Search

Contains fulltext : 249888.pdf (Publisher’s version ) (Open Access) BACKGROUND: In-depth insight into haemodynamic changes during normotensive pregnancy may help identify women at risk for gestational hypertensive complications. OBJECTIVES: To determine the magnitude of changes in cardiac output and its determinants stroke volume and heart rate, and total peripheral vascular resistance during singleton normotensive and hypertensive pregnancies. SEARCH STRATEGY: PubMed (NCBI) and Embase (Ovid) databases were searched from their inception up to November 2019. SELECTION CRITERIA: Studies reporting original measurements of haemodynamic parameters during pregnancy together with a non-pregnant reference measurement. Studies including women using antihypertensive medication were excluded. DATA COLLECTION AND ANALYSIS: Pooled mean differences between pregnant and non-pregnant women, and absolute values of haemodynamic parameters were calculated for predefined gestational intervals using a random-effects model in normotensive and hypertensive pregnancy. Meta-regression analysis was used to analyse group differences in adjustments and absolute values during pregnancy. MAIN RESULTS: In normotensive pregnancies, cardiac output increased from the first weeks on, reaching its highest level early in the third trimester (mean difference, 1.41 l·min(1) ; 95% CI 1.18-1.63 l·min). In parallel, vascular resistance decreased progressively until its nadir in the early third trimester (mean difference, -331 dyn·sec(-1) ·cm(-5) ; 95% CI -384 to -277 dyn·sec(-1) ·cm(-5) ) and then increased slightly at term. In hypertensive pregnancies, the initial cardiac output increase was higher and vascular resistance did not change throughout gestation compared with reference values. CONCLUSIONS: Hemodynamic changes in women who eventually develop hypertensive complications are substantially different. Serial monitoring and plotting against developed normograms can identify women at risk and may allow timely intervention. TWEETABLE ABSTRACT: Monitoring haemodynamic changes in pregnancy helps identify women at risk for hypertensive complications.

Background Hypertension is the leading risk factor for cardiovascular disease (CVD) and is the most substantial and neglected health burden in women. While treatment of high blood pressure is essential in the global prevention strategies of CVD it is assumed that effectiveness of pharmacological treatment may be hampered by sex differences. However, it is still not known whether sex differences exist in the effect of the antihypertensive medications. Purpose To evaluate sex-stratified effects for angiotensin receptor blockers (ARBs) on blood pressure (BP) and cardiac function in female compared to male hypertensive participants. Methods A series of systematic reviews and meta-analysis was performed. PubMed and EMBASE were systematically searched for studies evaluating the effects of the five major groups of antihypertensive medication from 1945 to May 2020. Randomized control trials and observational studies in humans (≥18 years) were included investigating beta-blockers (BB), angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), and diuretics. In this study data on ARB's was analyzed. Studies had to present both baseline and follow-up measurements of at least one of the outcome variables of interest and present their data in a sex-stratified manner. Data on BPand cardiac function where retrieved from studies. Risk of bias was assessed using the Cochrane risk of bias tool. Results The search strategy resulted in 73,867 hits. After first screening based on title and abstract, 15,130 articles where suitable for full test screening. After excluding all studies that matched the exclusion criteria, 205 studies with 15,570 participants where eligible for analysis for the five antihypertensive drugs. Studies investigating ARB's (n=17) where used in this review. Seven trials (41%) had a low risk of bias. ARB decreased BP significantly and comparably in both women and men. Systolic BP −18.2 mmHg (95% CI, −24.8 to −11.5) vs −20.1 mmHg (95% CI, −26.7 to −13.6) and diastolic BP −11.6 mmHg (95% CI, −14.7 to −8.4) vs −12.3 mmHg (95% CI, −16.4 to −8.1). LVEF did not change significantly in either group. LV mass was only reported in males and did not change significantly −11.8 g (95% CI, −25.6 to 1.9). Conclusion Our meta-analysis shows that based on the current studies, no sex differences exists in the effect of ARB on blood pressure or cardiac function. Funding Acknowledgement Type of funding sources: None.

