Safety and feasibility pilot study of continuous low-dose maternal supplemental oxygen in fetal single ventricle heart disease.

OBJECTIVES: Fetuses with single ventricle physiology (SVP) exhibit reductions in fetal cerebral oxygenation with associated delays in fetal brain growth and neurodevelopmental outcomes. Maternal supplemental oxygen (MSO) has been proposed to improve fetal brain growth but current evidence on dosing, candidacy, and outcomes are limited. In this pilot study, we evaluated the safety and feasibility of continuous low-dose MSO in the setting of SVP. METHODS: This single-centre, open-label, pilot phase 1 safety and feasibility clinical trial included 25 pregnant individuals with a fetal diagnosis of SVP. Participants self-administered continuous supplemental oxygen using medical-grade oxygen concentrators for up to 24 hours per day from the second half of gestation until delivery. The primary aim was the evaluation of the safety profile and feasibility of MSO. A secondary preliminary analysis was performed to assess the impact of MSO on the fetal circulation by echocardiography and late-gestational cardiovascular magnetic resonance, early outcomes including brain growth and pre-operative brain injury, and 18-month neurodevelopmental outcomes by the Bayley Scales of Infant and Toddler Development 3rd Edition compared to a contemporary fetal SVP cohort that received standard of care (SOC). RESULTS: Among 25 participants, the average maternal age at conception was 35 years, and fetal SVP diagnoses included 16 right ventricle dominant, 8 left ventricle dominant, and 1 indeterminant ventricular morphology. Participants started the trial at approximately 29.3 gestational weeks and took MSO for a median 16.1 hours per day for 63 days, cumulating a median 1029 hours of oxygen intake from enrollment until delivery. The only treatment-associated adverse events were nasal complications that were typically resolved by attaching a humidifier unit to the oxygen concentrator. No premature closure of the ductus arteriosus or unexpected fetal demise was observed. In the secondary analysis, MSO was not associated with any changes in fetal growth, middle cerebral artery pulsatility index, cerebroplacental ratio, nor head circumference to abdominal circumference ratio Z-scores over gestation compared to SOC. Although MSO was associated with changes in umbilical artery pulsatility index Z-score over gestation compared to SOC (p=0.02), this was likely due to initial baseline differences in placental resistance. At late-gestational cardiovascular magnetic resonance, MSO was not associated with any significant increase in umbilical vein oxygen saturation, fetal oxygen delivery, or fetal cerebral oxygen delivery. Similarly, we observed no differences in newborn outcomes including brain volume and pre-operative brain injury, nor mortality by 18 months of age, nor neurodevelopmental outcomes at 18 months of age. CONCLUSIONS: This pilot phase 1 clinical trial indicates low-dose maternal supplemental oxygen therapy is safe and well tolerated in pregnancies diagnosed with fetal SVP. However, our protocol was not associated with any significant changes in fetal circulatory physiology or improvements in early neurologic or neurodevelopmental outcomes. This article is protected by copyright. All rights reserved.

MRI characterization of hemodynamic patterns of human fetuses with cyanotic congenital heart disease.

OBJECTIVES: To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. METHODS: Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. RESULTS: Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. CONCLUSIONS: Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Long-term postnatal outcome of fetuses with prenatally suspected septo-optic dysplasia.

OBJECTIVES: Septo-optic dysplasia (SOD) is a clinical syndrome characterized by varying combinations of optic nerve hypoplasia, pituitary gland hypoplasia and abnormal cavum septi pellucidi. It is suspected on prenatal imaging when there is non-visualization or hypoplasia of the septal leaflets. Long-term postnatal outcomes of fetuses with prenatally suspected SOD have been documented poorly. The aims of this study were to describe the natural history of deficient septal leaflets, to quantify the incidence of postnatally confirmed SOD and to document the visual, endocrine and long-term neurodevelopmental outcomes of these infants. METHODS: This was an observational retrospective study of all fetuses with prenatal imaging showing isolated septal agenesis, assessed at a single tertiary center over an 11-year period. Pregnancy, delivery and neonatal outcomes and pre- and postnatal imaging findings were reviewed. Neonatal evaluations or fetal autopsy reports were assessed for confirmation of SOD. Ophthalmologic, endocrine, genetic and long-term developmental evaluations were assessed. Imaging findings and outcome were compared between infants with and those without postnatally confirmed SOD. RESULTS: Of 214 fetuses presenting with septal absence on prenatal ultrasound and magnetic resonance imaging (MRI), 18 (8.4%) were classified as having suspected isolated septal agenesis suspicious for SOD. Uniform prenatal MRI findings in cases with suspected SOD included remnants of the leaflets of the cavum septi pellucidi, fused forniceal columns, normal olfactory bulbs and tracts and a normal optic chiasm. Twelve fetuses were liveborn and five (27.8%) had postnatally confirmed SOD. Only two of these five fetuses had additional prenatal imaging features (pituitary cyst, microphthalmia and optic nerve hypoplasia) supporting a diagnosis of SOD. The other three confirmed SOD cases had no predictive prenatal or postnatal imaging findings that reliably differentiated them from cases without confirmed SOD. Visual and endocrine impairments were present in two (40%) and four (80%) cases with confirmed SOD, respectively. In those with visual and/or endocrine impairment, developmental delay (median age at follow-up, 2.5 (interquartile range, 2.5-7.0) years) was common (80%) and mostly severe. Neonates with isolated septal agenesis and a lack of visual or endocrine abnormalities to confirm SOD had normal development. CONCLUSIONS: Only a quarter of fetuses with isolated septal agenesis suggestive of SOD will have postnatal confirmation of the diagnosis. Clinical manifestations of SOD are variable, but neurodevelopmental delay may be more prevalent than thought formerly. © 2020 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Relationships of nutritional plane and feed efficiency with sexual development and fertility related measures in young beef bulls.

