Particle Dynamics in a Diblock-Copolymer-Based Dodecagonal Quasicrystal and Its Periodic Approximant by X-Ray Photon Correlation Spectroscopy.

Temperature-dependent x-ray photon correlation spectroscopy (XPCS) measurements are reported for a binary diblock-copolymer blend that self-assembles into an aperiodic dodecagonal quasicrystal and a periodic Frank-Kasper σ phase approximant. The measured structural relaxation times are Bragg scattering wavevector independent and are 5 times faster in the dodecagonal quasicrystal than the σ phase, with minimal temperature dependence. The underlying dynamical relaxations are ascribed to differences in particle motion at the grain boundaries within each of these tetrahedrally close-packed assemblies. These results identify unprecedented particle dynamics measurements of tetrahedrally coordinated micellar block polymers, thus expanding the application of XPCS to ordered soft materials.

Pedigree diversity and implications for genetic selection of Katahdin sheep.

The Katahdin hair breed gained popularity in the United States as low input and prolific, with a propensity to exhibit parasite resistance. With the introduction of genomically enhanced estimated breeding values (GEBV) to the Katahdin genetic evaluation, defining the diversity present in the breed is pertinent. Utilizing pedigree records (n = 92,030) from 1984 to 2019 from the National Sheep Improvement Program, our objectives were to (i) estimate the completeness and quality of the pedigree, (ii) calculate diversity statistics for the whole pedigree and relevant reference subpopulations and (iii) assess the impact of current diversity on genomic selection. Reference 1 was Katahdins born from 2017 to 2019 (n = 23,494), while reference 2 was a subset with at least three generations of Katahdin ancestry (n = 9327). The completeness of the whole pedigree, and the pedigrees of reference 1 and reference 2, were above 50% through the fourth, fifth and seventh generation of ancestors, respectively. Effective population size (Ne) averaged 111 animals with a range from 42.2 to 451.0. The average generation interval was 2.9 years for the whole pedigree and reference 1, and 2.8 years for reference 2. The mean individual inbreeding and average relatedness coefficients were 1.62% and 0.91%, 1.74% and 0.90% and 2.94% and 1.46% for the whole pedigree, reference 1, and reference 2, respectively. There were over 300 effective founders in the whole pedigree and reference 1, with 169 in reference 2. Effective number of ancestors were over 150 for the whole pedigree and reference 1, while there were 67 for reference 2. Prediction accuracies increased as the reference population grew from 1k to 7.5k and plateaued at 15k animals. Given the large number of founders and ancestors contributing to the base genetic variation in the breed, the Ne is sufficient to maintain diversity while achieving progress with selection. Stable low rates of inbreeding and relatedness suggest that incorporating genetic conservation in breeding decisions is currently not of high priority. Current Ne suggests that with limited genotyping, high levels of accuracy for genomic prediction can be achieved. However, intense selection on GEBV may cause loss of genetic diversity long term.

SNP- and haplotype-based single-step genomic predictions for body weight, wool, and reproductive traits in North American Rambouillet sheep.

Rambouillet sheep are commonly raised in extensive grazing systems in the US, mainly for wool and meat production. Genomic evaluations in US sheep breeds, including Rambouillet, are still incipient. Therefore, we aimed to evaluate the feasibility of performing genomic prediction of breeding values for various traits in Rambouillet sheep based on single nucleotide polymorphisms (SNP) or haplotypes (fitted as pseudo-SNP) under a single-step GBLUP approach. A total of 28,834 records for birth weight (BWT), 23,306 for postweaning weight (PWT), 5,832 for yearling weight (YWT), 9,880 for yearling fibre diameter (YFD), 11,872 for yearling greasy fleece weight (YGFW), and 15,984 for number of lambs born (NLB) were used in this study. Seven hundred forty-one individuals were genotyped using a moderate (50 K; n = 677) or high (600 K; n = 64) density SNP panel, in which 32 K SNP in common between the two SNP panels (after genotypic quality control) were used for further analyses. Single-step genomic predictions using SNP (H-BLUP) or haplotypes (HAP-BLUP) from blocks with different linkage disequilibrium (LD) thresholds (0.15, 0.35, 0.50, 0.65, and 0.80) were evaluated. We also considered different blending parameters when constructing the genomic relationship matrix used to predict the genomic-enhanced estimated breeding values (GEBV), with alpha equal to 0.95 or 0.50. The GEBV were compared to the estimated breeding values (EBV) obtained from traditional pedigree-based evaluations (A-BLUP). The mean theoretical accuracy ranged from 0.499 (A-BLUP for PWT) to 0.795 (HAP-BLUP using haplotypes from blocks with LD threshold of 0.35 and alpha equal to 0.95 for YFD). The prediction accuracies ranged from 0.143 (A-BLUP for PWT) to 0.330 (A-BLUP for YGFW) while the prediction bias ranged from -0.104 (H-BLUP for PWT) to 0.087 (HAP-BLUP using haplotypes from blocks with LD threshold of 0.15 and alpha equal to 0.95 for YGFW). The GEBV dispersion ranged from 0.428 (A-BLUP for PWT) to 1.035 (A-BLUP for YGFW). Similar results were observed for H-BLUP or HAP-BLUP, independently of the LD threshold to create the haplotypes, alpha value, or trait analysed. Using genomic information (fitting individual SNP or haplotypes) provided similar or higher prediction and theoretical accuracies and reduced the dispersion of the GEBV for body weight, wool, and reproductive traits in Rambouillet sheep. However, there were no clear improvements in the prediction bias when compared to pedigree-based predictions. The next step will be to enlarge the training populations for this breed to increase the benefits of genomic predictions.

Assessing Population Structure and Genetic Diversity in US Suffolk Sheep to Define a Framework for Genomic Selection.

Long-term sustainability of breeds depends on having sufficient genetic diversity for adaptability to change, whether driven by climatic conditions or by priorities in breeding programs. Genetic diversity in Suffolk sheep in the United States was evaluated in four ways: 1) using genetic relationships from pedigree data [(n = 64 310 animals recorded in the US National Sheep Improvement Program (NSIP)]; 2) using molecular data (n = 304 Suffolk genotyped with the OvineHD BeadChip); 3) comparing Australian (n = 109) and Irish (n = 55) Suffolk sheep to those in the United States using molecular data; and 4) assessing genetic relationships (connectedness) among active Suffolk flocks (n = 18) in NSIP. By characterizing genetic diversity, a goal was to define the structure of a reference population for use for genomic selection strategies in this breed. Pedigree-based mean inbreeding level for the most recent year of available data was 5.5%. Ten animals defined 22.8% of the current gene pool. The effective population size (Ne) ranged from 27.5 to 244.2 based on pedigree and was 79.5 based on molecular data. Expected (HE) and observed (HO) heterozygosity were 0.317 and 0.306, respectively. Model-based population structure included 7 subpopulations. From Principal Component Analysis, countries separated into distinct populations. Within the US population, flocks formed genetically disconnected clusters. A decline in genetic diversity over time was observed from both pedigree and genomic-based derived measures with evidence of population substructure as measured by FST. Using these measures of genetic diversity, a framework for establishing a genomic reference population in US Suffolk sheep engaged in NSIP was proposed.

Stability of the A15 phase in diblock copolymer melts.

The self-assembly of block polymers into well-ordered nanostructures underpins their utility across fundamental and applied polymer science, yet only a handful of equilibrium morphologies are known with the simplest AB-type materials. Here, we report the discovery of the A15 sphere phase in single-component diblock copolymer melts comprising poly(dodecyl acrylate)-block-poly(lactide). A systematic exploration of phase space revealed that A15 forms across a substantial range of minority lactide block volume fractions (fL = 0.25 - 0.33) situated between the σ-sphere phase and hexagonally close-packed cylinders. Self-consistent field theory rationalizes the thermodynamic stability of A15 as a consequence of extreme conformational asymmetry. The experimentally observed A15-disorder phase transition is not captured using mean-field approximations but instead arises due to composition fluctuations as evidenced by fully fluctuating field-theoretic simulations. This combination of experiments and field-theoretic simulations provides rational design rules that can be used to generate unique, polymer-based mesophases through self-assembly.

Interobserver and Intraobserver Agreement are Unsatisfactory When Determining Abstract Study Design and Level of Evidence.

BACKGROUND: Understanding differences between types of study design (SD) and level of evidence (LOE) are important when selecting research for presentation or publication and determining its potential clinical impact. The purpose of this study was to evaluate interobserver and intraobserver reliability when assigning LOE and SD as well as quantify the impact of a commonly used reference aid on these assessments. METHODS: Thirty-six accepted abstracts from the Pediatric Orthopaedic Society of North America (POSNA) 2021 annual meeting were selected for this study. Thirteen reviewers from the POSNA Evidence-Based Practice Committee were asked to determine LOE and SD for each abstract, first without any assistance or resources. Four weeks later, abstracts were reviewed again with the guidance of the Journal of Bone and Joint Surgery (JBJS) LOE chart, which is adapted from the Oxford Centre for Evidence-Based Medicine. Interobserver and intraobserver reliability were calculated using Fleiss' kappa statistic (k). χ2 analysis was used to compare the rate of SD-LOE mismatch between the first and second round of reviews. RESULTS: Interobserver reliability for LOE improved slightly from fair (k=0.28) to moderate (k=0.43) with use of the JBJS chart. There was better agreement with increasing LOE, with the most frequent disagreement between levels 3 and 4. Interobserver reliability for SD was fair for both rounds 1 (k=0.29) and 2 (k=0.37). Similar to LOE, there was better agreement with stronger SD. Intraobserver reliability was widely variable for both LOE and SD (k=0.10 to 0.92 for both). When matching a selected SD to its associated LOE, the overall rate of correct concordance was 82% in round 1 and 92% in round 2 (P<0.001). CONCLUSION: Interobserver reliability for LOE and SD was fair to moderate at best, even among experienced reviewers. Use of the JBJS/Oxford chart mildly improved agreement on LOE and resulted in less SD-LOE mismatch, but did not affect agreement on SD. LEVEL OF EVIDENCE: Level II.

Origins of low-symmetry phases in asymmetric diblock copolymer melts.

Cooling disordered compositionally asymmetric diblock copolymers leads to the formation of nearly spherical particles, each containing hundreds of molecules, which crystallize upon cooling below the order-disorder transition temperature (TODT). Self-consistent field theory (SCFT) reveals that dispersity in the block degrees of polymerization stabilizes various Frank-Kasper phases, including the C14 and C15 Laves phases, which have been accessed experimentally in low-molar-mass poly(isoprene)-b-poly(lactide) (PI-PLA) diblock copolymers using thermal processing strategies. Heating and cooling a specimen containing 15% PLA above and below the TODT from the body-centered cubic (BCC) or C14 states regenerates the same crystalline order established at lower temperatures. This memory effect is also demonstrated with a specimen containing 20% PLA, which recrystallizes to either C15 or hexagonally ordered cylinders (HEXC) upon heating and cooling. The process-path-dependent formation of crystalline order shapes the number of particles per unit volume, n/V, which is retained in the highly structured disordered liquid as revealed by small-angle X-ray scattering (SAXS) experiments. We hypothesize that symmetry breaking during crystallization is governed by the particle number density imprinted in the liquid during ordering at lower temperature, and this metastable liquid is kinetically constrained from equilibrating due to prohibitively large free energy barriers for micelle fusion and fission. Ordering at fixed n/V is enabled by facile chain exchange, which redistributes mass as required to meet the multiple particle sizes and packing associated with specific low-symmetry Frank-Kasper phases. This discovery exposes universal concepts related to order and disorder in self-assembled soft materials.

Lamb wool shedding is a good predictor of ewe wool shedding.

Interest in reducing labour costs due to shearing has led to development of breed types that shed their wool naturally. Selection at young ages can facilitate response. Reliability of predictions of adult from lamb wool shedding (WS) is thus key in the design of breeding programmes to increase shedding. Our objectives were to estimate heritabilities and genetic relationships between WS measured once in lambs and repeatedly in ewes and to assess the accuracy of lamb WS EBV to predict ewe WS EBV based on a multi-trait threshold or a repeatability model. Data were 4,971 lamb and 3,335 ewe WS records on a Romanov, White Dorper and Katahdin composite flock. For the multivariate model, WS heritability ranged from 0.47 ± 0.03 in lambs to 0.59 ± 0.04 at 1 year of age. For the repeatability model, WS in adult ewes was moderately heritable (0.50 ± 0.03) and repeatable (0.60 ± 0.02). Genetic correlations were 0.72 ± 0.04, 0.65 ± 0.05, 0.50 ± 0.09 and 0.51 ± 0.09 between lamb WS and 1st through 4th record, respectively. Given the moderately high heritability and high correlations between WS performance in lambs and ewes, selecting animals early in life would effectively increase WS in crossbred flocks.

FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver.

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Evaluation and Management of Testosterone Deficiency: AUA Guideline.

PURPOSE: There has been a marked increase in testosterone prescriptions in the past decade resulting in a growing need to give practicing clinicians proper guidance on the evaluation and management of the testosterone deficient patient. MATERIALS AND METHODS: A systematic review utilized research from the Mayo Clinic Evidence Based Practice Center and additional supplementation by the authors. Evidence-based statements were based on body of evidence strength Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This guideline was developed by a multi-disciplinary panel to inform clinicians on the proper assessment of patients with testosterone deficiency and the safe and effective management of men on testosterone therapy. Additional statements were developed to guide the clinician on the appropriate care of patients who are at risk for or have cardiovascular disease or prostate cancer as well as patients who are interested in preserving fertility. CONCLUSIONS: The care of testosterone deficient patients should focus on accurate assessment of total testosterone levels, symptoms, and signs as well as proper on-treatment monitoring to ensure therapeutic testosterone levels are reached and symptoms are ameliorated. Future longitudinal observational studies and clinical trials of significant duration in this space will improve diagnostic techniques and treatment of men with testosterone deficiency as well as provide more data on the adverse events that may be associated with testosterone therapy.

Role of Chain Length in the Formation of Frank-Kasper Phases in Diblock Copolymers.

The phase behavior of poly(styrene)-b-poly(1,4-butadiene) diblock copolymers with a polymer block invariant degree of polymerization N[over ¯]_{b}≈800 shows no evidence of Frank-Kasper phases, in contrast to low molar mass diblock copolymers (N[over ¯]_{b}<100) with the same conformational asymmetry. A universal self-concentration crossover parameter N[over ¯]_{x}≈400 is identified, directly related to the crossover to entanglement dynamics in polymer melts. Mean-field behavior is recovered when N[over ¯]_{b}>N[over ¯]_{x}, while complex low symmetry phase formation is attributed to fluctuations and space-filling constraints, which dominate when N[over ¯]_{b}

Conformational Asymmetry and Quasicrystal Approximants in Linear Diblock Copolymers.

Small angle x-ray scattering experiments on three model low molar mass diblock copolymer systems containing minority polylactide and majority hydrocarbon blocks demonstrate that conformational asymmetry stabilizes the Frank-Kasper σ phase. Differences in block flexibility compete with space filling at constant density inducing the formation of polyhedral shaped particles that assemble into this low symmetry ordered state with local tetrahedral coordination. These results confirm predictions from self-consistent field theory that establish the origins of symmetry breaking in the ordering of block polymer melts subjected to compositional and conformational asymmetry.

Factors associated with suicide in patients with genitourinary malignancies.

BACKGROUND: Approximately 70% of all suicides in patients aged >60 years are attributed to physical illness, with higher rates noted in patients with cancer. The purpose of the current study was to characterize suicide rates among patients with genitourinary cancers and identify factors associated with suicide in this specific cohort. METHODS: Patients with prostate, bladder, kidney, testis, and penile cancer were identified in the Surveillance, Epidemiology, and End Results database (1988-2010). Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated for each anatomic site. Multivariable logistic regression models generated odds ratios (ORs) for the identification of factors associated with suicide for each malignancy. RESULTS: There were 2268 suicides identified among 1,239,522 individuals with genitourinary malignancies observed for 7,307,377 person-years. The SMRs for patients with cancer were 1.37 for prostate cancer (95% CI, 0.99-1.86), 2.71 for bladder cancer (95% CI, 2.02-3.62), 1.86 for kidney cancer (95% CI, 1.32-2.62), 1.23 for testis cancer (95% CI, 0.88-1.73), and 0.95 for penile cancer (95% CI, 0.65-1.35). On multivariable analysis, male sex was found to be associated with odds of suicide among patients with bladder cancer (OR, 6.63) and kidney cancer (OR, 4.98). Increasing age was associated with suicide for patients with prostate, bladder, and testis cancer (OR range, 1.03-1.06). Distant disease was associated with suicide in patients with prostate, bladder, and kidney cancer (OR range, 2.82-5.43). Among patients with prostate, bladder, and kidney cancer, African American patients were less likely to commit suicide compared with white individuals (OR range, 0.26-0.46). CONCLUSIONS: Suicide in patients with genitourinary malignancies poses a public health dilemma, especially among men, the elderly, and those with aggressive disease. Clinicians should be aware of risk factors for suicide in these patients.

