via increased PGHS-dependent vasoconstriction. An enhanced contribution of endothelium-dependent hyperpolarization to coronary artery vasodilation was observed in prenatally hypoxic males and females. No changes in endothelial NO synthase (eNOS) and PGHS-1 expressions were observed, while PGHS-2 expression was decreased in only prenatally hypoxic males. At 4 months, ET-1 responses were similar between groups, while ETB inhibition (with BQ788) tended to decrease ET-1-mediated responses in only prenatally hypoxic females. At 9.5 months, ET-1-mediated responses were decreased in only prenatally hypoxic females. Our data suggest that prenatal hypoxia has long-term similar effects on the mechanisms of impaired endothelium-dependent vasodilation in coronary arteries from adult male and female offspring; however, coronary artery contractile capacity is impaired only in prenatally hypoxic females. Understanding the mechanistic pathways involved in the programming of CV disease may allow for the development of therapeutic interventions. more...

Advanced maternal age (≥35 years old) increases the risk of pregnancy complications such as preeclampsia and fetal growth restriction. We previously demonstrated vascular dysfunction and abnormal pregnancy outcomes in a rat model of advanced maternal age. However, vascular adaptations to pregnancy in aging were not studied. We hypothesize that advanced maternal age is associated with a more vasoconstrictive phenotype due to reduced nitric oxide (NO) and increased activity of matrix metalloproteinases (MMPs), contributing to impaired vascular adaptations to pregnancy. A rat model of advanced maternal age was used: young (4 months) and aged (9.5 months; ∼35 years in humans) non-pregnant and pregnant rats. On gestational day 20 (term = 22 days; non-pregnant rats were aged-matched), blood pressure and heart rate were measured (tail cuff plethysmography) and vascular function was assessed in mesenteric arteries (wire myography). Endothelium-dependent relaxation to methylcholine (MCh) was assessed in the presence/absence of nitric oxide synthase inhibitor (L-NAME), or inhibitors of endothelium-dependent hyperpolarization (EDH; apamin and TRAM-34). Vasoconstriction responses to big endothelin-1 (bigET-1), in the presence/absence of MMPs-inhibitor (GM6001) or endothelin converting enzyme (ECE-1) inhibitor (CGS35066), in addition, ET-1 responsiveness, were measured. Blood pressure was elevated only in aged non-pregnant rats (p < 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (p < 0.01) and aged pregnant rats (p < 0.001), and decreased MCh sensitivity in young non-pregnant rats (p < 0.01), without effects in aged non-pregnant rats. EDH contribution to relaxation was similar in young non-pregnant, and aged non-pregnant and pregnant rats, while EDH-mediated relaxation was absent in young pregnant rats (p < 0.001). BigET-1 responses were enhanced in aged non-pregnant (p < 0.01) and pregnant rats (p < 0.05). No significant changes in bigET-1 conversion occurred in the presence of MMP-inhibitor, whereas ECE-1 inhibition reduced bigET-1 constriction in aged rats (p < 0.01). No differences in ET-1 sensitivity were observed. In conclusion, contrary to our hypothesis, reduced blood pressure, and an increased EDH-dependent contribution to vasodilation suggest a compensatory mechanism that may reflect beneficial adaptations in these aged rats that were able to maintain pregnancy. These data increase our understanding of how the vascular adaptive pathways in pregnancy compensate for advanced maternal age. more...

Subtraction errors can inform teachers about students’ mathematical reasoning. Not every subtraction error is informative, it’s implications for students’ mathematical reasoning depends on the item characteristics. Diagnostic items are specifically designed to elicit specific subtraction errors. This study evaluated how the diagnostic capacity of subtraction items is related to their characteristics. The item characteristics being studied are open-ended and multiple-choice (MC) items, bare number, and word problems. As well as various number features, such as the number of digits in the subtrahend and minuend. Diagnostic capacity is defined as the extent to which multi-digit subtraction items that require borrowing (e.g., 1000−680) elicit bridging errors, such as the smaller-from-larger-error. Item response theory (IRT) was used to estimate item properties. Subsequently, the item properties were used in two separate ANOVA analyses to compare the diagnostic capacity of MC versus open-ended items, bare number versus word problems, and number features. As expected, MC items have a higher diagnostic capacity than open-ended items. More interestingly, it was found that the number of digits in the subtrahend and minuend influenced the diagnostic capacity of the items. Items characterized as 3/4n−3n, like 1000−680 had the highest diagnostic capacity, whereas items characterized as 3/4n−2n, such as 1000−20 had the lowest diagnostic capacity. The discussion focuses on the implications of this study for further research into the design of diagnostic items. more...

