Correlations between a deep learning-based algorithm for embryo evaluation with cleavage-stage cell numbers and fragmentation.

RESEARCH QUESTION: Do cell numbers and degree of fragmentation in cleavage-stage embryos, assessed manually, correlate with evaluations made by deep learning algorithm model iDAScore v2.0? DESIGN: Retrospective observational study (n = 5040 embryos; 1786 treatments) conducted at two Swedish assisted reproductive technology centres between 2016 and 2021. Fresh single embryo transfer was carried out on days 2 or 3 after fertilization. Embryo evaluation using iDAScore v2.0 was compared with manual assessment of numbers of cells and grade of fragmentation, analysed by video sequences. RESULTS: Data from embryos transferred on days 2 and 3 showed that having three or fewer cells compared with four or fewer cells on day 2, and six or fewer cells versus seven to eight cells on day 3, correlated significantly with a difference in iDAScore (medians 2.4 versus 4.0 and 2.6 versus 4.6 respectively; both P < 0.001). The iDAScore for 0-10% fragmentation was significantly higher compared with the groups with higher fragmentation (P < 0.001). When combining cell numbers and fragmentation, iDAScore values decreased as fragmentation increased, regardless of cell number. iDAScore discriminated between embryos that resulted in live birth or no live birth (AUC of 0.627 and 0.607), compared with the morphological model (AUC of 0.618 and 0.585) for day 2 and day 3, respectively. CONCLUSIONS: The iDAScore v2.0 values correlated significantly with cell numbers and fragmentation scored manually for cleavage-stage embryos on days 2 and 3. iDAScore had some predictive value for live birth, conditional that embryo selection was based on morphology.

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.

Comparing performance between clinics of an embryo evaluation algorithm based on time-lapse images and machine learning.

PURPOSE: This article aims to assess how differences in maternal age distributions between IVF clinics affect the performance of an artificial intelligence model for embryo viability prediction and proposes a method to account for such differences. METHODS: Using retrospectively collected data from 4805 fresh and frozen single blastocyst transfers of embryos incubated for 5 to 6 days, the discriminative performance was assessed based on fetal heartbeat outcomes. The data was collected from 4 clinics, and the discrimination was measured in terms of the area under ROC curves (AUC) for each clinic. To account for the different age distributions between clinics, a method for age-standardizing the AUCs was developed in which the clinic-specific AUCs were standardized using weights for each embryo according to the relative frequency of the maternal age in the relevant clinic compared to the age distribution in a common reference population. RESULTS: There was substantial variation in the clinic-specific AUCs with estimates ranging from 0.58 to 0.69 before standardization. The age-standardization of the AUCs reduced the between-clinic variance by 16%. Most notably, three of the clinics had quite similar AUCs after standardization, while the last clinic had a markedly lower AUC both with and without standardization. CONCLUSION: The method of using age-standardization of the AUCs that is proposed in this article mitigates some of the variability between clinics. This enables a comparison of clinic-specific AUCs where the difference in age distributions is accounted for.

Monitoring process-related impurities in biologics-host cell protein analysis.

During biologics development, manufacturers must demonstrate clearance of host cell impurities and contaminants to ensure drug purity, manufacturing process consistency, and patient safety. Host cell proteins (HCPs) are a major class of process-related impurities and require monitoring and documentation of their presence through development and manufacturing. Even in residual amounts, they are known to affect product quality and efficacy as well as patient safety. HCP analysis using enzyme-linked immunosorbent assay (HCP-ELISA) is the standard technique, due to its simple handling, short analysis time, and high sensitivity for protein impurities. Liquid chromatography mass spectrometry (LC-MS) is an orthogonal method for HCP analysis and is increasingly included in regulatory documentation. LC-MS offers advantages where HCP-ELISA has drawbacks, e.g., the ability to identify and quantify individual HCPs. This article summarizes the available knowledge about monitoring HCPs in biologics and presents the newest trends in HCP analysis with current state-of-the-art HCP measurement tools. Through case studies, we present examples of HCP control strategies that have been used in regulatory license applications, using an MS-based coverage analysis and HCP-ELISA and LC-MS for HCP quantification. This provides novel insight into the rapid evolving strategy of HCP analysis. Improvements in technologies to evaluate HCP-ELISA suitability and the implementation of orthogonal LC-MS methods for HCP analysis are important to rationally manipulate, engineer, and select suitable cell lines and downstream processing steps to limit problematic HCPs.

Prevalence of parental mental health conditions among children aged 0-16 years in Denmark: A nationwide register-based cross-sectional study.