A comprehensive history of injection therapy for erectile dysfunction, 1982-2023.

INTRODUCTION: Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982. OBJECTIVES: To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy. METHODS: Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed. RESULTS: The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine. CONCLUSIONS: After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.

Impact of planning horizon length on traits in an economic breeding goal and ranking of selection candidates in beef cattle.

In beef production herds, unique situations such as breeding system, economic parameters, and current phenotypic performance can affect the emphasis of traits in the breeding goal and consequently the weighting of traits within a selection index. An often overlooked component of breeding goals is the planning horizon, or the time span to consider the economic impact of a selection decision, that varies between enterprises. A platform for constructing economic selection indexes (iGENDEC) was used to determine the impact of planning horizon length, breeding system, and sale endpoint on the relative emphasis of traits in the breeding goal and the re-ranking of selection candidates. As part of this investigation, the adjustment of phenotypic means for hot carcass weight and planning horizons were used to determine the impact of the relative emphasis on hot carcass weight as its mean approached a predetermined discount threshold. General-purpose indexes were created for animals sold at weaning and slaughter for three breeding systems with six different planning horizons (2, 5, 10, 20, 30, and 50 yr). As planning horizon increased, the relative emphasis on weaning weight or hot carcass weight, which affected revenue, decreased while the relative emphasis on stayability and mature weight increased. As the phenotypic mean for hot carcass weight approached and surpassed a predetermined discount threshold, the relative emphasis decreased before increasing again, once the mean weight surpassed the threshold. Rank correlations between indexes with different sale endpoints was 0.71 ±â€…0.1. Within a slaughter endpoint, re-ranking occurred between short and long planning horizons (r = 0.78 ±â€…0.09) while that of a weaning endpoint was less substantial (r = 0.85 ±â€…0.10). Jacard index scores between indexes with different planning horizons ranged from 39.7% to 87.9% and from 47.9% to 78.7% for weaning and carcass endpoints, respectively, for the top 5% of selection candidates. These results illustrate that the determination of a planning horizon can impact the rank of selection candidates and increases in net profit.

Genetic impact of external Targhee sires at the U.S. Sheep Experiment Station: a case study of introgression.

Sheep breeders requested that the U.S. Sheep Experiment Station (USSES) to participate in national genetic evaluation through the National Sheep Improvement Program (NSIP). The reasons included the need for (1) a comparison of the productivity of industry and United States Department of Agriculture (USDA) lines, (2) transparency of USDA flocks, (3) genetic ties for NSIP by sampling of industry flocks, and (4) development of premium genetic lines for public release. In response, USSES began to incorporate external sires from NSIP participating flocks into the USSES Targhee flock. Our objective, based on a pedigree analysis, was to test if introgression of external genetics into the flock was achieved. The pedigree included 13,189 animals with mean maximum generations, mean complete generations, and mean equivalent complete generations of 4.2, 1.8, and 2.6, respectively. The mean generation interval was 3.1 yr. The reference population was defined as lambs born from 2021 to 2023 (n = 792). Two additional populations were defined as the current mature ewe flock (n = 123) and the current mature rams (n = 14). The Genetic Conservation Index averaged 7.7 for the full population and 25.7 for the reference population. Overall inbreeding was 0.003 for the full population and 0.006 for the reference population. The rate of inbreeding was 0.0003 per generation. Average relatedness was 0.015 for the full population and 0.018 for the reference population. The effective number of founders, effective number of ancestors, and founder genome equivalents contributing to the reference population were 60, 39, and 19.1, respectively. The ratio of the effective number of founders to the effective number of ancestors was 1.5, indicating the presence of genetic bottlenecks. Measures of effective population size ranged from 102 to 547. Of the 704 offspring produced by external sires, 17 ram lambs and 132 ewe lambs were retained for breeding. The USSES sires produced 299 offspring with 2 ram lambs and 51 ewe lambs retained. Incorporating external sires resulted in a cumulative percentage of genetic variance of 48.8, 49.1, and 44.2 of external genetics for the reference population, current mature ewe flock, and current mature rams, respectively. Stakeholder needs were addressed by introgression of external sires and participation in NSIP, but future selection practices need to be modified to maintain a minimum of 50% USSES core genetics in the flock.