Whereas, past research has shown that using environmental arguments to reduce meat intake are unsuccessful in awareness campaigns, popular documentaries might have the potential to successfully change the public awareness of the environmental implications of meat consumption today. This preliminary study aimed to provide first empirical evidence of the potential effects of watching a popular documentary on a less-known environmental topic among a population that are habitual performers of the behavior under discussion. More precisely, the effects of watching “Cowspiracy: The Sustainability Secret” on the awareness of the environmental implications of meat consumption, the attitude toward eating less meat, and the intention to eat less meat in young adults who consume meat on an (almost) daily basis was studied. The potential impact of Cowspiracy was investigated from the Integrated Change Model perspective. Paper-and-pencil questionnaires were administered to N = 47 participants aged between 19 and 32 before and after watching either Cowspiracy (experimental group, n = 26) or Planet Earth (control group, n = 21). Controlling for the influence of predisposing factors (sociodemographic characteristics gender, age, and socioeconomic status), the results show that watching a popular documentary about the environmental impact of meat production (Cowspiracy) can have a significant effect on the awareness of the environmental consequences of meat consumption, the attitude toward eating less meat, and the intention to reduce meat consumption of young (almost) daily meat eaters. However, results should be interpreted with caution, given the preliminary nature of our study. more...

Advanced maternal age (≥35 years) increases the risk of vascular complications in pregnancy that can result in fetal growth restriction and preeclampsia. Endoplasmic reticulum (ER) stress has been linked to adverse pregnancy outcomes in these complicated pregnancies. However, the role of ER stress in advanced maternal age is not known. We hypothesize that increased ER stress contributes to altered vascular function and poor pregnancy outcomes, and that treatment with the ER-stress inhibitor TUDCA will improve pregnancy outcomes. First, young and aged non-pregnant/pregnant rats were used to assess ER stress markers in mesenteric arteries; mesenteric artery phospho-eIF2α and CHOP expression were increased in aged dams compared to young dams. In a second study, young and aged control and TUDCA-treated dams were studied on gestational day (GD) 20 (term = 22 days). TUDCA treatment was provided via the drinking water throughout pregnancy (GD0-GD20; calculated dose of 150 mg/kg/day TUDCA). ER stress markers were quantified in mesenteric arteries, blood pressure was measured, pregnancy outcomes were recorded, mesenteric and main uterine arteries were isolated and vascular function was assessed by wire myography. Aged dams had increased phospho-eIF2α and CHOP expression, reduced fetal weight, reduced litter size, and impaired uterine artery relaxation. In the aged dams, TUDCA treatment reduced phospho-eIF2α and CHOP expression, reduced blood pressure, improved fetal body weight, and tended to improve uterine artery function compared to control-treated aged dams. In conclusion, our data illustrate the role of ER stress, as well as TUDCA as a potential therapeutic that may benefit pregnancy outcomes in advanced maternal age. more...

Objective To pilot a three-step diagnostic model for young and old patients with Parkinson's disease dementia (PDD). Methods Prospective investigator-blinded study. We developed a screening questionnaire for patients with Parkinson's disease (PD) and their caregivers. Further, patients were subjected to three screening instruments (Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Addenbrooke's Cognitive Examination-revised (ACE-R) and a detailed neuropsychological examination (NPE). Based on the NPE, patients were divided in a PD (without dementia) and a PDD-group. Results Forty-one PD patients, aged 37–94 years, participated in this study. Patients were divided in a young group, ≤65 (n = 22) and an old group >65 years (n = 19). In the young group (PDD, n = 5) the patient-screening questionnaire predicted PDD with a sensitivity/specificity of 100.0%/94.1%; in the old group (PDD, n = 10) the proxy-screening questionnaire predicted PDD with a sensitivity/specificity of 88.9%/66.7%. In the young group, ACE-R had the largest Area Under the Curve (AUC) 0.88 (0.70–1.00), in the old group MoCA (AUC 1.00). However, the three instruments did not differ significantly. Conclusions It seems feasible and efficient to use three consecutive diagnostic steps for PDD: (1) a screening questionnaire, (2) if positive: MoCA, FAB or ACE-R as screening instrument and (3) if positive: a detailed NPE for diagnosing PDD. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR] more...

Pregnancy complications associated with chronic fetal hypoxia have been linked to the development of adult cardiovascular disease in the offspring. Prenatal hypoxia has been shown to increase placental oxidative stress and impair placental function in a sex-specific manner, thereby affecting fetal development. As oxidative stress is central to placental dysfunction, we developed a placenta-targeted treatment strategy using the antioxidant MitoQ encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative/nitrosative stress and improve placental function without direct drug exposure to the fetus in order to avoid off-target effects during development. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ prevents hypoxia-induced placental oxidative/nitrosative stress, promotes angiogenesis, improves placental morphology, and ultimately improves fetal oxygenation. Additionally, we assessed whether there were sex differences in the effectiveness of nMitoQ treatment. Pregnant rats were intravenously injected with saline or nMitoQ (100 μl of 125 μM) on gestational day (GD) 15 and exposed to either normoxia (21% O2) or hypoxia (11% O2) from GD15 to 21. On GD21, placentae from both sexes were collected for detection of superoxide, nitrotyrosine, nitric oxide, CD31 (endothelial cell marker), and fetal blood spaces, Vegfa and Igf2 mRNA expression in the placental labyrinth zone. Prenatal hypoxia decreased male fetal weight, which was not changed by nMitoQ treatment; however, placental efficiency (fetal/placental weight ratio) decreased by hypoxia and was increased by nMitoQ in both males and females. nMitoQ treatment reduced the prenatal hypoxia-induced increase in placental superoxide levels in both male and female placentae but improved oxygenation in only female placentae. Nitrotyrosine levels were increased in hypoxic female placentae and were reduced by nMitoQ. Prenatal hypoxia reduced placental Vegfa and Igf2 expression in both sexes, while nMitoQ increased Vegfa and Igf2 expression only in hypoxic female placentae. In summary, our study suggests that nMitoQ treatment could be pursued as a potential preventative strategy against placental oxidative stress and programming of adult cardiovascular disease in offspring exposed to hypoxia in utero. However, sex differences need to be taken into account when developing therapeutic strategies to improve fetal development in complicated pregnancies, as nMitoQ treatment was more effective in placentae from females than males. more...