Aim: Parental mental health conditions adversely affect the children. Information on the prevalence of parental mental health conditions is needed to help policymakers allocate resources appropriately. Therefore, the aim of this study was to estimate the prevalence of children with parental mental health conditions in Denmark and further estimate the age-specific prevalence and geographical variation. Methods: In this nationwide register-based cross-sectional study, we included all children born between 2000 and 2016 if they resided in Denmark on 31 December 2016. Information on both maternal and paternal mental health conditions was retrieved from primary and secondary healthcare registers. Parental mental health conditions were categorised in three severity groups: minor, moderate, and severe. We estimated the proportion of children with parental mental health conditions on 31 December 2016. Results: Of the 1,106,459 children aged 0-16 years, 39.1% had at least one parent with a mental health condition. The prevalence increased with age of the children until the age of six years. Geographical variation in the prevalence ranged from 29.0% to 48.3% in the 98 municipalities. Minor parental mental health conditions (23.5%) were more common than moderate (13.5%) and severe parental mental health conditions (2.2%). Hospital-diagnosed parental mental health conditions were prevalent in 12.8% of the children. Conclusions: Two in five children aged 0-16 years in Denmark have parents with a mental health condition and geographical variation exists. The high prevalence of children with parental mental health conditions is an important public health challenge, which calls for attention.

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.

Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis.

Disclosed here is a dual copper and nickel catalytic system with a silyl hydride source for promoting the linear selective hydroalkylation of vinylarenes. This carbon-carbon bond-forming protocol is applied to couple a variety of functionalized vinylarenes with alkyl halides applying a nickel(II) NNN pincer complex in the presence of an NHC-ligated copper catalyst. This combination allows for a 1 mol % loading of the nickel catalyst leading to turnover numbers of up to 72. Over 40 examples are presented, including applications for pharmaceutical diversification. Labeling experiments demonstrated the regioselectivity of the reaction and revealed that the copper catalyst plays a crucial role in enhancing the rate for formation of the reactive linear alkyl nickel complex. Overall, the presented work provides a complimentary approach for hydroalkylation reactions, whilst providing a preliminary mechanistic understanding of the cooperativity between the copper and nickel complexes.

Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma - An external validation study.

BACKGROUND: We recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9. METHODS: Patients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort. RESULTS: Patients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70-8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42-6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69-0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89-0.96) in the primary study and 0.85 (95% CI 0.79-0.91) in the validation study. CONCLUSION: In this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.

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.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Arrhythmias in Patients on Maintenance Dialysis: A Cross-sectional Study.

RATIONALE & OBJECTIVE: Patients with kidney failure treated with maintenance dialysis experience a high rate of mortality, in part due to sudden cardiac death caused by arrhythmias. The prevalence of arrhythmias, including the subset that are clinically significant, is not well known. This study sought to estimate the prevalence of arrhythmias, characterize the pattern of arrhythmic events in relation to dialysis treatments, and identify associated clinical characteristics. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 152 patients with kidney failure treated with maintenance dialysis in Denmark. EXPOSURES: Dialysis treatment; clinical characteristics; cardiac output and preload defined using echocardiography. OUTCOMES: Prevalence and pattern of arrhythmias on 48-hour Holter monitoring; odds ratios for arrhythmias. ANALYTICAL APPROACH: Descriptive analysis of the prevalence of arrhythmias. Pattern of arrhythmias described using a repeated-measures negative binomial regression model. Associations between clinical characteristics and echocardiographic findings with arrhythmias were assessed using logistic regression. RESULTS: Among the 152 patients studied, 83.6% were treated with in-center dialysis; 10.5%, with home hemodialysis; and 5.9%, with peritoneal dialysis. Premature atrial and ventricular complexes were seen in nearly all patients and 41% had paroxysmal supraventricular tachycardia. Clinically significant arrhythmias included persistent atrial fibrillation observed among 8.6% of patients, paroxysmal atrial fibrillation among 3.9%, nonsustained ventricular tachycardia among 19.7%, bradycardia among 4.6%, advanced second-degree atrioventricular block among 1.3%, and third-degree atrioventricular block among 2.6%. Premature ventricular complexes were more common on dialysis days, while tachyarrhythmias were more often observed during dialysis and in the immediate postdialytic period. Older age (OR per 10 years older, 1.53; 95% CI, 1.15-2.03; P=0.003), elevated preload (OR, 4.02; 95% CI, 1.05-15.35; P=0.04), and lower cardiac output (OR per 1L/min greater, 0.66; 95% CI, 0.44-1.00; P=0.05) were independently associated with clinically significant arrhythmias. LIMITATIONS: Arrhythmia monitoring limited to 48 hours; small sample size; heterogeneous nature of the population, risk for residual confounding. CONCLUSIONS: Arrhythmias, including clinically significant abnormal rhythms, were common. Tachyarrhythmias were more frequent during dialysis and the immediate postdialytic period. The relevance of these findings to clinical outcomes requires additional study.

Regression models using parametric pseudo-observations.

Pseudo-observations based on the nonparametric Kaplan-Meier estimator of the survival function have been proposed as an alternative to the widely used Cox model for analyzing censored time-to-event data. Using a spline-based estimator of the survival has some potential benefits over the nonparametric approach in terms of less variability. We propose to define pseudo-observations based on a flexible parametric estimator and use these for analysis in regression models to estimate parameters related to the cumulative risk. We report the results of a simulation study that compares the empirical standard errors of estimates based on parametric and nonparametric pseudo-observations in various settings. Our simulations show that in some situations there is a substantial gain in terms of reduced variability using the proposed parametric pseudo-observations compared with the nonparametric pseudo-observations. The gain can be measured as a reduction of the empirical standard error by up to about one third; corresponding to an additional 125% larger sample size. We illustrate the use of the proposed method in a brief data example.

Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides.

A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.

Reporting and handling of equivocal imaging findings in diagnostic studies of bone metastasis in prostate cancer.

BACKGROUND: Equivocal scanning results occur. It remains unclear how these results are presented and their management influence diagnostic characteristics. PURPOSE: To investigate the reporting and handling of equivocal imaging findings in diagnostic studies of bone metastases, and to assess the impact on diagnostic performance of the methods used to analyze equivocal findings. The conceptual issue was reified based on two actual observations. MATERIAL AND METHODS: A recent meta-analysis of bone metastases in prostate cancer was conducted and data were obtained from a large clinical trial with a true reference of bone metastasis, where diagnostic characteristics were calculated with equivocal scans handled by: removal; considered malignant; considered benign; and intention-to-diagnose. RESULTS: The meta-analysis included 18 trials where the median proportion of reported equivocal results was 27%. Eleven (61%) studies reported an equivocal option for the index test, 42% reported equivocal results and described how these were analyzed. The clinical trial included 583 prostate cancer patients with 20% equivocal results. The different methods of managing equivocal findings resulted in highly variable outcomes: sensitivity = 85%-100%; specificity = 78%-99%; and positive and negative predictive values = 44%-94% and 97%-100%, respectively. The diagnostic performances obtained using the four methods were differentially susceptible to the proportion of equivocal imaging findings and the prevalence of bone metastases. CONCLUSION: Reporting of equivocal results was inadequate in bone imaging trials. The handling of equivocal findings strongly influenced diagnostic accuracy.

Educational level and living arrangements are associated with dietary intake of red meat and fruit/vegetables: A Danish cross-sectional study.

Aims: To evaluate the association between education and living arrangements and the intake of fish, red meat and fruit and vegetables.Methods: The study design was cross-sectional and conducted in Denmark in 2013. Participants filled in questionnaires about their educational level and living arrangements (living alone or with others) and dietary intake including fish, red meat, fruit and vegetables. Regression analyses were performed to assess the associations within 85,456 randomly sampled healthy men and women who were at least 25 years old.Results: Length of education was statistically significant and positively associated with the intake of fruit and vegetables and negatively associated with the intake of red meat for both men and women. Men with a high level of education had a 187g/week (95% confidence interval: 199-175g/week) lower intake of red meat and a 109g/day (95% confidence interval: 102-117g/day) higher intake of fruit and vegetables than men with a low level of education. Women with a high level of education had a 175g/week (95% confidence interval: 186-164g/week) lower intake of red meat and a 106g/day (95% confidence interval: 97-114g/day) higher intake of fruit and vegetables than women with a low level of education. Living with others was statistically significant and positively associated with the intake of red meat, and fruit and vegetables. There were no clear associations between education, living arrangements and intake of fish.Conclusions: Men and women with a high educational level ate more fruit and vegetables but less red meat than men and women with a low educational level. Men and women living with others ate more red meat, fruit and vegetables than men and women living alone.

Medication adherence, biological and lifestyle risk factors in patients with myocardial infarction: a ten-year follow-up on socially differentiated cardiac rehabilitation.

Objective: There is strong evidence that medication adherence and lifestyle changes are essential in patients undergoing secondary cardiovascular disease prevention. Cardiac rehabilitation (CR) increases medication adherence and improves lifestyle changes. Patients with cardiac diseases and a low educational level and patients with little social support are less responsive to improve medication adherence and to adapt lifestyle changes. The aim of the present study was to investigate the long-term effects of a socially differentiated CR intervention on medication adherence as well as changes in biological and lifestyle risk factors at two- five- and ten-year follow-up. Design: A prospective cohort study. Setting: The cardiac ward at Aarhus University Hospital, Denmark. Intervention: A socially differentiated CR intervention in addition to the standard CR program. Subjects: Patients admitted with first-episode myocardial infarction between 2000 and 2004, N = 379. Patients were defined as socially vulnerable or non-socially vulnerable according to their educational level and extent of social network. Main outcome measures: Primary outcome was medication adherence to antithrombotics, beta-blockers, statins and angiotensin-converting enzyme inhibitors. Secondary outcomes were biological and lifestyle risk factors defined as; total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, glycated hemoglobin, blood pressure and smoking status. Results: No significant long-term effect of the intervention was found. Conclusions: The results indicate a non-significant effect of the intervention. However, it was found that equality in health was improved in the study population except concerning smoking. General practitioners manage to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status. Key points The socially differentiated intervention did not significantly improve medication adherence or biological and lifestyle risk factors. Despite the non-significant effect of the intervention, equality in health was improved except concerning smoking. General practitioners managed to support the long-term secondary cardiovascular disease prevention in all patients regardless of social status.