Sexual development in beef bulls appears to be influenced by nutritional plane and feed efficiency. Yearling bulls fed high (GRAIN = 49) and moderate (ROUGHAGE = 109) nutritional planes, were submitted to a performance test where scrotal circumference (SC), scrotum and testis ultrasonograms and hormones were monitored throughout. Scrotal thermographs, blood cell counts and semen were evaluated at the end of the test. Residual feed intake (RFI) was the measure of feed efficiency, and bulls within each population were characterized as efficient and inefficient. During the test period, the GRAIN group had greater triiodothyronine (T3), leptin and scrotal skin thickness (SST) while having greater T3, leptin, % motile sperm, % normal sperm, scrotal temperature and values for red blood cell variables at the end of the test when compared to the ROUGHAGE group. During the test, the efficient GRAIN group had lesser testis pixel intensity while at the end of the performance test the bulls of this group had greater % normal sperm and lower testis pixel intensity compared to bulls in inefficient GRAIN group. In comparison, the efficient ROUGHAGE group had less T3, SC and SST while at the end of the test these bulls had less T3, leptin, SC, SST and scrotal temperature compared to bulls in the inefficient ROUGHAGE group. Complete blood cell variables, semen quality, scrotal biometry and thermography explained most of the variation in RFI. Results of the present study support the hypothesis that there is an antagonistic relationship between feed efficiency and sexual development in young bulls, which seems partially offset when there is a greater plane of nutrition. Thus, feed efficiency should be factored in the reproductive evaluation of sires.

Associations of rumen parameters with feed efficiency and sampling routine in beef cattle.

Characterizing ruminal parameters in the context of sampling routine and feed efficiency is fundamental to understand the efficiency of feed utilization in the bovine. Therefore, we evaluated microbial and volatile fatty acid (VFA) profiles, rumen papillae epithelial and stratum corneum thickness and rumen pH (RpH) and temperature (RT) in feedlot cattle. In all, 48 cattle (32 steers plus 16 bulls), fed a high moisture corn and haylage-based ration, underwent a productive performance test to determine residual feed intake (RFI) using feed intake, growth, BW and composition traits. Rumen fluid was collected, then RpH and RT logger were inserted 5.5±1 days before slaughter. At slaughter, the logger was recovered and rumen fluid and rumen tissue were sampled. The relative daily time spent in specific RpH and RT ranges were determined. Polynomial regression analysis was used to characterize RpH and RT circadian patterns. Animals were divided into efficient and inefficient groups based on RFI to compare productive performance and ruminal parameters. Efficient animals consumed 1.8 kg/day less dry matter than inefficient cattle (P⩽0.05) while achieving the same productive performance (P⩾0.10). Ruminal bacteria population was higher (P⩽0.05) (7.6×1011 v. 4.3×1011 copy number of 16S rRNA gene/ml rumen fluid) and methanogen population was lower (P⩽0.05) (2.3×109 v. 4.9×109 copy number of 16S rRNA gene/ml rumen fluid) in efficient compared with inefficient cattle at slaughter with no differences (P⩾0.10) between samples collected on-farm. No differences (P⩾0.10) in rumen fluid VFA were also observed between feed efficiency groups either on-farm or at slaughter. However, increased (P⩽0.05) acetate, and decreased (P⩽0.05) propionate, butyrate, valerate and caproate concentrations were observed at slaughter compared with on-farm. Efficient had increased (P⩽0.05) rumen epithelium thickness (136 v. 126 µm) compared with inefficient cattle. Efficient animals also spent 318% and 93.2% more time (P⩽0.05) in acidotic (4.14% v. 1.30%) (pH⩽5.6) and optimal (5.6

Recruitment of PP1 to the centrosomal scaffold protein CEP192.

Centrosomal protein of 192 kDa (CEP192) is a scaffolding protein that recruits the mitotic protein kinases Aurora A and PLK1 to the centrosome. Here we demonstrate that CEP192 also recruits the type one protein phosphatase (PP1) via a highly conserved KHVTF docking motif. The threonine of the KHVTF motif is phosphorylated during mitosis and protein kinase inhibition studies suggest this to be a PLK1-dependent process.

Expression of DNA damage response proteins in cervical cancer patients treated with radical chemoradiotherapy.

OBJECTIVE: The management of locally advanced cervical cancer has improved significantly with the advent of cisplatin-based chemoradiotherapy (CRT) as the primary treatment regimen. Nevertheless, a significant proportion of patients fail to respond or relapse on this treatment and have a very poor prognosis. Our goal was to determine the prognostic value of a panel of proteins involved in detection and repair of DNA damage. METHODS: We performed fluorescence immunohistochemistry, and used software analysis to assess expression of DNA damage response proteins ATM, DNA-PKcs, PARP-1, Ku70 and Ku86 in 117 pre-treatment specimens from patients with locally advanced cervical cancer. We compared expression to clinicopathologic correlates to determine prognostic significance. RESULTS: Five-year progression-free survival was significantly lower in the low expressors than in high expressors of ATM (35% vs. 58%, p=0.044) and PARP-1 (24% vs. 61%, p=0.003), and showed a trend to significance for DNA-PKcs (30% vs. 60%, p=0.050). Low expression of the same proteins also correlated significantly with lower overall survival. In multivariable analysis, adjusted for FIGO stage and tumor size, low ATM and PARP-1 expression was significantly associated with both poorer progression-free and overall survival. Pairwise analyses indicated that expression levels of these proteins were correlated. CONCLUSIONS: Expression of DNA damage response proteins in cervical cancer is associated with outcome in patients treated with CRT. Immunohistochemical analysis of these proteins may be useful in guiding treatment decisions in such patients.

Associations of acute stress and overnight heart rate with feed efficiency in beef heifers.

Proxies have the potential to accelerate feed efficiency (residual feed intake (RFI); kg dry matter/day) improvement, assisting with the reduction of beef cattle feed costs and environmental impact. Heart rate (HR) (beats per minute (BPM)) is associated with feed efficiency and influenced by autonomic activity and peripheral metabolism, suggesting HR could be used as a proxy for feed efficiency. Objectives were to assess associations between overnight HR, lying patterns and RFI, and between acute stress HR and RFI. Heifer calves (n=107; 408±28 days of age, 341±42.2 kg) and yearling heifers (n=36; 604±92 days of age, 539±52.2 kg) were exposed to a performance test to determine productive performance. Overnight HR (electrode based) and lying patterns (accelerometer based) were monitored on a subgroup of heifer calves (n=40; 20 lowest RFI; 20 highest RFI). In the 10-min acute stress assessment, all heifers were individually exposed to the opening and closing of an umbrella and HR before (HRBEF), in response to (HRMAX), after (HRAFT) and change (HRCHG; HRAFT-HRBEF) as a result of exposure were determined. Using polynomial regression, rate of HR decrease pre-exposure (ß 1) and rates of HR increase (ß 2) and decrease (ß 3, ß 4) post-exposure were determined. Heifer calves in the overnight assessment were classified into equal RFI groups (low RFI; high RFI) and HR means were treated as repeated measures and compared using multiple regression. In the acute stress assessment, heifers were classified within cattle category into equal RFI groups (low RFI; high RFI) and means and polynomial regression parameters were compared using multiple regression. Low-RFI heifer calves had a lower overnight HR (69.2 v. 72.6 BPM), similar HR change from lying to standing intervals (8.9 v. 9.2 BPM) and similar time lying (61.1% v. 64.5%) compared with high-RFI heifer calves. Low-RFI heifer calves had a higher absolute HRMAX (162.9 v. 145.7 BPM) and ß 2 (-0.34 v. -0.20) than high-RFI heifer calves. Low-RFI yearling heifers had similar acute stress HR means and a lower ß 1 (0.003 v. 0.006) than high-RFI yearling heifers. Overnight HR and acute stress HR are potential indicators of RFI in heifer calves. However, acute stress HR results varied in yearling heifers, suggesting previous handling experience and/or age influence stress response. Pending further development (predictive ability, repeatability), the acute stress assessment could have potential for on-farm application as a feed efficiency proxy in young heifers with minimal handling experience.

Genomic clustering helps to improve prediction in a multibreed population.

Genomic prediction for crossbred beef cattle has shown limited results using low- to moderate-density SNP panels. The relationship between the training and validation populations, as well as the size of the reference population, affects the prediction accuracy for genomic selection. Rotational crossbreeding systems require the usage of crossbred animals as sires and dams of future generations, so crossbred animals require accurate evaluation. Here, a novel method for grouping of purebred and crossbred animals (based exclusively on genotypes) for genomic selection was investigated. Clustering of animals to investigate the genetic similarity among different groups was performed using several genomic relationship criteria between individuals. Hierarchical clusters based on average-link criteria (computed as the mean distance between elements of each subcluster) were formed. The accuracy of genomic prediction was assessed using 1,500 bulls genotyped for 54,609 markers. Estimated breeding values based on all available phenotypic records for birth weight, weaning gain, postweaning gain, and yearling gain were calculated using BLUP methodologies and deregressed to ensure unbiased comparisons could be made across populations. A 5-fold validation technique was used to calculate direct genomic values for all genotyped bulls; the addition of unrelated animals in the reference population was also investigated. We demonstrate a decrease in genomic selection accuracy after including animals from disconnected clusters. A method to improve genomic selection for crossbred and purebred animals by clustering animals based on their genotype is suggested. Unlike traditional approaches for genomic selection with a fixed reference population, genomic prediction using clusters (GPC) chooses the best reference population for better accuracy of genomic prediction of crossbred and purebred animals using clustering methods based on genotypes. An overall average gain in accuracy of 1.30% was noted over all scenarios across all traits investigated when the GPC approach was implemented. Further investigation is required to assess this difference in accuracy when a larger genotyped population is available, especially for the comparison of groups with higher genetic dissimilarity, such as those found in industry-wide across-breed genetic evaluations.

Seminal plasma protein concentrations vary with feed efficiency and fertility-related measures in young beef bulls.

Fertility-associated proteins (FAP) found in seminal plasma indicate sexual maturity, which appears to be influenced by feed efficiency in cattle. This study characterized FAP via proteomics and verified associations of these proteins with feed efficiency, body composition and fertility-related measures in yearling beef bulls. Assessments including testicular ultrasonography, infrared thermography, seminal quality, seminal plasma proteomics, carcass composition, and reproductive organ biometry were obtained. From a population of 31 bulls, the seven most and least feed efficient (efficient, inefficient) bulls were used for categorical comparisons. Correlations between FAP, productive performance and fertility-related measures were determined. These traits were also correlated with orthogonal factors summarized from the FAP. Efficient bulls had increased epididymal sperm-binding protein-1 and decreased concentration of protein-C inhibitor compared to inefficient bulls. Correlations between FAP with age, body size, body composition, reproductive organ biometry, scrotal temperature, and seminiferous tubule maturity are reported. Acrosin and cathepsin D increased with development of the testes and osteopontin increased with greater numbers of mature seminiferous tubules. Phosphoglycerate kinase-2 was higher in animals with a higher scrotum temperature and a higher prevalence of sperm morphology defects. The principal factor indicated that FAP variability concentrations were positively correlated with age, reproductive organ biometry, body size and composition. Our results indicate that FAP changes with body size and sexual development, and demonstrates differences in the proteomics of bulls with diverging feed efficiency. This is related to the delay in the sexual maturity of efficient young bulls.

Accuracy of genomic predictions for feed efficiency traits of beef cattle using 50K and imputed HD genotypes.

