Using blastocyst re-expansion rate for deciding when to warm a new blastocyst for single vitrified-warmed blastocyst transfer.

RESEARCH QUESTION: Can predictive post-warm parameters that support the decision to transfer a warmed blastocyst or to warm another blastocyst be identified in women with multiple frozen-vitrified blastocysts? DESIGN: Retrospective single-centre observational cohort analysis. A total of 1092 single vitrified-warmed blastocyst transfers (SVBT) with known Gardner score, maternal age and live birth were used to develop live birth prediction models based on logistic regression, including post-warm re-expansion parameters. Time-lapse incubation was used for pre-vitrification and post-warm embryo culture. A dataset of 558 SVBT with the same inclusion criteria was used to validate the model, but with known clinical pregnancy outcome instead of live birth outcome. RESULTS: Three different logistic regression models were developed for predicting live birth based on post-warm blastocyst re-expansion. Different post-warm assessment times indicated that a 2-h post-warm culture period was optimal for live birth prediction (model 1). Adjusting for pre-vitrification Gardner score (model 2) and in combination with maternal age (model 3) further increased predictability (area under the curve [AUC] = 0.623, 0.633, 0.666, respectively). Model validation gave an AUC of 0.617, 0.609 and 0.624, respectively. The false negative rate and true negative rate for model 3 were 2.0 and 10.1 in the development dataset and 3.5 and 8.0 in the validation dataset. CONCLUSIONS: Clinical application of a simple model based on 2 h of post-warm re-expansion data, pre-vitrification Gardner score and maternal age can support a standardized approach for deciding if warming another blastocyst may increase the likelihood of live birth in SVBT.

Parental mental health, socioeconomic position and the risk of asthma in children-a nationwide Danish register study.

BACKGROUND: Parental mental illness affects child health. However, less is known about the impact of different severities of maternal depression and anxiety as well as other mental health conditions. The objective of this study was to examine the impact of different severities of maternal and paternal mental health conditions on child asthma. METHODS: This nationwide, register-based cohort study included all children in Denmark born from 2000 to 2014. Exposure was parental mental health conditions categorized in three severities: minor (treated at primary care settings), moderate (all ICD-10 F-diagnoses given at psychiatric hospital) and severe (diagnoses of severe mental illness). The children were followed from their third to sixth birthday. Child asthma was identified by prescribed medication and hospital-based diagnoses. Incidence rate ratios were calculated using negative binomial regression analyses. RESULTS: The analyses included 925 288 children; 26% of the mothers and 16% of the fathers were classified with a mental health condition. Exposed children were more likely to have asthma (10.6-12.0%) compared with unexposed children (8.5-9.0%). The three severities of mental health conditions of the mother and the father increased the risk of child asthma, most evident for maternal exposure. Additive interaction between maternal mental health conditions and disadvantaged socioeconomic position was found. CONCLUSION: We found an increased risk of asthma in exposed children, highest for maternal exposure. Not only moderate and severe, but also minor mental health conditions increased the risk of child asthma. The combination of mental health condition and disadvantaged socioeconomic position for mothers revealed a relative excess risk.

Six-year-old children had greater risks of functional gastrointestinal disorders if their parents had mental health conditions.

AIM: This study examined any associations between parents' mental health conditions and hospital diagnoses of functional gastrointestinal disorders (FGIDs) in offspring at the age of six. We also examined any associations between children who met these criteria and attended routine Danish preventive child health appointments. METHODS: Nationwide registers identified all children born in Denmark from 2000 to 2011 and parents' mental health conditions. Negative binomial regression analyses estimated the incidence rate ratios (IRRs) with 95% confidence intervals (CIs) of children receiving their first hospital diagnosis for an FGID at the age of six. RESULTS: We identified 750,379 children and 38% had at least one parent with a mental health condition: 24% were minor, 12% were moderate, and 2% were severe. These children faced a higher risk of an FGID diagnosis than children whose parents did not have mental health conditions. The IRRs were highest for maternal exposure: minor (1.35, 95% CI 1.29-1.42), moderate (1.58, 95% CI 1.48-1.67) and severe (1.58, 95% CI 1.38-1.81). Attending routine preventive child health examinations was associated with a higher risk of FGIDs associated with parents' mental health conditions. CONCLUSION: Paediatric FGIDs were associated with parents' mental health conditions, especially mothers, and attending routine preventive child health examinations.