Background Hypertension is one of the leading global risk factors for cardiovascular disease-related morbidity and mortality. Females have historically been underrepresented in clinical trials resulting in presumed sex-related disparities in antihypertensive treatment effects. The past decade, widespread attention has been paid to this shortcoming aiming at increasing females' representation in clinical trials. Purpose To investigate whether in studies investigating the effect of antihypertensive drugs 1) the representation of females and 2) presentation of sex-stratified data has increased over the past decades. Methods We performed a scoping review after systematically searching PubMed and Embase for studies evaluating the effects of the five major groups of antihypertensive medication from inception (1945) until May 2020. The review was registered in Prospero database. Studies were only included if they 1) investigated one class of the five main groups of antihypertensive medications (beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and diuretics, 2) human studies, 3) investigated adults ≥18 years of age, 4) were written in English or Dutch. We excluded articles if 1) only abstract was available and full report was not found, 2) unsuitable study design, 3) no reference group included, 4) outcome not related to cardiovascular health, 5) no registration of specific dose and duration information. The primary outcome was the proportion of included females over time, stratified per decade. The secondary outcome was whether sex-stratification was reported. Linear regression analysis with beta coefficient (β) and 95% CI was performed to explore the associations between the percentage of females included in the studies over time. Results The search strategy resulted in 73,867 potential articles. After study selection based on title/abstract and full text, 2,079 original studies were eligible for our study. These included 1,395,264 adults of which the mean percentage of females participating in all included studies was 27.9% (Figure 1, Table 1). The percentage of females participating in antihypertensive studies showed a slight increase each year by 0.4% (95% CI 0.36–0.53, P Conclusion Despite yearly increase in female participation in antihypertensive studies, females still only account for only one third of the study population. Moreover, less than 10% of studies report sex stratified data. Considering the global burden of hypertension, more differentiated sex-specific attention remains critically needed. Funding Acknowledgement Type of funding sources: None.

Dietary fibre fermentation in humans and monogastric animals is considered to occur in the hindgut, but it may also occur in the lower small intestine. This study aimed to compare ileal and hindgut fermentation in the growing pig fed a human-type diet using a combined in vivo/in vitro methodology. Five pigs (23 (sd 1·6) kg body weight) were fed a human-type diet. On day 15, pigs were euthanised. Digesta from terminal jejunum and terminal ileum were collected as substrates for fermentation. Ileal and caecal digesta were collected for preparing microbial inocula. Terminal jejunal digesta were fermented in vitro with a pooled ileal digesta inoculum for 2 h, whereas terminal ileal digesta were fermented in vitro with a pooled caecal digesta inoculum for 24 h. The ileal organic matter fermentability (28 %) was not different from hindgut fermentation (35 %). However, the organic matter fermented was 66 % greater for ileal fermentation than hindgut fermentation (P = 0·04). Total numbers of bacteria in ileal and caecal digesta did not differ (P = 0·09). Differences (P < 0·05) were observed in the taxonomic composition. For instance, ileal digesta contained 32-fold greater number of the genus Enterococcus, whereas caecal digesta had a 227-fold greater number of the genus Ruminococcus. Acetate synthesis and iso-valerate synthesis were greater (P < 0·05) for ileal fermentation than hindgut fermentation, but propionate, butyrate and valerate synthesis was lower. SCFA were absorbed in the gastrointestinal tract location where they were synthesised. In conclusion, a quantitatively important degree of fermentation occurs in the ileum of the growing pig fed a human-type diet.

Background Substantial microbial fermentation may occur mainly in the lower small intestine (SI) of human adults, but there is no established methodology to determine this. Objective The study aimed to develop a combined in vivo and in vitro methodology for ileal fermentation based on the pig as an animal model for digestion in human adults. Methods Several aspects of a combined in vivo/in vitro ileal fermentation assay were evaluated. Male 9-wk-old pigs (n = 30; mean ± SD body weight: 23 ± 1.6 kg) were fed a human-type diet (143, 508, 45, 49, and 116 g/kg dry matter diet of crude protein, starch, total lipid, ash, and total dietary fiber) for 15 d. On day 15, pigs were killed, and the last third of the SI was collected to prepare an ileal digesta-based inoculum. Terminal jejunal digesta (last 50 cm of the second third of the SI) were collected as substrate for the assay to test the form of substrate (fresh or freeze-dried), origin (location in jejunum or SI) of the substrate, storage of the inoculum, incubation time (1.2-6.8 h), pH of the medium, and inoculum concentration (6-26 mg inoculum/100 mg substrate). Results The group of donor pigs used to prepare the inoculum, form of the substrate, origin of the substrate, origin of the inoculum (location in the SI), storage of the inoculum, incubation time, and inoculum concentration did not influence the in vitro ileal organic matter (OM) fermentability (P > 0.05). The in vitro ileal OM fermentability decreased when the pH of the medium increased from 5.5 to 7.5 (31% to 28%; P ≤ 0.05). Predicted (in vivo/in vitro) apparent ileal OM digestibility was similar to the value measured in vivo. Conclusions Thirty-percent of the terminal jejunal digesta OM was fermented in the ileum. Fiber fermentation in the ileum can be studied using the optimized in vivo/in vitro ileal fermentation method.