The accuracy of genomic predictions can be used to assess the utility of dense marker genotypes for genetic improvement of beef efficiency traits. This study was designed to test the impact of genomic distance between training and validation populations, training population size, statistical methods, and density of genetic markers on prediction accuracy for feed efficiency traits in multibreed and crossbred beef cattle. A total of 6,794 beef cattle data collated from various projects and research herds across Canada were used. Illumina BovineSNP50 (50K) and imputed Axiom Genome-Wide BOS 1 Array (HD) genotypes were available for all animals. The traits studied were DMI, ADG, and residual feed intake (RFI). Four validation groups of 150 animals each, including Angus (AN), Charolais (CH), Angus-Hereford crosses (ANHH), and a Charolais-based composite (TX) were created by considering the genomic distance between pairs of individuals in the validation groups. Each validation group had 7 corresponding training groups of increasing sizes ( = 1,000, 1,999, 2,999, 3,999, 4,999, 5,998, and 6,644), which also represent increasing average genomic distance between pairs of individuals in the training and validations groups. Prediction of genomic estimated breeding values (GEBV) was performed using genomic best linear unbiased prediction (GBLUP) and Bayesian method C (BayesC). The accuracy of genomic predictions was defined as the Pearson's correlation between adjusted phenotype and GEBV (), unless otherwise stated. Using 50K genotypes, the highest average achieved in purebreds (AN, CH) was 0.41 for DMI, 0.34 for ADG, and 0.35 for RFI, whereas in crossbreds (ANHH, TX) it was 0.38 for DMI, 0.21 for ADG, and 0.25 for RFI. Similarly, when imputed HD genotypes were applied in purebreds (AN, CH), the highest average was 0.14 for DMI, 0.15 for ADG, and 0.14 for RFI, whereas in crossbreds (ANHH, TX) it was 0.38 for DMI, 0.22 for ADG, and 0.24 for RFI. The of GBLUP predictions were greatly reduced with increasing genomic average distance compared to those from BayesC predictions. The results indicate that 50K genotypes, used with BayesC, are more effective for predicting GEBV in purebred cattle. Imputed HD genotypes found utility when dealing with composites and crossbreds. Formulation of a fairly large training set for genomic predictions in beef cattle should consider the genomic distance between the training and target populations.

Utilization of macrominerals and trace elements in pregnant heifers with distinct feed efficiencies.

The objective of the study was to evaluate utilization of dietary minerals and trace elements in pregnant heifers with distinct residual feed intakes (RFI). Feed intake, body weight (BW), and body composition traits were recorded in 36 crossbred heifers over a period of 37 wk, starting shortly after weaning at 8.3 (0.10; standard deviation) mo of age with an average BW of 276 (7.8) kg. Both BW and body composition were monitored regularly throughout the study, whereas individual feed intake was assessed during the last 84 d of the trial. Data recorded were used to calculate RFI for each heifer. Heifers were ranked based on RFI and assigned to high (n=14) or low (n=10) RFI groups. After the RFI study, 24 selected heifers [age 18.2 (0.14) mo; 87.5 (4.74) d in gestation; 497 (8.5) kg of BW] were used in an indirect digestibility trial (lignin as internal marker). Heifers were fed a ration containing corn silage, haylage, and a mineral premix in which Ca, P, K, Na, Mg, S, Cu, Fe, Mn, Mo, Se, Zn, and Co were provided in the diet according to National Research Council requirements of pregnant replacement heifers. The digestibility trial lasted 1 wk, during which samples of feces were gathered twice daily, and blood and liver biopsy samples were collected on the last day. We noted no significant differences between low- and high-RFI heifers in dry matter digestibility. Apparent absorption of Cu, Zn, and Mn was increased in heifers with low RFI, and apparent absorption of Co tended to be greater for these animals. Concentrations of macrominerals and trace elements in serum of pregnant heifers were similar for both groups except for Se, which was increased in the serum of low-RFI heifers. Liver concentrations of Cu, Fe, Mn, Mo, Se, and Zn did not differ between low- and high-RFI heifers. In conclusion, whereas improved absorption of some trace elements (Cu, Zn, Mn, and Co) and increased Se serum concentration appear to be associated with superior feed efficiency in pregnant heifers, further studies are needed to investigate the causality of such relationships.

Associations between feed efficiency, sexual maturity and fertility-related measures in young beef bulls.

The beef industry has emphasized the improvement of feed utilization, as measured by modeling feed intake through performance traits to calculate residual feed intake (RFI). Evidence supports an inverse relationship between feed efficiency and reproductive function. The objective of this study was to determine the relationship of reproductive assessments and RFI unadjusted (RFI(Koch)) or adjusted for body composition (RFI(us)) and the relationship among fertility-related parameters. In total, 34 crossbred bulls were housed together for 112 days of performance evaluation, followed by assessment of scrotum IR imaging, scrotal circumference, testes ultrasonography and semen quality parameters at 377±33.4 days of age. Bulls were slaughtered at 389±34.0 days of age, and analyses of carcass composition, biometrics and histomorphometry of the testis and epididymis were conducted. Bulls were grouped into two subpopulations based on divergence of RFI, and within each RFI model either by including 50% of the population (Halves, high and low RFI, n=17) or 20.6% extremes of the population (Tails, high and low RFI, n=7). The means of productive performance and fertility-related measures were compared through these categories. Pearson's correlation was calculated among fertility-related measures. In the Halves subpopulation of the RFI(us), sperm of low-RFI bulls had decreased progressive motility (47.30% v. 59.90%) and higher abundance of tail abnormalities (4.30% v. 1.80%) than that of high-RFI bulls. In the Tails subpopulation of the RFI(Koch), low RFI displayed less variation in the scrotum surface temperature (0.62°C v. 1.16°C), decreased testis echogenicity (175.50 v 198.00 pixels) and larger (60.90 v. 56.80 mm(2)) but less-developed seminiferous tubules than high-RFI bulls. The evaluation of fertility-related parameters indicated that a higher percentage of immature seminiferous tubules was correlated with occurrence of sperm with distal droplets (r=0.59), a larger temperature variation at the top of the scrotum was correlated with improved sperm progressive motility (r=0.38), a lower occurrence of sperm loose head abnormalities was correlated with larger temperature variation at the lower part of the scrotum (r=-0.43), and a lower minimum testis echogenicity (r=-0.59) and smaller scrotal circumference (r=0.72) were correlated with age. The adjustment for body composition (RFI determination) enabled distinct biological inferences about reproduction and feed efficiency when compared with the non-adjusted model. However, both RFI models and the correlation analysis supported the hypothesis that feed-efficient bulls have features of delayed sexual maturity. Overall, the assessment of fertility-related measurements is important to avoid the improvement of feed efficiency at the expense of reproductive function in young bulls.

Tract-Based Spatial Statistics in Preterm-Born Neonates Predicts Cognitive and Motor Outcomes at 18 Months.

BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. MATERIALS AND METHODS: Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. RESULTS: Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes. CONCLUSIONS: The strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population.

Estimation of genomic breeding values for residual feed intake in a multibreed cattle population.

Residual feed intake (RFI) is a measure of the efficiency of animals in feed utilization. The accuracies of GEBV for RFI could be improved by increasing the size of the reference population. Combining RFI records of different breeds is a way to do that. The aims of this study were to 1) develop a method for calculating GEBV in a multibreed population and 2) improve the accuracies of GEBV by using SNP associated with RFI. An alternative method for calculating accuracies of GEBV using genomic BLUP (GBLUP) equations is also described and compared to cross-validation tests. The dataset included RFI records and 606,096 SNP genotypes for 5,614 Bos taurus animals including 842 Holstein heifers and 2,009 Australian and 2,763 Canadian beef cattle. A range of models were tested for combining genotype and phenotype information from different breeds and the best model included an overall effect of each SNP, an effect of each SNP specific to a breed, and a small residual polygenic effect defined by the pedigree. In this model, the Holsteins and some Angus cattle were combined into 1 "breed class" because they were the only cattle measured for RFI at an early age (6-9 mo of age) and were fed a similar diet. The average empirical accuracy (0.31), estimated by calculating the correlation between GEBV and actual phenotypes divided by the square root of estimated heritability in 5-fold cross-validation tests, was near to that expected using the GBLUP equations (0.34). The average empirical and expected accuracies were 0.30 and 0.31, respectively, when the GEBV were estimated for each breed separately. Therefore, the across-breed reference population increased the accuracy of GEBV slightly, although the gain was greater for breeds with smaller number of individuals in the reference population (0.08 in Murray Grey and 0.11 in Hereford for empirical accuracy). In a second approach, SNP that were significantly (P < 0.001) associated with RFI in the beef cattle genomewide association studies were used to create an auxiliary genomic relationship matrix for estimating GEBV in Holstein heifers. The empirical (and expected) accuracy of GEBV within Holsteins increased from 0.33 (0.35) to 0.39 (0.36) and improved even more to 0.43 (0.50) when using a multibreed reference population. Therefore, a multibreed reference population is a useful resource to find SNP with a greater than average association with RFI in 1 breed and use them to estimate GEBV in another breed.

The relationship between feed efficiency and the circadian profile of blood plasma analytes measured in beef heifers at different physiological stages.