Combined purebred and crossbred genetic evaluation of Columbia, Suffolk, and crossbred lamb birth and weaning weights: systematic effects and heterogeneous variances.

Despite the benefits of crossbreeding on animal performance, genetic evaluation of sheep in the U.S. does not directly incorporate records from crossbred lambs. Crossbred animals may be raised in different environments as compared to purebreds. Systemic factors such as age of dam and birth and rearing type may, therefore, affect purebred and crossbred performance differently. Furthermore, crossbred performance may benefit from heterozygosity, and genetic and environmental variances may be heterogeneous in different breeds and their crosses. Such issues must be accounted for in a combined (purebred and crossbred) genetic evaluation. The objectives of this study were to i) determine the effect of dam age and birth type on birth weight, and dam age and birth-rearing type on weaning weight, in purebred and crossbred lambs, ii) test for heterogeneous genetic and environmental variances in those weights, and iii) assess the impact of including weights on crossbred progeny on sire estimated breeding values (EBV). Performance records were available on purebred Columbia and Suffolk lambs. Crossbred information was available on lambs sired by Suffolk, Columbia or Texel rams mated to Columbia, Suffolk, or crossbred ewes. A multiple-trait animal model was fitted in which weights from Columbia, Suffolk, or crossbred lambs were considered different traits. At birth, there were 4,160, 2,356, and 5,273 Columbia, Suffolk, and crossbred records, respectively, with means (SD) of 5.14 (1.04), 5.32 (1.14), and 5.43 (1.23) kg, respectively. At weaning, on average at 122 (12) d, there were 2,557, 980, and 3,876 Columbia, Suffolk, and crossbred records, respectively, with corresponding means of 39.8 (7.2), 40.3 (7.9), and 39.6 (8.0) kg. Dam age had a large positive effect on birth and weaning weight in pure and crossbred lambs. At birth, however, the predicted effect was larger in crossbred and Suffolk lambs. While an increase in a number of lambs born and reared had a strong and negative influence on birth and weaning weight, the size of the effect did not differ across-breed types. Environmental variances were similar at birth and weaning, but additive variances differed among breed types for both weights. Combining purebred and crossbred information in the evaluation not only improved predictions of genetic merit in purebred sires but also allowed for direct comparisons of sires of different breeds. Breeders thus can benefit from an additional tool for making selection decisions.

Combining multiple breeds in a genetic evaluation allows for their direct comparison. However, differences in management and other systematic effects among breeds may affect the evaluation. Estimates of genetic merit of sires may also be biased by heterosis in crossbred progeny. We examined genetic and environmental factors that affect the efficacy of a multi-breed genetic evaluation. Birth and weaning weights of Columbia, Suffolk, and their cross, were available. Depending on the breed type, the systematic effects of dam age and either birth or birth-rearing type on weights differed. Separately for birth and weaning, weights were defined as a different trait for each breed type. A multi-breed, multi-trait model was fitted that accounted for systematic effects unique to a breed type, and heterosis. Estimated direct and maternal heritabilities were moderate. Genetic correlations between breeds were moderate to high. Estimates of genetic merit of Columbia and Suffolk sires were unaffected by bias due to heterosis and environmental effects when crossbred lambs were included in a purebred or a combined Columbia, Suffolk, and crossbred evaluation. For direct across-breed comparisons, breed type-specific adjustments for systematic effects are necessary when combining weight data on pure and crossbred lambs in a joint genetic evaluation.

A phase II, single-blind, randomized, crossover evaluation of the safety and efficacy of avanafil using visual sexual stimulation in patients with mild to moderate erectile dysfunction.