Contains fulltext : 182368.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To establish reference values for flow-mediated dilatation (FMD) and brachial artery diameter (BAD) in pregnancy and to provide insight into the physiological and pathological course of endothelial adaptation throughout human singleton pregnancy. METHODS: A meta-analysis was performed following a systematic review of current literature on FMD, as a derivative for endothelial function, and BAD, throughout uncomplicated and complicated pregnancy. PubMed (NCBI) and EMBASE (Ovid) electronic databases were used for the literature search, which was performed from inception to 9 June 2016. To allow judgment of changes in comparison with the non-pregnant state, studies were required to report both non-pregnant mean reference of FMD (matched control group, prepregnancy or postpartum measurement) and mean FMD at a predetermined and reported gestational age. Pooled mean differences between the reference and pregnant FMD values were calculated for predefined intervals of gestational age. RESULTS: Fourteen studies that enrolled 1231 participants met the inclusion criteria. Publication dates ranged from 1999 to 2014. In uncomplicated pregnancy, FMD was increased in the second and third trimesters. Between 15 and 21 weeks of gestation, absolute FMD increased the most, by a mean (95% CI) of 1.89% (0.25-3.53%). This was a relative increase of 22.5% (3.0-42.0%) compared with the non-pregnant reference. BAD increased progressively, in a steady manner, by the second trimester but not significantly in the first half of the second trimester. We could not discern differences in FMD and BAD between complicated and uncomplicated pregnancies at 29-35 weeks' gestation, reported in the three studies that met our inclusion criteria. Despite the increase in FMD and BAD throughout gestation, both reference curves were characterized by wide 95% CIs. CONCLUSION: During healthy pregnancy, endothelium-dependent vasodilatation and BAD increase. Women with a complicated pregnancy had FMD values within the lower range when compared with those with uncomplicated pregnancy but, as a group, did not differ from each other. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd.

Traditional plant breeding relies on meiotic recombination for mixing of parental alleles to create novel allele combinations. Detailed analysis of recombination patterns in model organisms shows that recombination is tightly regulated within the genome, but frequencies vary extensively along chromosomes. Despite being a model organism for fruit developmental studies, high-resolution recombination patterns are lacking in tomato. In this study, we developed a novel methodology to use low-coverage resequencing to identify genome-wide recombination patterns and applied this methodology on 60 tomato Recombinant Inbred Lines (RILs). Our methodology identifies polymorphic markers from the low-coverage resequencing population data and utilizes the same data to locate the recombination breakpoints in individuals by using a variable sliding window. We identified 1,445 recombination sites comprising 112 recombination prone regions enriched for AT-rich DNA motifs. Furthermore, the recombination prone regions in tomato preferably occurred in gene promoters over intergenic regions, an observation consistent with Arabidopsis thaliana, Zea mays and Mimulus guttatus. Overall, our cost effective method and findings enhance the understanding of meiotic recombination in tomato and suggest evolutionarily conserved recombination associated genomic features.

OBJECTIVES: This study aimed to compare ileal and hindgut fermentations in the pig model using a combined in vivo/in vitro methodology. METHODS: Pigs (23 kg bodyweight, n = 5) were fed a human-type diet for 15 days. On day 15, pigs were euthanased and the small intestine was immediately dissected out and ligated in three equal lengths. Digesta from the last 50 cm of the second (terminal jejunum) and last (terminal ileum) third sections of the small intestine were collected as substrates. Digesta from the remaining last third (i.e., last third minus 50 cm) of the small intestine (ileum) was collected along with caecal digesta for preparing inocula. Terminal jejunal digesta substrates were fermented in vitro with a pooled ileal digesta inoculum for 2 h (ileal fermentation), while terminal ileal digesta substrates were fermented in vitro with a pooled caecal digesta inoculum for 24 h (hindgut fermentation). RESULTS: The ileal organic matter (OM) fermentability (28%) was similar than the hindgut counterpart (35%) (P > 0.05). However, the fermentable OM was 63% higher during ileal fermentation than hindgut fermentation (P

Objective To describe the physiological pattern of gestational plasma volume adjustments in normal singleton pregnancy and compare this with the pattern in pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction. Methods We performed a meta-analysis of the current literature on plasma volume adjustments during physiological and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies reported both reference plasma volume measurements (non-pregnant, prepregnancy or postpartum) and measurements obtained during predetermined gestational ages. Mean differences bet ween the reference and pregnancy plasma volume measurements were calculated for predefined intervals of gestational age using a random-effects model described by DerSimonian and Laird. Results Thirty studies were included in the meta-analysis with publication dates ranging from 1934 to 2007. Plasma volume increased in the first weeks of pregnancy, with the steepest increase occurring during the second trimester. Plasma volume continued to increase in the third trimester with a pooled maximum increase of 1.13 L (95% CI, 1.07–1.19 L), an increase of 45.6% (95% CI, 43.0–48.1%) in physiological pregnancies compared with the reference value. The plasma volume expansion in gestational hypertensive and growth-restricted pregnancies was 0.80 L (95% CI, 0.59–1.02 L), an increase of 32.3% (95% CI, 23.6–41.1%) in the third trimester, a smaller increase than in physiological pregnancies (P

Copyright © 2018 ASME. The UK Department of Business, Energy and Industrial Strategy (BEIS) recently launched an R&D programme in Digital Reactor Design, incorporating the development of a Nuclear Virtual Engineering Capability with an integrated Modelling and Simulation programme. A key challenge of nuclear reactor design and analysis is the system complexity, which arises from a wide range of multi-physics phenomena being important across multiple length scales. This project constitutes the first step towards developing an integrated nuclear digital environment (INDE) linking together models across physical domains and incorporating real world data across all stages of the nuclear lifecycle. Simulation case studies will be developed within the INDE framework, delivering an enhanced modelling capability while ensuring the framework has immediate application. For these case studies have been specified that are relevant to design and operation phases for AGR and PWR type reactors. The AGR case considers the through-life structural performance of graphite bricks. This involves modelling of multi-scale, multi-physics phenomena in the support of reactor operations. The PWR case study is based on core multiphysics modelling, with potential relevance to operating and future PWRs, and in particular in the design of SMRs.

Contains fulltext : 208669.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To review systematically current literature on kidney function changes during pregnancy, in order to estimate the extent of adaptation over the course of both healthy physiological and complicated singleton pregnancies, and to determine healthy pregnancy reference values. METHODS: PubMed (NCBI) and EMBASE (Ovid) electronic databases were searched, from inception to July 2017, for studies on kidney function during uncomplicated and complicated pregnancies. Included studies were required to report a non-pregnant reference value of kidney function (either in a non-pregnant control group or as a prepregnancy or postpartum measurement) and a pregnancy measurement at a predetermined and reported gestational age. Kidney function measures assessed were glomerular filtration rate (GFR) measured by inulin clearance, GFR measured by creatinine clearance and serum creatinine level. Pooled mean differences between pregnancy measurements and reference values were calculated for predefined intervals of gestational age in uncomplicated and complicated pregnancies using a random-effects model described by DerSimonian and Laird. RESULTS: Twenty-nine studies met the inclusion criteria and were included in the analysis. As early as the first trimester, GFR was increased by up to 40-50% in physiological pregnancy when compared with non-pregnant values. Inulin clearance in uncomplicated pregnancy was highest at 36-41 weeks, with a 55.6% (53.7; 95% CI, 44.7-62.6 mL/min) increase when compared with non-pregnant values, and creatinine clearance was highest at 15-21 weeks' gestation, with a 37.6% (36.6; 95% CI, 26.2-46.9 mL/min) increase. Decrease in serum creatinine level in uncomplicated pregnancy was most prominent at 15-21 weeks, with a 23.2% (-0.19; 95% CI, -0.23 to -0.15 mg/dL) decrease when compared with non-pregnant values. Eight studies reported on pregnancies complicated by a hypertensive disorder. Meta-regression analysis showed a significant difference in all kidney function parameters when comparing uncomplicated and hypertensive complicated pregnancies. CONCLUSIONS: In healthy pregnancy, GFR is increased as early as the first trimester, as compared with non-pregnant values, and the kidneys continue to function at a higher rate throughout gestation. In contrast, kidney function is decreased in hypertensive pregnancy. (c) 2018 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Contains fulltext : 182443.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of this systematic review and meta-analysis was to describe comprehensively the pattern of cardiac remodeling during normotensive human singleton pregnancy and to compare it with that of pregnancy complicated by hypertension. METHODS: We performed a meta-analysis of the current literature on cardiac remodeling during normotensive and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies needed to report a reference measurement (matched non-pregnant control group, prepregnancy or postpartum) and measurements made during predetermined gestational-age intervals. Mean differences between reference and pregnancy data were calculated using the random-effects model described by DerSimonian and Laird. RESULTS: Forty-eight studies were included in the meta-analysis, with publication dates ranging from 1977 to 2016. During normotensive pregnancy, most geometric indices started to increase in the second trimester. Left ventricular mass (LVM) increased by 28.36 (95% CI, 19.73-37.00) g (24%), and relative wall thickness (RWT) increased by 0.03 (95% CI, 0.02-0.05) (10%) compared with those in the reference group. During hypertensive pregnancy, LVM and RWT increased more than during normotensive pregnancy (92 (95% CI, 75.46-108.54) g (95%) and 0.14 (95% CI, 0.09-0.19) (56%), respectively). CONCLUSIONS: During normotensive pregnancy, most cardiac geometric indices change from the second trimester onwards. Both LVM and RWT increase, by 20% and 10%, respectively, consistent with concentric rather than eccentric remodeling. Cardiac adaptation in hypertensive pregnancy deviates from that in healthy pregnancy by a greater change in LVM (95% increase from reference) and RWT (56% increase from reference). Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd.