The characterization of blood metabolite concentrations over the circadian period and across physiological stages is important for understanding the biological basis of feed efficiency, and may culminate in indirect methods for assessing feed efficiency. Hematological analyses for albumin, urea, creatine kinase, glutamate dehydrogenase, aspartate aminotransferase, carbon dioxide, and acetate were carried out in growing and gestating heifers. These measures were carried out in a sample of 36 Bos taurus crossed beef heifers held under the same husbandry conditions. Hourly blood samples were collected over a 24-h period on three separate sampling occasions, corresponding approximately to the yearling (and open), early-gestation and late-gestation stages. This design was used to determine variation throughout the day, effects due to physiological status and any associations with feed efficiency, as measured by residual feed intake. Blood analyte levels varied with time of day, with the most variation occurring between 0800 and 1600 h. There were also considerable differences in analyte levels across the three physiological stages; for example, creatine kinase was higher (P<0.05) in open heifers, followed by early- and late-gestation heifers. Feed efficiency was also associated with analyte abundance. In more feed-efficient open heifers, there were higher activities of creatine kinase (P<0.05) and aspartate aminotransferase (P<0.05), and lower concentrations of carbon dioxide (P<0.05). Furthermore, in late gestation, more efficient heifers had lower urea concentrations (P<0.05) and lower creatine kinase levels (P<0.05). Over the whole experimental period, carbon dioxide concentrations were numerically lower in more feed efficient heifers (P=0.079). Differences were also observed across physiological stages. For instance, open heifers had increased levels (P<0.05) of creatine kinase, aspartate aminotransferase, carbon dioxide than early and late pregnancy heifers. In essence, this study revealed relevant information about the metabolic profile in the context of feed efficiency and physiological stages. Further optimization of our approach, along with the evaluation of complementary analytes, will aid in the development of robust, indirect assessments of feed efficiency.

Reliability of molecular breeding values for Warner-Bratzler shear force and carcass traits of beef cattle - an independent validation study.

Interest in genetic improvement of carcass and tenderness traits of beef cattle using genome-based selection (GS) and marker-assisted management programs is increasing. The success of such a program depends on the presence of linkage disequilibrium between the observed markers and the underlying QTL as well as on the relationship between the discovery, validation, and target populations. For molecular breeding values (MBV) predicted for a target population using SNP markers, reliabilities of these MBV can be obtained from validation analyses conducted in an independent population distinct from the discovery set. The objective of this study was to test MBV predicted for carcass and tenderness traits of beef cattle in a Canadian-based validation population that is largely independent of a United States-based discovery set. The discovery data set comprised of genotypes and phenotypes from >2,900 multibreed beef cattle while the validation population consisted of 802 crossbred feeder heifers and steers. A bivariate animal model that fitted actual phenotype and MBV was used for validation analyses. The reliability of MBV was defined as square of the genetic correlation (R(2) g) that represents the proportion of the additive genetic variance explained by the SNP markers. Several scenarios involving different starting marker panels (384, 3K, 7K, and 50K) and different sets of SNP selected to compute MBV (50, 100, 200, 375, 400, 600, and 800) were investigated. Validation results showed that the most reliable MBV (R(2) g) were 0.34 for HCW, 0.36 for back fat thickness, 0.28 for rib eye area, 0.30 for marbling score, 0.25 for yield grade, and 0.38 for Warner-Bratzler shear force across the different scenarios explored. The results indicate that smaller SNP panels can be developed for use in genetic improvement of beef carcass and tenderness traits to exploit GS benefits.

Impact of reference population on accuracy of imputation from 6K to 50K single nucleotide polymorphism chips in purebred and crossbreed beef cattle.

Genotyping with lower density but lower cost panels enables more animals to be genotyped for genomic selection. Imputation enables the determination of missing SNP genotypes in animals genotyped with a low-density panel by using information from a reference population genotyped with a higher density panel, which should increase accuracy of genomic EBV. In this study, population imputation, using linkage disequilibrium among markers, was implemented using the software BEAGLE, FIMPUTE 2.2, and IMPUTE2 in a multibreed, crossbred taurine beef cattle population genotyped with the Illumina SNP50. Different combinations of reference populations and imputed animals were defined based on breed composition. Number of animals (n = 250 to 4,932) and the presence of closer relatives in the reference population (only for Angus animals) were investigated. The overall average imputation accuracy for purebred animals ranged from 94.20 to 97.93% using FIMPUTE, from 95.35 to 98.31% using IMPUTE2, and from 90.02 to 96.38% when BEAGLE software was used. Imputation accuracy of crossbred animals ranged from 54.15 to 97.53% (FIMPUTE), from 57.04 to 97.46% (IMPUTE2), and from 54.35 to 95.64% (BEAGLE). Higher imputation accuracies were obtained when closer relatives along with the breed composition of imputed animals was well represented in the reference population. Within breed imputation from 6K to 50K did not improve when an additional purebred population was added to the reference population. FIMPUTE reduced the run time by 13 to 52 times compared to BEAGLE and 51 to 108 times compared to IMPUTE2.

A meta-analysis of the effects of dietary copper, molybdenum, and sulfur on plasma and liver copper, weight gain, and feed conversion in growing-finishing cattle.

