Mylonitic deformation at the Kane oceanic core complex : implications for the rheological behavior of oceanic detachment faults

Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry, Geophysics, Geosystems 14 (2013): 3085–3108, doi:10.1002/ggge.20184.The depth extent, strength, and composition of oceanic detachment faults remain poorly understood because the grade of deformation-related fabrics varies widely among sampled oceanic core complexes (OCCs). We address this issue by analyzing fault rocks collected from the Kane oceanic core complex at 23°30′N on the Mid-Atlantic Ridge. A portion of the sample suite was collected from a younger fault scarp that cuts the detachment surface and exposes the interior of the most prominent dome. The style of deformation was assessed as a function of proximity to the detachment surface, revealing a ∼450 m thick zone of high-temperature mylonitization overprinted by a ∼200 m thick zone of brittle deformation. Geothermometry of deformed gabbros demonstrates that crystal-plastic deformation occurred at temperatures >700°C. Analysis of the morphology of the complex in conjunction with recent thermochronology suggests that deformation initiated at depths of ∼7 km. Thus we suggest the detachment system extended into or below the brittle-plastic transition (BPT). Microstructural evidence suggests that gabbros and peridotites with high-temperature fabrics were dominantly deforming by dislocation-accommodated processes and diffusion creep. Recrystallized grain size piezometry yields differential stresses consistent with those predicted by dry-plagioclase flow laws. The temperature and stress at the BPT determined from laboratory-derived constitutive models agree well with the lowest temperatures and highest stresses estimated from gabbro mylonites. We suggest that the variation in abundance of mylonites among oceanic core complexes can be explained by variation in the depth of the BPT, which depends to a first order on the thermal structure and water content of newly forming oceanic lithosphere.Knorr Cruise 180-2 data and sample acquisition was supported by NSF grant 0118445.2014-02-2

Prospective Study Delivering Simultaneous Integrated High-dose Tumor Boost (≤70 Gy) With Image Guided Adaptive Radiation Therapy for Radical Treatment of Localized Muscle-Invasive Bladder Cancer

PurposeImage guided adaptive radiation therapy offers individualized solutions to improve target coverage and reduce normal tissue irradiation, allowing the opportunity to increase the radiation tumor dose and spare normal bladder tissue.Methods and MaterialsA library of 3 intensity modulated radiation therapy plans were created (small, medium, and large) from planning computed tomography (CT) scans performed at 30 and 60 minutes; treating the whole bladder to 52 Gy and the tumor to 70 Gy in 32 fractions. A “plan of the day” approach was used for treatment delivery. A post-treatment cone beam CT (CBCT) scan was acquired weekly to assess intrafraction filling and coverage.ResultsA total of 18 patients completed treatment to 70 Gy. The plan and treatment for 1 patient was to 68 Gy. Also, 1 patient's plan was to 70 Gy but the patient was treated to a total dose of 65.6 Gy because dose-limiting toxicity occurred before dose escalation. A total of 734 CBCT scans were evaluated. Small, medium, and large plans were used in 36%, 48%, and 16% of cases, respectively. The mean ± standard deviation rate of intrafraction filling at the start of treatment (ie, week 1) was 4.0 ± 4.8 mL/min (range 0.1-19.4) and at end of radiation therapy (ie, week 5 or 6) was 1.1 ± 1.6 mL/min (range 0.01-7.5; P=.002). The mean D98 (dose received by 98% volume) of the tumor boost and bladder as assessed on the post-treatment CBCT scan was 97.07% ± 2.10% (range 89.0%-104%) and 99.97% ± 2.62% (range 96.4%-112.0%). At a median follow-up period of 19 months (range 4-33), no muscle-invasive recurrences had developed. Two patients experienced late toxicity (both grade 3 cystitis) at 5.3 months (now resolved) and 18 months after radiation therapy.ConclusionsImage guided adaptive radiation therapy using intensity modulated radiation therapy to deliver a simultaneous integrated tumor boost to 70 Gy is feasible, with acceptable toxicity, and will be evaluated in a randomized trial

Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials

Every institution that is involved in research with animals is expected to have in place policies and procedures for the management of allegations of noncompliance with the Animal Welfare Act and the U.S. Public Health Service Policy on the Humane Care and Use of Laboratory Animals. We present here a model set of recommendations for institutional animal care and use committees and institutional officials to ensure appropriate consideration of allegations of noncompliance with federal Animal Welfare Act regulations that carry a significant risk or specific threat to animal welfare. This guidance has 3 overarching aims: 1) protecting the welfare of research animals; 2) according fair treatment and due process to an individual accused of noncompliance; and 3) ensuring compliance with federal regulations. Through this guidance, the present work seeks to advance the cause of scientific integrity, animal welfare, and the public trust while recognizing and supporting the critical importance of animal research for the betterment of the health of both humans and animals.â Hansen, B. C., Gografe, S., Pritt, S., Jen, K.â L. C., McWhirter, C. A., Barman, S. M., Comuzzie, A., Greene, M., McNulty, J. A., Michele, D. E., Moaddab, N., Nelson, R. J., Norris, K., Uray, K. D., Banks, R., Westlund, K. N., Yates, B. J., Silverman, J., Hansen, K. D., Redman, B. Ensuring due process in the IACUC and animal welfare setting: considerations in developing noncompliance policies and procedures for institutional animal care and use committees and institutional officials. FASEB J. 31, 4216â 4225 (2017). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154293/1/fsb2fj201601250r.pd

Hepatitis C prevalence in Denmark -an estimate based on multiple national registers

Background: A national survey for chronic hepatitis C has not been performed in Denmark and the prevalence is unknown. Our aim was to estimate the prevalence of chronic hepatitis C from public registers and the proportion of these patients who received specialized healthcare. Methods: Patients with a diagnosis of chronic hepatitis C were identified from four national registers: a laboratory register, the Hospital Discharge Register, a clinical database of chronic viral hepatitis and the Register of Communicable Diseases. The total population diagnosed with hepatitis C was estimated by capture-recapture analysis. The population with undiagnosed hepatitis C was derived from the national register of drug users by comparing diagnosed and tested persons. Results: A total of 6,935 patients diagnosed with chronic hepatitis C were identified in the four registers and the estimated population diagnosed with the disease was 9,166 persons (95% C.I. interval 8,973 – 9,877), corresponding to 0.21% (95% CI 0.21%-0.23%) of the Danish population over 15years of age. The prevalence was highest among persons 40–49years old (0.39%) and males (0.28%). It was estimated that 40% of the diagnosed patients lived in the capital region, and 33.5% had attended specialised healthcare. It was estimated that 46% of hepatitis C patients had not been diagnosed and the total population with chronic hepatitis C in Denmark was 16,888 (95% C.I. 16,474-18,287), corresponding to 0.38% (95% CI 0.37-0.42) of the population over 15years of age. Conclusions: The estimated prevalence of chronic hepatitis C in Denmark was 0.38%. Less than half of the patients with chronic hepatitis C in Denmark have been identified and among these patients, one in three has attended specialised care

Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations