Genome-Wide Genomic and Functional Association Study for Workability and Calving Traits in Holstein Cattle.

The goal of our study was to identify the SNPs, metabolic pathways (KEGG), and gene ontology (GO) terms significantly associated with calving and workability traits in dairy cattle. We analysed direct (DCE) and maternal (MCE) calving ease, direct (DSB) and maternal (MSB) stillbirth, milking speed (MSP), and temperament (TEM) based on a Holstein-Friesian dairy cattle population consisting of 35,203 individuals. The number of animals, depending on the trait, ranged from 22,301 bulls for TEM to 30,603 for DCE. We estimated the SNP effects (based on 46,216 polymorphisms from Illumina BovineSNP50 BeadChip Version 2) using a multi-SNP mixed model. The SNP positions were mapped to genes and the GO terms/KEGG pathways of the corresponding genes were assigned. The estimation of the GO term/KEGG pathway effects was based on a mixed model using the SNP effects as dependent variables. The number of significant SNPs comprised 59 for DCE, 25 for DSB and MSP, 17 for MCE and MSB, and 7 for TEM. Significant KEGG pathways were found for MSB (2), TEM (2), and MSP (1) and 11 GO terms were significant for MSP, 10 for DCE, 8 for DSB and TEM, 5 for MCE, and 3 for MSB. From the perspective of a better understanding of the genomic background of the phenotypes, traits with low heritabilities suggest that the focus should be moved from single genes to the metabolic pathways or gene ontologies significant for the phenotype.

Effect of Calving Difficulties and Calf Mortality on Functional Longevity in Polish Holstein-Friesian Cows.

Longevity is one of the functional traits that considerably affect dairy herd profitability. A Weibull proportional hazards model was used to evaluate the impact of difficult calvings and calf stillbirths on cow functional longevity, defined as length of productive life corrected for milk production. The data for analysis comprised calving ease and calf mortality scores of 2,163,426 calvings, 34.4% of which came from primiparous cows. The percentage of male calves was 53.4%. Calving ease was scored as "without assistance" (34.44%), "with assistance" (62.03%), "difficult-hard pull" (3.39%), and "very difficult, including caesarean section" (0.14%). Calf mortality scores were "live born" (94.21%) and "stillborn or died within 24 h" (5.79%). The Weibull proportional hazards model included classes of calving ease or calf mortality scores × parity (1, ≥2) × sex of calf as time-dependent fixed effect. The model also included time-dependent fixed effects of year × season, parity × stage of lactation, annual change in herd size, fat yield and protein yield, time-independent fixed effect of age at first calving, and time dependent random herd × year × season. In first-parity cows, very difficult birth of a bull or heifer increased the relative risk of culling, respectively, 2.18 or 1.26 times as compared with calving without assistance. In later parities, the relative risk of culling related to very difficult calving was 2.0 times (for male calves) and 1.33 times (for female calves) higher than the relative risk of culling associated with calving without assistance. Calf mortality showed a negative impact on longevity in both heifers and cows. First-parity stillbirth increased the relative risk of culling depending on sex of calf by 18% in females and by 15% in males; in later parities the increase of the relative risk of culling was lower (by 7% for females, 9% for males). Difficult calvings and their consequences, especially in primiparous cows, may negatively influence dairy herd profitability by reducing the length of cows' productive life.

Hematologic Nadirs During Chemoradiation for Anal Cancer: Temporal Characterization and Dosimetric Predictors.

PURPOSE: Pelvic bone marrow (BM) constraints may offer a means to reduce the toxicity commonly associated with chemoradiation for anal cancer. We conducted a bi-institutional analysis of dose-volume metrics in a time-sensitive fashion to devise practical metrics to minimize hematologic toxicity. METHODS AND MATERIALS: Fifty-six anal cancer patients from 2 institutions received definitive radiation therapy (median primary dose of 54 Gy) using intensity modulated radiation therapy (IMRT, n=49) or 3-dimensional (3D) conformal therapy (n=7) with concurrent 5-fluorouracil (5-FU) and mitomycin C. Weekly blood counts were retrospectively plotted to characterize the time course of cytopenias. Dose-volume parameters were correlated with blood counts at a standardized time point to identify predictors of initial blood count nadirs. RESULTS: Leukocytes, neutrophils, and platelets reached a nadir at week 3 of treatment. Smaller volumes of the pelvic BM correlated most strongly with lower week 3 blood counts, more so than age, sex, body mass index (BMI), or dose metrics. Patients who had ≥750 cc of pelvic BM spared from doses of ≥30 Gy had 0% grade 3+ leukopenia or neutropenia at week 3. Higher V40 Gy to the lower pelvic BM (LP V40) also correlated with cytopenia. Patients with an LP V40 >23% had higher rates of grade 3+ leukopenia (29% vs 4%, P=.02), grade 3+ neutropenia (33% vs 8%, P=.04), and grade 2+ thrombocytopenia (32% vs 7%, P=.04) at week 3. On multivariate analysis, pelvic BM volume and LP V40 remained associated with leukocyte count, and all marrow subsite volumes remained associated with neutrophil counts at week 3 (P<.1). CONCLUSIONS: Larger pelvic BM volumes correlate with less severe leukocyte and neutrophil nadirs, suggesting that larger total "marrow reserve" can mitigate cytopenias. Sparing a critical marrow reserve and limiting the V40 Gy to the lower pelvis may reduce the risk of hematologic toxicity.