To describe the physiological pattern of gestational plasma volume adjustments in normal singleton pregnancy and compare this with the pattern in pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction.We performed a meta-analysis of the current literature on plasma volume adjustments during physiological and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies reported both reference plasma volume measurements (non-pregnant, prepregnancy or postpartum) and measurements obtained during predetermined gestational ages. Mean differences bet ween the reference and pregnancy plasma volume measurements were calculated for predefined intervals of gestational age using a random-effects model described by DerSimonian and Laird.Thirty studies were included in the meta-analysis with publication dates ranging from 1934 to 2007. Plasma volume increased in the first weeks of pregnancy, with the steepest increase occurring during the second trimester. Plasma volume continued to increase in the third trimester with a pooled maximum increase of 1.13 L (95% CI, 1.07-1.19 L), an increase of 45.6% (95% CI, 43.0-48.1%) in physiological pregnancies compared with the reference value. The plasma volume expansion in gestational hypertensive and growth-restricted pregnancies was 0.80 L (95% CI, 0.59-1.02 L), an increase of 32.3% (95% CI, 23.6-41.1%) in the third trimester, a smaller increase than in physiological pregnancies (P 0.0001).During physiological pregnancy, plasma volume increases by, on average, more than 1 L as compared with non-pregnant conditions. In pregnancies complicated by pregnancy-induced hypertension, pre-eclampsia or fetal growth restriction, plasma volume increase in the third trimester is 13.3% lower than in normal pregnancy. Copyright © 2016 ISUOG. Published by John WileySons Ltd. Adaptación fisiológica del volumen del plasma materno durante el embarazo: una revisi\xF3n sistemática y metaanálisis RESUMEN OBJETIVO: Describir el patrón fisiológico de los cambios en el volumen del plasma gestacional en embarazos normales con feto único y compararlo con el patrón en los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal. MÉTODOS: Se realizó un metaanálisis de la literatura actual sobre los cambios en el volumen de plasma durante embarazos complicados y fisiológicos. La literatura se obtuvo de las bases de datos PubMed (NCBI) y EMBASE (Ovid). Los estudios incluidos mencionaban tanto mediciones de referencia del volumen plasmático (no embarazada, antes del embarazo o después del parto) como mediciones tomadas a edades gestacionales predeterminadas. Se calcularon las medias de las diferencias entre las mediciones de referencia y las del embarazo para el volumen plasmático a intervalos predefinidos de la edad gestacional, utilizando un modelo de efectos aleatorios descrito por DerSimonian y Laird.En el metaanálisis se incluyeron treinta estudios con fechas de publicación entre 1934 y 2007. El volumen plasmático aumentó en las primeras semanas de embarazo y el mayor incremento se produjo durante el segundo trimestre. El volumen de plasma continuó aumentando en el tercer trimestre con un aumento combinado máximo de 1,13L (IC 95%, 1,7-1,19 L), lo que supone un aumento del 45,6% (IC 95%, 43,0-48,1%) en embarazos fisiológicas en comparación con el valor de referencia. El aumento del volumen plasmático en los embarazos con hipertensión y con crecimiento intrauterino restringido fue de 0,80L (IC 95%, 0,59-1,02 L), lo que supone un aumento del 32,3% (IC 95%, 23,6-41,1%) en el tercer trimestre, y un incremento menor que en los embarazos fisiológicos (P0,0001).Durante el embarazo fisiológico el volumen de plasma aumenta, en promedio, más de 1L, en comparación con el de las no embarazadas. En los embarazos complicados por hipertensión gestacional, preeclampsia o restricción del crecimiento fetal, el aumento del volumen plasmático en el tercer trimestre es un 13,3% menor que en el embarazo normal. :meta : ,、。 : meta。PubMed(NCBI)EMBASE(Ovid)。(、)。DerSimonianLaird,。 : Meta30,19342007。,。,1.13 L(95% CI,1.07~1.19 L),,45.6%(95% CI,43.0%~48.1%)。0.80 L(95%CI,0.59~1.02 L),32.3%(95% CI,23.6%~41.1%),(P0.0001)。 : ,,1 L。、,13.3%。.

Background: Inhibition of vascular endothelial growth factor (VEGF) signaling by bevacizumab (Bv; Avastin) combined with chemotherapy (chemo) is associated with improved clinical benefit in several malignancies, including metastatic breast cancer (mBC). Bv+chemo was evaluated in HER2 negative mBC in AVADO where baseline biomarker (BM) sampling was included as an optional element to identify prognostic and predictive biomarkers. Different angiogenic markers have been evaluated in trials containing Bv, with most trials having focused on circulating VEGF. Thus far, VEGF seems to have more a prognostic than predictive value as demonstrated across different indications (lung, renal, and colorectal cancer [Bernaards et al. ASCO 2010]). Trends for the predictive value of intracellular adhesion molecule-1 (ICAM-1) have been noted in two NSCLC studies (E4599 and AVAiL) and for basic fibroblast growth factor in AVAiL. The value of angiogenic plasma markers has not yet been established in mBC. Material and Methods: In AVADO, 736 mBC patients (pts) were randomized to docetaxel 100mg/m2 plus either Bv7.5mg/kg, Bv15mg/kg or placebo. Primary endpoint was progression-free survival (PFS). Baseline plasma samples were analyzed for VEGF, ICAM-1, VEGF Receptor 1 and 2 (VEGFR1, 2), E-selectin and vascular cell adhesion molecule-1 using a novel ELISA based multiplex assay. Samples for BM analysis were available for 396 pts, equally distributed across treatment arms. Median levels of these markers were pre-specified as a cut point to categorize pts as low or high. Pre-treatment values were correlated with PFS (before start of subsequent antineoplastic therapy) using simple and multiple regression approaches as well as subgroup analyses. Results: All subgroups had HR point estimates in favor of the Bv arms, with the exception of pts with low VEGFR2 levels at a Bv dose of 7.5mg/kg. In general, high plasma levels of VEGF and VEGFR2 were associated with better treatment effect in this study. Low ICAM-1 levels did not show the trend towards a larger treatment effect previously seen in E4599 and AVAiL. Further analyses will be presented. Discussion: We report the first plasma BM data in a phase III placebo-controlled randomized study in mBC with Bv. In this subset analysis, using a novel ELISA assay, VEGF and VEGFR2 were identified as promising candidates for predictive value for PFS. A similar observation has been made in an independent BM analysis of pancreatic cancer (AVITA; data on file). Plasma data have so far not shown these trends in mCRC and mNSCLC. Further prospective evaluation of these markers is warranted. Authors D.W.M. and S.L.d.H. contributed equally. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-16-04.

