Prediction of cross performance in barley

In this thesis opportunities for prediction of cross performance in a plant breeding program are investigated. For this research 20 SSD-line populations from crosses between European two-row spring barley lines were evaluated for four quantitative agronomic traits in seven environments, divided over two years.The midparent value appeared to be a good predictor of average offspring performance and useful in practical breeding. However, for most crosses the midparent values for grain yield overestimated the offspring average. The relatedness between parents was expected to predict the variance among the offspring. However, predictions using genetic distances based on pedigree data, morphological trait data, and AFLP-marker data, performed poorly. A genetic distance based on AFLP-markers associated with the trait variation among the parents gave a somewhat better prediction.The correlation between the parental responses to different environments appeared to be a reasonable predictor of grain yield among the offspring. Other variance predictors based on parental differences for agronomic trait data or early generation (F4) variance among the offspring, mainly predicted variance resulting from segregating major genes. These genes are often fixed in practical breeding programmes and therefore not very relevant. Grain yield data from small three-row plots in an early generation evaluation did not correspond with large plot yield data due to interplot competition.</p

Prognostic value of left atrial size and function in adults with tetralogy of Fallot

Background: Left atrial (LA) size predicts cardiovascular outcome in chronic heart failure. Its prognostic value in adults with repaired tetralogy of Fallot (ToF) is unknown. This study therefore investigated the association of LA size and function with cardiovascular events in adults with ToF. Methods: Clinically stable adults with ToF who visited the outpatient clinic between 2011 and 2013 underwent echocardiography and were prospectively followed for the occurrence of death, heart failure, hospitalizations, arrhythmia, thromboembolic events, and re-interventions. LA maximal, minimal and pre-A wave volume, area and length were measured on the apical four-chamber view. Total, passive and active emptying fractions were calculated. Results: In total, 134 patients were included (median age 35 [IQR 29-45] years, 65% male, 91% NYHA I). Median follow-up was 40 [IQR 32-47] months. Patients with a dilated LA (≥34mL/m2, 43%) were at higher risk of cardiovascular events (n=33, adjusted HR 2.48 [1.09-5.62], P =0.030). Analysis of LA volumes as continuous variables yielded similar conclusions. In addition, LA length (adjusted HR 2.49 [1.51-4.09], P <0.001), total emptying fraction (adjusted HR 0.96 [0.93-0.99], P =0.008), and active emptying fraction (adjusted HR 0.92 [0.87-0.96], P =0.001) were significantly associated with cardiovascular events. Standardized HRs indicated that LA length was the strongest prognostic marker. In addition, none of the patients with a normally sized LA died or developed heart failure. Conclusions: LA size and function can provide relevant prognostic information in clinically stable adults with repaired ToF. Especially LA length may be a valuable additional tool in the risk stratification of these patients

A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine. This multisite study by Meijer et al. establishes a standardized in vitro approach to study synapse formation and function in single iPSC-derived human neurons. They validate this approach for GABA and glutamatergic human neurons. The methodology is scalable and suitable for compound screening and disease modeling

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1):a multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): A multicenter stepped-wedge cluster randomized controlled trial

Background: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. Methods/design: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. Discussion: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. Trial registration: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018

Prediction of barley progeny performance in the presence of genotype-environment interaction

Twenty recombinant inbred line (RIL) populations of European two-row spring barley and their parents were tested in six environments in the Netherlands to investigate the prediction of progeny yield level, yield variance, stability level and stability variance, based on parent information. Progeny yield level is positively correlated with midparent value for average yield. Progeny yield variance is more difficult to predict, but there does appear to be a promising negative correlation between progeny yield variance and Habgood's (1977) parental similarity measure. To quantify yield stability, three statistics were calculated: Finlay and Wilkinson's (1963) regression coefficient bi, Shukla's (1972) stability variance i2 and Eberhart and Russell's (1966) mean squared deviation di2. The first stability statistic describes a different aspect of the response pattern to change in environment from the last two. Parents with high bi values appear to have a better average yield, i.e. they react more positively to an improvement in the environment than the other genotypes. The average bi value of the progeny is positively correlated with the midparent value, indicating its heritable nature. There are also indications that di2 and i2 are heritable but their repeatability is poor. Therefore, it is concluded that only prediction of bi is useful in practical plant breeding. There is a positive correlation between progeny yield variance and progeny variance for bi but we conclude that the inaccuracy of the stability variance estimates is too high for good predictors for progeny stability variance to be found