Simultaneously integrated boost (SIB) spares OAR and reduces treatment time in locally advanced cervical cancer.

We performed a dosimetric comparison of sequential IMRT (sIMRT) and simul-taneously integrated boost (SIB) IMRT to boost PET-avid lymph nodes while concurrently treating pelvic targets to determine the potential of SIB IMRT to reduce overall treatment duration in locally advanced cervical cancer. Ten patients receiving definitive radiation therapy were identified retrospectively. RTOG consensus guidelines were followed to delineate the clinical target volume and organs at risk (OAR), which were then expanded per IMRT consortium guidelines to yield the planning target volume (PTV). Dosimetric parameters for PTVs and OAR including conformity (CI95%) were collected and compared using Wilcoxon signed-rank tests with Bonferroni correction. The median PTV volume was 1843 cc (1088-2225 cc) and the median boost volume was 43 cc (15-129 cc). Comparable target volume coverage was achieved with sIMRT and SIB plans, while hot spots were significantly reduced using SIB. SIB plans improved sparing for all OAR, though only rectum and small bowel doses were statistically significant. Comparing sIMRT and SIB plans averaged over all patients, rectal doses were V45: 70.8% vs. 64.5% (p = 0.002) and 0.1 cc: 50.7 Gy vs. 48.7 Gy (p = 0.006). For small bowel, sIMRT and SIB IMRT plans yielded V45: 13.4% vs. 11.4% (p = 0.006) and 1 cc: 54.4 Gy vs. 52.6 Gy (p = 0.006), respectively. Doses to femoral heads and blad-der trended towards significance in favor of SIB plans. The mean treatment time was 25 versus 29 days for SIB and sIMRT plans, respectively. When compared to sIMRT, SIB for treatment of nodal targets provides a significant, but small, dose reduction (3.8%-4.4%) to OAR, which leads to comparable biological dose despite higher fractional doses. Furthermore, SIB IMRT reduces overall treatment time and simplifies the planning process, and should be considered for targeting PET-positive nodal disease in patients with locally advanced cervical cancer.

Long-term Impact of Mode of Delivery on Stress Urinary Incontinence and Urgency Urinary Incontinence: A Systematic Review and Meta-analysis.

CONTEXT: Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) are associated with physical and psychological morbidity, and large societal costs. The long-term effects of delivery modes on each kind of incontinence remain uncertain. OBJECTIVE: To investigate the long-term impact of delivery mode on SUI and UUI. EVIDENCE ACQUISITION: We searched Medline, Scopus, CINAHL, and relevant major conference abstracts up to October 31, 2014, including any observational study with adjusted analyses or any randomized trial addressing the association between delivery mode and SUI or UUI ≥1 yr after delivery. Two reviewers extracted data, including incidence/prevalence of SUI and UUI by delivery modes, and assessed risk of bias. EVIDENCE SYNTHESIS: Pooled estimates from 15 eligible studies demonstrated an increased risk of SUI after vaginal delivery versus cesarean section (adjusted odds ratio [aOR]: 1.85; 95% confidence interval [CI], 1.56-2.19; I(2)=57%; risk difference: 8.2%). Metaregression demonstrated a larger effect of vaginal delivery among younger women (p=0.005). Four studies suggested no difference in the risk of SUI between spontaneous vaginal and instrumental delivery (aOR: 1.11; 95% CI, 0.84-1.45; I(2)=50%). Eight studies suggested an elevated risk of UUI after vaginal delivery versus cesarean section (aOR: 1.30; 95% CI, 1.02-1.65; I(2)=37%; risk difference: 2.6%). CONCLUSIONS: Compared with cesarean section, vaginal delivery is associated with an almost twofold increase in the risk of long-term SUI, with an absolute increase of 8%, and an effect that is largest in younger women. There is also an increased risk of UUI, with an absolute increase of approximately 3%. PATIENT SUMMARY: In this systematic review we looked for the long-term effects of childbirth on urinary leakage. We found that vaginal delivery is associated with an almost twofold increase in the risk of developing leakage with exertion, compared with cesarean section, with a smaller effect on leakage in association with urgency.

