User’s Guide to C2R: A Set of C Language Output Routines Compatible with the R Statistics Language

C2R is a collection of C routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 C2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the C2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer C2R to others in the hope that they will find it useful. (PDF contains 27 pages

User’s Guide to For2R: A Module of Fortran 95 Output Routines Compatible with the R Statistics Language

For2R is a collection of Fortran routines for saving complex data structures into a file that can be read in the R statistics environment with a single command.1 For2R provides both the means to transfer data structures significantly more complex than simple tables, and an archive mechanism to store data for future reference. We developed this software because we write and run computationally intensive numerical models in Fortran, C++, and AD Model Builder. We then analyse results with R. We desired to automate data transfer to speed diagnostics during working-group meetings. We thus developed the For2R interface to write an R data object (of type list) to a plain-text file. The master list can contain any number of matrices, values, dataframes, vectors or lists, all of which can be read into R with a single call to the dget function. This allows easy transfer of structured data from compiled models to R. Having the capacity to transfer model data, metadata, and results has sharply reduced the time spent on diagnostics, and at the same time, our diagnostic capabilities have improved tremendously. The simplicity of this interface and the capabilities of R have enabled us to automate graph and table creation for formal reports. Finally, the persistent storage in files makes it easier to treat model results in analyses or meta-analyses devised months—or even years—later. We offer For2R to others in the hope that they will find it useful. (PDF contains 31 pages

Multiple gene aberrations and breast cancer: lessons from super-responders.

BackgroundThe presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.Case presentationsWe performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.ConclusionsPatients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted

Human Engineering of Space Vehicle Displays and Controls

Proper attention to the integration of the human needs in the vehicle displays and controls design process creates a safe and productive environment for crew. Although this integration is critical for all phases of flight, for crew interfaces that are used during dynamic phases (e.g., ascent and entry), the integration is particularly important because of demanding environmental conditions. This panel addresses the process of how human engineering involvement ensures that human-system integration occurs early in the design and development process and continues throughout the lifecycle of a vehicle. This process includes the development of requirements and quantitative metrics to measure design success, research on fundamental design questions, human-in-the-loop evaluations, and iterative design. Processes and results from research on displays and controls; the creation and validation of usability, workload, and consistency metrics; and the design and evaluation of crew interfaces for NASA's Crew Exploration Vehicle are used as case studies

Hospitalisations from one to six years of age: Effects of Gestational Age and Severe Neonatal Morbidity

Background: To investigate whether the adverse infant health outcomes associated with early birth and severe neonatal morbidity (SNM) persist beyond the first year of life and impact on paediatric hospitalisations for children up to six years of age. Methods: The study population included all singleton live births, >32 weeks gestation in New South Wales, Australia in 2001-2005, with follow-up to six years of age. Birth data were probabilistically linked to hospitalisation data (n=392,964). The odds of hospitalisation, mean hospital length of stay (LOS) and costs, and cumulative LOS were evaluated by gestational age and SNM using multivariable analyses. Results: A total of 74,341 (18.9%) and 41,404 (10.5%) infants were hospitalized once and more than once, respectively. SNM was associated with increased odds of hospitalisation once (adjusted odds ratio (aOR) 1.16 [95% CI 1.10, 1.22]), and more than once (aOR 1.51 [1.42, 1.60]). Decreasing gestational age was associated with increasing odds of hospitalisation more than once from aOR 1.19 at 37-38 weeks to 1.49 at 33-34 weeks. Average LOS and costs per hospital admission were increased with SNM but not with decreasing gestational age. Cumulative LOS was significantly increased with SNM and decreasing gestational age. Conclusions: Adverse effects of SNM and early birth persist between one and six years of age. Strategies to prevent early birth and reduce SNM, and to increase health monitoring of vulnerable infants throughout childhood may help reduce paediatric hospitalisations.NHMRC, NSW Health Population Health and Health Services Gran

Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway.

BackgroundSince PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated.Patients and methodsWe evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates.ResultsFull doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC.ConclusionsCombination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. CLINICAL TRAILS INCLUDED: NCT01197170

Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice

Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice: increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r-/- mice into the C57BL/6J (B6) background. Female obese Mc4r-/- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid oxidation following exposure to high fat diets compared to obese Lep ob/Lepob mice. The reduced energy expenditure and fatty acid oxidation correlates with changes in hepatic gene expression. The expression of genes involved in fatty acid oxidation increased in obese Lep ob/Lepob mice compared to wild type and obese Mc4r-/- mice. In contrast, a key lipogenic enzyme (fatty acid synthase) is increased in obese Mc4r-/- mice compared to obese Lepob/Lepob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r-/- mice. However, Mc4r-/- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver fatty acid metabolism this is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in this strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice

Complement in reproductive white adipose tissue characterizes the obese preeclamptic-like BPH/5 mouse prior to and during pregnancy

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Preeclampsia (PE) is a serious hypertensive disorder of pregnancy characterized by abnormal placental development with an unknown etiology. To better understand which women will develop PE, a number of maternal risk factors have been identified, including obesity. Visceral white adipose tissue (WAT) contains inflammatory mediators that may contribute to PE. To explore this, we utilized the blood pressure high (BPH)/5 mouse model of superimposed PE that spontaneously recapitulates the maternal PE syndrome. We hypothesized that BPH/5 visceralWAT adjacent to the female reproductive tract (reproductiveWAT) is a source of complement factors that contribute to the inflammatory milieu and angiogenic imbalance at the maternal-fetal interface in this model and in preeclamptic women. To test our hypothesis, we calorie-restricted BPH/5 females for two weeks prior to pregnancy and the first seven days of pregnancy, which attenuated complement component 3 (C3) but not complement factor B, nor complement factor D, (adipsin) in the reproductiveWAT or the implantation site in BPH/5. Furthermore, calorie restriction during pregnancy restored vascular endothelial and placental growth factor mRNA levels in the BPH/5 implantation site. These data show maternal reproductive WAT may be a source of increased C3 during pregnancy, which is increased at the maternal-fetal interface in preeclamptic BPH/5 mice. It also suggests that calorie restriction could regulate inflammatory mediators thought to contribute to placental dysfunction in PE. Future studies are necessary to examine the e_ect of calorie restriction on C3 throughout pregnancy and the role of maternal obesity in PE