Syncytiotrophoblast extracellular vesicles (STBEVs) are placenta derived particles that are released into the maternal circulation during pregnancy. Abnormal levels of STBEVs have been proposed to affect maternal vascular function. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multi-ligand scavenger receptor. Increased LOX-1 expression and activation has been proposed to contribute to endothelial dysfunction. As LOX-1 has various ligands, we hypothesized that, being essentially packages of lipoproteins, STBEVs are able to activate the LOX-1 receptor thereby impairing vascular function via the production of superoxide and decreased nitric oxide bioavailability. Uterine arteries were obtained in late gestation from Sprague-Dawley rats and incubated for 24h with or without human STBEVs (derived from a normal pregnant placenta) in the absence or presence of a LOX-1 blocking antibody. Vascular function was assessed using wire myography. Endothelium-dependent maximal vasodilation to methylcholine was impaired by STBEVs (MCh Emax: 57.7±5.9% in STBEV-incubated arteries vs. 77.8±2.9% in controls, p more...

Machine learning techniques are increasingly being applied to clinical text that is already captured in the Electronic Health Record for the sake of delivering quality care. Applications for example include predicting patient outcomes, assessing risks, or performing diagnosis. In the past, good results have been obtained using classical techniques, such as bag-of-words features, in combination with statistical models. Recently however Deep Learning techniques, such as Word Embeddings and Recurrent Neural Networks, have shown to possibly have even greater potential. In this work, we apply several Deep Learning and classical machine learning techniques to the task of predicting violence incidents during psychiatric admission using clinical text that is already registered at the start of admission. For this purpose, we use a novel and previously unexplored dataset from the Psychiatry Department of the University Medical Center Utrecht in The Netherlands. Results show that predicting violence incidents with state-of-the-art performance is possible, and that using Deep Learning techniques provides a relatively small but consistent improvement in performance. We finally discuss the potential implication of our findings for the psychiatric practice. more...

INTRODUCTION: Both nonclassical and intermediate monocytes have been implicated in different inflammatory conditions. We hypothesized that these monocytes would increase during pregnancy, a condition associated with generalized activation of inflammatory responses and that they would increase even more during preeclampsia, in which inflammatory responses are further stimulated. In the present study we investigated changes in monocyte subsets during healthy pregnancy and preeclampsia in humans and rats. METHODS: Blood monocyte subsets of nonpregnant, preeclamptic and healthy pregnant women were identified with CD14 and CD16. In nonpregnant and pregnant rats, blood monocytes were identified with CD172a and CD43, as well as in rats infused with adenosine triphosphate (ATP), a pro-inflammatory stimulus known to induce preeclampsia-like symptoms. Total and CD206-positive macrophages were quantified in placentas of these animals. RESULTS: Lower percentages of classical monocytes were found in pregnant women (91%-[83-98%]) compared to nonpregnant women (94%-[90-98%]) and even less in preeclamptic patients (90%-[61-92%]). In contrast, the percentage of combined nonclassical/intermediate monocytes was higher in pregnant women (8.5%-[2.3-16.6%] vs. 5.6%-[1.9-9.5%]) and even higher in preeclamptic patients (9.9%-[7.8-38.7%]), which was caused by a selective increase of intermediate monocytes. In rats, we also found lower percentages of classical monocytes and higher percentages of nonclassical monocytes in pregnant versus nonpregnant rats. ATP infusion increased the percentage of nonclassical monocytes in pregnant rats even further but not in nonpregnant rats. These nonclassical monocytes showed a more activated phenotype in pregnant ATP-infused rats only. Mesometrial triangles of ATP-infused rats had less CD206-positive macrophages as compared to those of saline-infused rats. CONCLUSION: The higher percentage of nonclassical/intermediate monocytes found in pregnancy and preeclampsia confirms their association with inflammatory responses. The observation that ATP stimulated numbers/activation of nonclassical monocytes in pregnant rats only, suggests that nonclassical monocytes are specifically altered in pregnancy and may play a role in the pathophysiology of preeclampsia. more...