Background: In HER2+ early breast cancer (eBC) pCR rates after standard neoadjuvant chemo- + anti-HER2 therapy differ according to hormone-receptor (HR) status. Molecular analysis reveals HER2+/HR+ BC as a distinct entity within HER2+ BC. The ADAPT HER2+/HR+ phase II trial aims to identify early responders to endocrine + anti-HER2 therapy. Methods: The trial completed recruitment in January 2015 (n=376). Patients (pts.) were randomized to 12 weeks of neoadjuvant therapy: A:T-DM1 (3.6 mg/kg q3w) vs. B:T-DM1 with endocrine therapy (ET) (pre-: tamoxifen; postmenopausal: aromatase inhibitor) vs C:trastuzumab q3w+ET. After surgery, standard chemotherapy at investigators' discretion and completion of 1y trastuzumab were recommended. Trial tests pCR (yPN0 and ypT0/is) in after T-DM1 or T-DM1+ET compared to T+ET. Biomarkers are measured at baseline and after 3 weeks. Results: Pre-planned interim analysis (n=130) aimed to identify an early-response biomarker (e.g. Ki-67 drop) and to validate trial assumptions. Median age was 49 years; 55% were pre-menopausal; 40% had cT1 tumors, 51% cT2; 68% had cN0, 27% cN1; 75% had G3. Median baseline Ki67 was 30%. In all arms, more than 95% received all 4 therapy cycles. 16 SAEs were reported in 13 pts (A:7; B:6; C:3); all CTC grade 1 (1), 2 (11) or 3 (4); all pts completely recovered without sequelae. Overall pCR rate was 30.8%: T-DM1: 40.5%, T-DM1+ET: 45.8%, T+ET: 6.7%. The difference between either arm T-DM1 arm vs. T+ET was significant (p Conclusions: The WSG-ADAPT HER2+/HR+ phase II trial is internationally the first large prospective randomized phase II trial specifically conducted within this distinct subtype. Interim analysis demonstrated for the first time clinically meaningful pCR rates (>40%) after short therapy (12 weeks) of T-DM1 ± ET without systemic chemotherapy in HER2+/HR+ eBC. Final efficacy and safety data will be presented at the meeting together with results of the correlative science program. Citation Format: Harbeck N, Gluz O, Christgen M, Braun M, Kuemmel S, Schumacher C, Potenberg J, Kraemer S, Kleine-Tebbe A, Augustin D, Aktas B, Forstbauer H, Tio J, Liedtke C, Kates RE, Wuerstlein R, de Haas SL, Kiermaier A, Kreipe HH, Nitz U. Final analysis of WSG-ADAPT HER2+/HR+ phase II trial: Efficacy, safety, and predictive markers for 12-weeks of neoadjuvant TDM1 with or without endocrine therapy versus trastuzumab+endocrine therapy in HER2-positive hormone-receptor-positive early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-03.

The paper discusses the use of computer technology as a tool for increasing access to and quality of our electrical engineering program at the California State University, Sacramento. Using readily available software and Internet access, a comprehensive set of lecture materials, student exercises and basic laboratory demonstrations are produced in electronic format in order to promote learning, reinforcement and consistency. While the central focus of this work is on learning, the convenience aspect of this method of delivery has proven to be effective tool for increasing performance as well as enrolment.

Acute epididymo-orchitis occasionally responds poorly to conservative measures. Testicular infarction may be one reason for this complication. Ultrasonography and radionuclide scanning can elucidate the cause. A patient with this complication is described.