Is Cardiac Rehabilitation Equally Effective in Improving Dietary Intake in All Patients with Ischemic Heart Disease?

OBJECTIVE: To investigate the association between sociodemographic characteristics and changes in dietary intake in patients with ischemic heart disease who were following a cardiac rehabilitation program. METHODS: Longitudinal study among patients with first-time admission to outpatient cardiac rehabilitation after ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina pectoris or stable angina pectoris. We used a validated self-administered food frequency questionnaire to assess the dietary intake before rehabilitation, post rehabilitation and 6 months after baseline. The intake was summarized into a fat and fish-fruit-vegetable score for both sexes. To assess the within-patient differences in dietary scores, a paired t-test was applied. Regression analyses were performed to assess the association between sociodemographic characteristics and changes in diet. RESULTS: 186 patients completed two measurements, 157 patients completed all three measurements. Fat and fish-fruit-vegetable scores increased statistically significantly and improvements remained statistically significant at follow-up. Fat scores increased less in employed men than in retired men (-11 (95% CI -17; -5)). Fish-fruit-vegetable scores increased less in men with a bachelor degree than in men with a vocational education (-8 (95% CI -13; -3)) as well as in retired women compared with employed women (-18 (95% CI -32; -4)). CONCLUSIONS: Patients statistically significantly improved their dietary intake and improvements remained at follow-up. Dietary improvements were sensitive to marital status, living arrangements and employment status. Unemployed and retired women did not seem to improve their diet as much as employed women. Additional dietary intervention may become relevant in some patient groups defined by sociodemographic characteristics. (250).

Regression models for interval censored data using parametric pseudo-observations.

BACKGROUND: Time-to-event data that is subject to interval censoring is common in the practice of medical research and versatile statistical methods for estimating associations in such settings have been limited. For right censored data, non-parametric pseudo-observations have been proposed as a basis for regression modeling with the possibility to use different association measures. In this article, we propose a method for calculating pseudo-observations for interval censored data. METHODS: We develop an extension of a recently developed set of parametric pseudo-observations based on a spline-based flexible parametric estimator. The inherent competing risk issue with an interval censored event of interest necessitates the use of an illness-death model, and we formulate our method within this framework. To evaluate the empirical properties of the proposed method, we perform a simulation study and calculate pseudo-observations based on our method as well as alternative approaches. We also present an analysis of a real dataset on patients with implantable cardioverter-defibrillators who are monitored for the occurrence of a particular type of device failures by routine follow-up examinations. In this dataset, we have information on exact event times as well as the interval censored data, so we can compare analyses of pseudo-observations based on the interval censored data to those obtained using the non-parametric pseudo-observations for right censored data. RESULTS: Our simulations show that the proposed method for calculating pseudo-observations provides unbiased estimates of the cumulative incidence function as well as associations with exposure variables with appropriate coverage probabilities. The analysis of the real dataset also suggests that our method provides estimates which are in agreement with estimates obtained from the right censored data. CONCLUSIONS: The proposed method for calculating pseudo-observations based on the flexible parametric approach provides a versatile solution to the specific challenges that arise with interval censored data. This solution allows regression modeling using a range of different association measures.

The risk of preterm birth in combinations of socioeconomic position and mental health conditions in different age groups: a Danish nationwide register-based cohort study.