The minerals Cu, Mo, and S are essential for metabolic functions related to cattle health and performance. The interaction between Cu, Mo, and S can determine the utilization of each mineral, in particular Cu, by ruminants. A meta-analysis was performed to evaluate the effects of dietary Cu, Mo, and S and their interactions on plasma and liver Cu, ADG, and G:F in growing-finishing cattle. Data were collated from 12 published studies. The model with the best fit to data indicated plasma Cu was positively affected by dietary Cu (P < 0.01) and negatively affected by both dietary Mo (P < 0.01) and S (P < 0.01). Another model also indicated that plasma Cu concentration is positively related to Cu:Mo ratio in the diet (P < 0.01). Dietary Cu had a positive effect on liver Cu (P < 0.01), whereas Mo showed a negative effect (P < 0.05), and no effect of dietary S on liver Cu was observed (P > 0.05). Average daily gain was negatively affected by dietary Mo (P < 0.05) and S (P < 0.01) and positively affected by Cu:Mo ratio (P < 0.01), likely because an increased Cu:Mo ratio minimizes the antagonistic effect of Mo on Cu. The feed conversion ratio was negatively affected by Mo (P < 0.05) and S (P < 0.01), whereas effects of the Cu:Mo ratio and dietary Cu were not significant (P > 0.05). The interaction between S and Mo affected (P < 0.01) G:F, which was likely related to a positive response with the proper balance between these minerals. In conclusion, dietary Cu, Mo, and S and the Cu:Mo ratio caused changes in plasma Cu. Only dietary Mo and S led to a negative response in the performance of growing-finishing cattle, whereas the diet Cu:Mo ratio has a linear and quadratic effect on ADG. Nutritionists and producers need to consider with caution the supplementation of growing-finishing cattle diets with Mo and S because of their potentially adverse effects on animal performance. An appropriate Cu:Mo ratio is desirable to minimize the effects of an impaired supply of Mo on Cu metabolism and ADG.

Influence of pregnancy in mid-to-late gestation on circulating metabolites, visceral organ mass, and abundance of proteins relating to energy metabolism in mature beef cows.

In mid-to-late gestation, nutrient demand increases to meet the growth requirements of the conceptus and cows may alter metabolism in response to energy demands of pregnancy. By better understanding the metabolic role of pregnancy, there may be opportunities to better understand maintenance energy costs and improve overall feed efficiency. Eighteen mature Simmental/Angus crossbred cows, pregnant (PREG; n = 9) and nonpregnant (OPEN; n = 9), were used to investigate the effect of pregnancy on BW change, carcass traits, visceral organ mass, and circulating serum metabolites. Cows were blocked by day of expected parturition such that each block was slaughtered 4 to 5 wk before parturition. Cows were individually fed for ad libitum intake using Calan gates for 89 to 105 d. Cows were weighed, ultrasounded for rib (over the 12th and 13th rib) and rump fat, and a serum sample obtained at d 1, 56, and 3 to 5 d before slaughter. At slaughter, organs were removed, trimmed of fat, and weighed. Serum was analyzed for ß-hydroxybutyrate (BHBA), NEFA, glucose, urea, total cholesterol, and triiodothyronine (T3). Tissue samples from liver, kidney, sternomandibularis muscle, ruminal papillae, pancreas, and small intestinal mucosa were collected at slaughter and snap frozen in liquid N. Western blots were conducted to quantify abundance of: proliferating cell nuclear antigen (PCNA), ATP synthase, ubiquitin, and Na(+)/K+ ATPase for all tissues; PPARγ, PPARγ coactivator 1α (PGC1-α), 5'-adenosine monophosphate-activated protein kinase (AMPK) and phosphorylated-AMPK (pAMPK) for liver, muscle, and rumen; phosphoenolpyruvate carboxykinase (PEPCK) for liver and kidney; and uncoupling protein 2 (UCP2) for liver. Data were analyzed using PROC MIXED in SAS as a replicated randomized complete block. Liver weights (actual, relative to BW, relative to HCW) were heavier (P ≤ 0.02) in OPEN. Rumen mass and kidney fat weight, both relative to BW, were also greater (P ≤ 0.04) in OPEN. On d 56 and at preslaughter, PREG cows had greater (P ≤ 0.04) BHBA, NEFA and urea concentrations and lower (P = 0.04) cholesterol concentration. Hepatic Na(+)/K+ ATPase abundance was greater (P = 0.04) in PREG cows. In rumen papillae, abundance of pAMPKα was increased (P = 0.006) in PREG cows. These data indicate that PREG cows may metabolize energy reserves and alter their metabolism to meet the energetic demands of the growing fetus.