Mental stress tests are frequently used in drug research. However, the reproducibility of the test is largely unknown particularly after repeated performance. Eight healthy volunteers performed mental arithmetic for 6 min (mental stress test) on 2 occasions separated by 14 days (during morning and afternoon session). During the tests, heart rate (HR) and systolic (SBP) and diastolic blood pressure (DBP) were determined on a beat-to-beat basis. Before testing baselines of BP and HR were assessed over one minute intervals. Data are shown as means ± SD and comparisons were made using paired Student's t-tests. Baseline values and responses to mental stress are summarised in the table. Baseline HR was lower in the morning than in the afternoon on both occasions, but was not different between occasions. Baseline DBP values were lower during the second occasion, but no circadian variation was noted. No differences in SBP were observed. Except for a slightly higher HR response at the first test performance, no differences were found for the reponses to mental stress. (See Table) Although baseline values for HR were different in the morning and afternoon, responses to mental stress were similar, except for a slightly higher response at the first test, which may reflect some habituation to the test with regard to HR. Thus, the response to mental stress appeared reproducible over multiple test sessions and may be a suitable tool to be used in drug research. Clinical Pharmacology & Therapeutics (2004) 75, P54–P54; doi: 10.1016/j.clpt.2003.11.204 Table 1. Occasion 1 Occasion 2 a.m. p.m. a.m. p.m. * p

The chemistry of ruthenium, osmium, rhodium and iridium in (Na, K)CN eutectic has been investigated by diffuse reflectance and infrared measurements on the quenched melts. Ruthenium and osmium are present as Ru(CN) 4− 6 and Os(Cn) 4− 6 ions. Rhodium, when added as Rh(III), displays characteristic spectra of Rh(III), Rh(I) and possibly a Rh(O) species. Only the latter two species are observed when Rh(I) is added to the melt or when the metal is anodically dissolved. Spectroscopic and NMR studies show that the low oxidation state rhodium compounds are oxidised to Rh(CN) 3− 6 through the formation of the intermediates RhH(CN) 3− 5 and RhH(CN) 4 H 2 O 2− . Low oxidation state iridium species in quenched melts are less stable than rhodium compounds, but otherwise follow the behaviour or rhodium closely.

Electronic absorption spectra were recorded on molten (Na, K)CN solutions containing rhodium, iridium, nickel, palladium and platinum, at temperatures exceeding 500 °C. Only, those complexes which have characteristic bands at energies lower than 340 nm could be identified; alkali cyanide absorbs strongly at higher energies. The low-oxidation state species, Rh(CN) 3− 4 and Rh(O)-cyanide, Ir(CN) 3− 4 and Ir(O)-cyanide complexes are present in the molten salt when the metals are dissolved as III- and I-oxidation state compounds. The complex Pd(I)-cyanide is formed whenPdCl 2 is dissolved in the melt, while Pt(I)-cyanide and Pt(O)-cyanide are formed when K 2 PtCl 4 is dissolved in the melt. An Ni(I) complex,Ni 2 (CN) 4− 6 , was identified in the molten cyanide to which NiCl 2 and Ni sponge had been added. A description also given of the spectroscopic equipment used, as well as of the graphite sample cell with diamond windows.

The chemistry of nickel, palladium and platinum in quenched (Na, K)CN eutectic melts has been investigated by diffuse-reflectance and infrared measurements. Nickel, when added as Ni(II), displays the characteristic spectra of Ni(II), and Ni(0) cyanide species. Only the latter species is formed when Ni(I) is added to the melt. A Ni(I) complex, Ni2(CN)4−6 is formed when Ni(II) and Ni powder is added to the melt. Palladium, when added as Pd(II), displays the characteristic spectra of Pd(II) and Pd(I) cyanide compounds. A Pd(0) cyanide complex formed when sodium cyanamide (reducing agent) is added to the latter melt. Three species, characterised as Pt(II), Pt(I) and Pt(0) cyanide complexes are formed when Pt(II) compounds are added to the melt. The concentration of the Pt(0) species is increased by adding sodium cyanamide to the melt, while the concentration of the Pt(I) species is increased upon he addition of sodium dicyanamide (oxidising agent). The preparation and identification of a palladium cyanohydride complex is also described.

Das chemische Verhalten der Titelmetalle im Eutektikum aus NaCN und KCN wurde durch UV- und IR-spektroskopische Messungen an den geloschten Schmelzen untersucht.