BACKGROUND: Inequality in preterm birth is a world-wide challenge that has proved difficult for maternity care services to meet. Reducing the inequality requires identification of pregnant women at particularly high risk of preterm birth in order to target interventions. Therefore, the aim was to estimate the risk of preterm birth in women with different combinations of socioeconomic position, mental health conditions, and age. METHODS: In this nationwide register-based cohort study, we included all first-time mothers that gave birth to a singleton liveborn infant in Denmark between 2000 and 2016. The absolute and relative risk of preterm birth (< 37 weeks of gestation) was examined in different combinations of educational level (high, intermediate, and low) and mental health conditions (no, minor, and moderate/severe) in three age strata (≤23, 24-30, and ≥ 31 years). We estimated the relative risk using Poisson regression with a robust error variance. As additive interaction can help identify subgroups where limited resources can be of best use, we measured the attributable proportion to assess the risk that is due to interaction of the different exposures. RESULTS: Of the 415,523 included first-time mothers, 6.3% gave birth prematurely. The risk of preterm birth increased with decreasing educational level and increasing severity of mental health conditions in all age strata, but most in women aged ≥31 years. The highest absolute risk was 12.9% [95% CI: 11.2;14.8%] in women aged ≥31 years with low education and moderate/severe mental health conditions resulting in a relative risk of 2.23 [95% CI: 1.93-2.58] compared to the unexposed reference group in that age strata. We found positive additive interaction between low education and mental health conditions in women aged 24-30 and ≥ 31 years and between age ≥ 31 years and combinations of mental health conditions and educational levels. CONCLUSION: The inequality in preterm birth increased with increasing age. To reduce inequality in preterm birth focused attention on women with higher age further combined with lower educational levels and mental health conditions is essential.

Parental mental health conditions and use of healthcare services in children the first year of life- a register-based, nationwide study.

BACKGROUND: Parental mental health conditions have been associated with increased morbidity and use of healthcare services in offspring. Existing studies have not examined different severities of parental mental health conditions, and the impact of paternal mental health has been overlooked. We examined the association between two severities of parental mental health conditions and use of healthcare services for children during the first year of life and explored the impact of both maternal and paternal mental health conditions. METHODS: This register-based cohort study included all live-born children born in Denmark from 2000 to 2016. Information on socioeconomics, diagnoses, drug prescriptions, and healthcare contacts was extracted from nationwide public registries. Parents were grouped according to severity of mental condition based on the place of treatment of the mental health condition. Negative binominal regression analyses were performed to estimate the incidence rate ratio (IRR) of contacts to general practice (GP), out-of-hour medical service, emergency room (ER), and out- and inpatient hospital contacts during the first 12 months of the child's life. RESULTS: The analyses included 964,395 children. Twenty percent of the mothers and 12 % of the fathers were identified with mental health conditions. Paternal mental health conditions were independently associated with increased risk of infant healthcare contacts (GP IRR 1.05 (CI95% 1.04-1.06) and out-of-hour IRR 1.20 (CI95% 1.18-1.22)). Risks were higher for maternal mental health conditions (GP IRR 1.18 (CI95% 1.17-1.19) and out-of-hour IRR 1.39 (CI95% 1.37-1.41)). The risks were even higher if both parents were classified with a mental health condition (GP IRR 1.25 (CI95% 1.23-1.27) and out-of-hour contacts IRR 1.49 (CI95% 1.45-1.54)), including minor mental health condition (GP IRR 1.22 (CI95% 1.21-1.24) and out-of-hour IRR 1.37 (CI95% 1.34-1.41)). This pattern was the same for all types of healthcare contacts. CONCLUSIONS: Both maternal and paternal mental health conditions, including minor mental health conditions, were associated with increased utilization of healthcare services. Focus on both parents' mental health conditions (even if minor) may be warranted in service planning.

Machine Learning-Based Prediction of Brain Tissue Infarction in Patients With Acute Ischemic Stroke Treated With Theophylline as an Add-On to Thrombolytic Therapy: A Randomized Clinical Trial Subgroup Analysis.

Background and Purpose: The theophylline in acute ischemic stroke trial investigated the neuroprotective effect of theophylline as an add-on to thrombolytic therapy in patients with acute ischemic stroke. The aim of this pre-planned subgroup analysis was to use predictive modeling to virtually test for differences in the follow-up lesion volumes. Materials and Methods: A subgroup of 52 patients from the theophylline in acute ischemic stroke trial with multi-parametric MRI data acquired at baseline and at 24-h follow-up were analyzed. A machine learning model using voxel-by-voxel information from diffusion- and perfusion-weighted MRI and clinical parameters was used to predict the infarct volume for each individual patient and both treatment arms. After training of the two predictive models, two virtual lesion outcomes were available for each patient, one lesion predicted for theophylline treatment and one lesion predicted for placebo treatment. Results: The mean predicted volume of follow-up lesions was 11.4 ml (standard deviation 18.7) for patients virtually treated with theophylline and 11.2 ml (standard deviation 17.3) for patients virtually treated with placebo (p = 0.86). Conclusions: The predicted follow-up brain lesions for each patient were not significantly different for patients virtually treated with theophylline or placebo, as an add-on to thrombolytic therapy. Thus, this study confirmed the lack of neuroprotective effect of theophylline shown in the main clinical trial and is contrary to the results from preclinical stroke models.

Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma.

No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with Kaplan-Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients, 25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS) (4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazard rate (HR) of 3.48 (1.39-8.70). The validation cohort included 58 Gem-treated patients. Patients with phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). Adjusted Cox regression yielded an HR of 3.53 (1.85-6.74). In both cohorts, phSFRP1 was associated with poorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are more aggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment of patients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensive chemotherapy regimens.

Discontinuation of oral anticoagulation and risk of stroke and death after ablation for typical atrial flutter: A nation-wide Danish cohort study.

INTRODUCTION: Oral anticoagulation (OAC) is indicated for patients with atrial fibrillation (AF) and atrial flutter (AFL) with a CHA2DS2-VASc score ≥ 2 for men and ≥3 for women. This is regardless of successful catheter ablation for their arrhythmia. Studies have mainly focused on AF, and little is known regarding use of OAC in AFL patients following catheter ablation. PURPOSE: To describe discontinuation of OAC in a national cohort of patients who have undergone first-time cavo-tricuspid isthmus ablation (CTIA) for AFL. METHODS: We identified patients undergoing first-time CTIA during the period 2010-2016 using the Danish National Ablation Registry. Information on comorbidities and OAC use were gathered using the Danish National Patient Registry and the Danish National Prescription Registry. Patients were followed until March 1st, 2018. RESULTS: We identified 2409 consecutive patients. Median age was 66 (IQR 58-72) years, and 1952 (81%) were men. During mean follow-up of 4 ± 1.7 years, 723 (30%) patients discontinued OAC. Patients discontinuing OAC were younger, had less comorbidity, and a lower CHA2DS2-VASc score. During follow-up, 252 (10%) patients died, and 112 (5%) patients had a stroke. Incidence of both these events increased with increasing age and CHA2DS2-VASc score. In adjusted analysis, we observed higher mortality (p < 0.0001) in patients discontinuing OAC, while stroke rate was not significantly higher (p = 0.21). CONCLUSION: In this national cohort of patients who have undergone first-time CTIA, patients discontinuing OAC treatment were younger and had less comorbidities. Patients remain at elevated risk of death and stroke/TIA, increasing with their age and CHA2DS2-VASc score.

Level of Physical Activity, Left Ventricular Mass, Hypertension, and Prognosis.

Left ventricular hypertrophy is a strong predictor of prognosis in hypertension. Physical activity is associated with higher left ventricular mass but also reduced risk of cardiovascular outcomes. The aims were to explore whether (1) presence of hypertension modifies the association between physical activity and left ventricular mass; (2) the beneficial association between physical activity and prognostic outcome is modified by left ventricular hypertrophy. Randomly selected number of 3078 persons from the general population underwent echocardiogram. Left ventricular mass was indexed to body surface area. Level of physical activity was self-reported: inactivity, light activity, and moderate/high activity. Blood pressure was measured in rest: normal BP (<140/90 mm Hg) and hypertension (≥140/90 mm Hg or in pharmacological treatment for hypertension). Presence of hypertension modified the association between physical activity and left ventricular mass index significantly (test for interaction: P=0.01): in normal BP, higher levels of physical activity were associated with significantly higher left ventricular mass index (P<0.001), but this was not present in hypertension (P=0.90). Level of physical activity was associated with reduction in mortality and cardiovascular outcome independent of the presence of LVH (Persons with LVH: light activity HR, 0.77 [0.52-1.15], moderate/high activity HR, 0.61 [0.38-0.97]; test for interaction between LVH and level of physical activity P=0.71). In conclusion, persons with normal BP had higher left ventricular mass index at increased levels of physical activity, whereas this association was not present among persons with hypertension. Level of physical activity was associated with better prognosis independent of whether left ventricular hypertrophy was present or not.