OBJECTIVE: To evaluate the safety, efficacy and time course of three doses of avanafil (50 mg, 100 mg and 200 mg) compared with sildenafil 50 mg or placebo, given in conjunction with visual sexual stimulation (VSS) videos in men with mild to moderate erectile dysfunction (ED). PATIENTS AND METHODS: Male patients, 35-70 years of age, with mild to moderate ED of ≥6 months duration, were included in the study. During the course of the study, each patient received placebo, active control (sildenafil 50 mg), and one dose of avanafil (50 mg, 100 mg or 200 mg), all administered in random order at least 72 h apart. RigiScan® (Dacomed Corp., Minneapolis, MN, USA) monitoring was used in conjunction with 20-min VSS videos (20, 60, and 100 min after dosing) to determine the duration of and time to ≥60% penile rigidity, maximum rigidity, tumescent activity units (TAUs), rigidity activity units (RAUs), and responses to the five-point Erection Assessment Scale. Safety assessments included adverse events (AEs), vital sign changes in response to dosing, laboratory results (complete blood counts, chemistry panel, prostate-specific antigen, serum testosterone, prothrombin time and urine analysis) and physical examination findings. RESULTS: Eighty-three patients were randomized and received at least one dose of study medication; 82 patients completed the study. Peak response to avanafil occurred in the early interval (20-40 min after dosing), while peak response to sildenafil occurred either in the middle (60-80 min) or late (100-120 min) intervals after dosing. Results were qualitatively similar for all other efficacy endpoints. During the 20-40-min interval, the majority of values for TAUs and RAUs with the avanafil 50-mg, 100-mg and 200-mg treatments were significantly superior to placebo (P < 0.05). Avanafil treatment was generally well tolerated; facial flushing (7-15%) was the most commonly observed AE, and no visual disturbances were reported. CONCLUSION: A favourable safety profile and improvement in sexual function, coupled with rapid onset of action and durability of effect, make avanafil an attractive option for males with ED, especially in the setting of on-demand treatment.

Clustering climate and management practices to define environmental challenges affecting gastrointestinal parasitism in Katahdin sheep.

Gastrointestinal nematodes (GIN) negatively affect the performance and well-being of sheep. Due to anthelmintic resistance, GIN are difficult to control leading producers to choose breeds that can exhibit resistance to parasitism. An example is Katahdin sheep. Katahdins are raised in various climates and management systems in the United States. These environmental factors can be combined to form eco-management groupings or clusters. We hypothesized that GIN challenge varies predictably based on the characteristics of these environmental clusters. Forty Katahdin producers from across the United States were surveyed for management information, with body weights (BW), fecal egg counts (FEC), and FAMACHA scores (FAM) available from 17 of the 40 flocks. The performance data included 3,426 lambs evaluated around 90 d of age. Management and climate data were combined into clusters using multiple correspondence and principal component (PC) analysis. Performance data were aligned with their corresponding cluster. Depending on the trait, eco-management cluster, birth-rearing type, sex, and, as a covariate, dam age, were fitted as systematic effects with ANOVA. Clusters also were formed based on climate or management data alone. When compared with fitting the eco-management clusters, they defined less variation in each of the traits based on Akaike and Bayesian information criterion, and adjusted r2 values. To further examine variation defined by eco-management clusters, residuals from an ANOVA model excluding eco-management cluster were retained, and their correlation with PC loadings calculated. All PC loadings were included as potential independent variables and tested for significance using backward stepwise regression. The PC loadings with a correlation |≥0.49| explained significant variation in each trait and were included in the final models chosen; adjusted r2 values for BW, FEC, and FAM were 0.90, 0.81, and 0.97, respectively. When analyzing GIN challenge, eco-management clusters corresponding with hotter temperatures and greater rainfall, and with pasture-born lambs, suffered greater parasitism. Conversely, the eco-management clusters with lambs turned out to pasture at older ages benefited from reduced parasitism. Through the formation of eco-management clusters, an environmental variable can be defined to study interactions of genotypes to their environment, providing a potentially useful tool for identifying parasite-resistant sheep.