Anatomical variations of the anterior communicating artery complex: gender relationship.

PURPOSE: The anatomy of the anterior communicating artery complex plays a critical role in surgical treatment of anterior cerebral circulation aneurysms. A thorough description of vascular variations of the anterior communicating artery complex seems to be lacking. The aim of this study was to describe the anatomical variations of the anterior communicating artery complex. METHODS: The study group consisted of 411 subjects (52.31% women), without any intracranial pathologies, that had undergone head computed tomography angiography. We used maximum intensity projections, volume rendering and multi planar reconstructions to study and classify the anatomical variations of the anterior communicating and anterior cerebral arteries. RESULTS: Male subjects had a significantly higher prevalence of the typical anterior communicating artery complex (59.69 vs. 46.05%; p < 0.01). The aplastic anterior communicating artery (23.26 vs. 15.88%; p = 0.04) and triple A2 segment of the anterior cerebral artery (1.86 vs. 0.00%; p = 0.05) were more common in women than in men. CONCLUSION: Female subjects have a higher incidence of variations in the anterior communicating artery complex. There is a higher incidence of anterior communicating artery aplasia among women.

Image-guided radiotherapy using surgical clips as fiducial markers after prostatectomy: a report of total setup error, required PTV expansion, and dosimetric implications.

PURPOSE: To determine the total setup error and the required planning target volume (PTV) margin for prostate bed without image guided radiotherapy (IGRT), and to demonstrate the feasibility and dosimetric benefit of IGRT post prostatectomy using surgical clips. MATERIALS AND METHODS: Seventeen patients were treated with intensity modulated radiotherapy (IMRT) to the prostate bed with a 1cm PTV margin. Three-dimensional shifts of the surgical clips inside the prostate bed were measured with respect to the isocenter from 364 orthogonal kV image pairs, and the total setup error was calculated to determine the required PTV margin. Alternative IMRT plans using 5mm or 1cm PTV expansion were generated and compared for rectal and bladder sparing. RESULTS: Surgical clips were reproducibly and reliably identified. The mean (standard deviation) shifts in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP), axes were: -0.1 mm (1.7 mm), 0.6 mm (2.4 mm), and -2.1 mm (2.6 mm), respectively. The required PTV margins were calculated to be 6, 8, and 9 mm in the LR, AP, and SI axis, respectively. A PTV expansion of 5mm, compared to 1cm, significantly reduced V65 Gy to the rectum by 10%. CONCLUSIONS: In the absence of IGRT, a non-uniform PTV margin of 6mm LR, 8mm AP, and 9 mm SI should be considered. Use of clips as fiducial markers can decrease the total setup error, enable a smaller PTV margin, and improve rectal sparing.

Evaluating markers in selected genes for association with functional longevity of dairy cattle.

BACKGROUND: Longevity expressed as the number of days between birth and death is a trait of great importance for both human and animal populations. In our analysis we use dairy cattle to demonstrate how the association of Single Nucleotide Polymorphisms (SNPs) located within selected genes with longevity can be modeled. Such an approach can be extended to any genotyped population with time to endpoint information available. Our study is focused on selected genes in order to answer the question whether genes, known to be involved into the physiological determination of milk production, also influence individual's survival. RESULTS: Generally, the highest risk differences among animals with different genotypes are observed for polymorphisms located within the leptin gene. The polymorphism with a highest effect on functional longevity is LEP-R25C, for which the relative risk of culling for cows with genotype CC is 3.14 times higher than for the heterozygous animals. Apart from LEP-R25C, also FF homozygotes at the LEP-Y7F substitution attribute 3.64 times higher risk of culling than the YY homozygotes and VV homozygotes at LEP-A80V have 1.83 times higher risk of culling than AA homozygotes. Differences in risks between genotypes of polymorphisms within the other genes (the butyrophilin subfamily 1 member A1 gene, BTN1A1; the acyl-CoA:diacylglycerol acyltransferase 1 gene, DGAT1; the leptin receptor gene, LEPR; the ATP-binding cassette sub-family G member 2, ABCG2) are much smaller. CONCLUSIONS: Our results indicate association between LEP and longevity and are very well supported by results of other studies related to dairy cattle. In view of the growing importance of functional traits in dairy cattle, LEP polymorphisms should be considered as markers supporting selection decisions. Furthermore, since the relationship between both LEP polymorphism and its protein product with longevity in humans is well documented, with our result we were able to demonstrate that livestock with its detailed records of family structure, genetic, and environmental factors as well as extensive trait recording can be a good model organism for research aspects related to humans.