Katahdin sheep are a popular maternal hair breed that can exhibit resistance to gastrointestinal nematodes (GIN). Still, the consequences of GIN infection on performance levels, even in this breed, depend on the climatic and management conditions in which they are raised. Information on management practices in 40 U.S. Katahdin flocks was collected with an online survey. Climate data corresponding with these flock's locations were gathered from the National Weather Service. Using multivariate analysis to combine these data, nine distinct eco-management groupings or clusters were identified. These clusters differed in temperature, rainfall, grain supplementation, and the age at which the lambs were introduced to pasture. In 17 of these flocks, traits indicative of GIN parasitism­body weight, fecal egg count, and FAMACHA score­were measured in 90-d old Katahdin lambs. Eco-management cluster explained more variation in performance in all three traits than climate or management alone. Based on fecal egg counts, eco-management clusters corresponding with hotter temperatures and greater rainfall, and with pasture-born lambs, suffered greater parasitism. Conversely, eco-management clusters with lambs turned out to pasture at older ages benefited from reduced parasitism. Eco-management clusters provide a holistic approach to combine environmental factors that predispose lambs to parasitism.

Genotype by environment interaction and heteroscedasticity influence the expression of parasite resistance in Katahdin sheep.

Increasingly, sheep producers are choosing breeds that express resistance to gastrointestinal parasites due to reduced efficacy of anthelminthic drugs. One such breed is Katahdin. Katahdins are raised in various climates and management systems in the United States, which can be combined into eco-management clusters to describe production environments more holistically. The objectives of this study were to determine if genotype by environment interaction (G × E) and heteroscedasticity existed across these eco-management clusters for traits indicative of parasite resistance. Body weights (BW), FAMACHA scores (FAM), and fecal egg counts (FEC) were collected at around 90 d in 3,527 Katahdin lambs delineated into nine eco-management clusters. A tri-variate animal model including birth-rearing type, sex, and dam age (as a quadratic covariate) as fixed effects, and eco-management cluster, direct additive, uncorrelated maternal environmental (for BW), and residual as random effects, was fitted with ASReml. Heritability estimates for BW, FEC, and FAM were 0.36 ±â€…0.07, 0.31 ±â€…0.07, and 0.26 ±â€…0.05, respectively. The genetic (additive) correlation between BW with FEC was -0.26 ±â€…0.08 and with FAM was -0.16 ±â€…0.08, and thereby favorable. Heritabilities were also estimated univariately within eco-management clusters and ranged from 0.30 ±â€…0.05 to 0.37 ±â€…0.05 for BW, 0.18 ±â€…0.12 to 0.50 ±â€…0.13 for FEC, and 0.07 ±â€…0.06 to 0.40 ±â€…0.19 for FAM. Significant genetic and phenotypic heteroscedasticity among eco-management clusters was detected in FEC and FAM. A sire by eco-management cluster interaction term was added to the initial model fitted to evaluate G × E. This interaction defined substantial variation (P < 0.01) in all traits and explained 12% (FEC) to 20% (BW) of the phenotypic variation. Accounting for G × E and heteroscedasticity in the design and implementation of breeding programs may introduce operational challenges. Still, doing so would improve the efficacy of selection programs to improve parasite resistance.

Sheep producers increasingly rely on breeds that express resistance to gastrointestinal parasites because anthelminthic drugs are often ineffective. An example is Katahdin sheep, which are raised in various climates and management systems in the United States. These factors can be combined into eco-management clusters to describe production environments more holistically. Our objective was to determine if a genotype by eco-management cluster (environment) interaction (G × E) affected performance levels, particularly for traits indicative of parasite resistance. Body weights (BW), fecal egg counts (FEC), and FAMACHA scores (FAM) were collected at around 90 d in 3,527 Katahdin lambs delineated into nine eco-management clusters. Heritabilities of BW, FEC, and FAM were 0.36, 0.31, and 0.26, respectively. Genetic correlations of BW with FEC and FAM were low to moderate and favorable (negative). When estimated within eco-management cluster, heritabilities were 0.30 to 0.37 for BW, 0.18 to 0.50 for FEC, and 0.07 to 0.40 for FAM. For FEC and FAM, these differences corresponded with heterogenous variances (heteroscedasticity) across environments. Furthermore, G × E explained 13% (FAM) to 20% (BW) of the variation in a trait. In genetic evaluation of parasite resistance, G × E and heteroscedasticity should be incorporated to improve the efficacy of the breeding program.