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Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09).Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Supplementary Figure 1. Absolute Risk (With family history of prostate cancer)

Supplementary Figure 3. Absolute Risk (A model with only family history of prostate cancer)

Supplementary Notes. This document includes description of studies that they have been used for the analysis.

Supplementary Tables 1-8. Supplementary table 1: Total number of cases and controls in PRACTICAL III and GWAS stage 3 by population and study. Supplementary Table 2: Data information for family history and age at diagnosis/observation. Supplementary Table 3: Grade-specific and family history-specific odds ratios. Supplementary Table 4: PSA levels by genotype in controls. Supplementary Table 5: Age-specific odds ratios. Supplementary Table 6: The results of 29 pair wise interaction of 25 SNPs significant at P

Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Crohn's disease is a chronic inflammatory bowel disease characterized by alternating periods of exacerbation and remission. Surgical resection is not curative and postoperative recurrence (POR) remains a challenge in these patients. The aim of this study was to identify clinical variables that influence the risk of symptomatic anastomotic POR in patients with ileo-colonic Crohn's disease.A retrospective study of Crohn's disease patients who had undergone ileo-colic resection between January 2014 and December 2018 was performed. For each patient, data including demographic information, Crohn's disease clinical setting, preoperative radiological data, operative and histological data, pre- and postoperative medication history and postoperative clinical course, including recurrence of disease, were extracted. Symptomatic anastomotic POR was defined as symptoms of Crohn's disease in the presence of confirmed anastomotic POR (endoscopic and/or radiological POR).For the study period, 104 patients were eligible and included for analysis. The cumulative probability of symptomatic anastomotic POR was 14%, 30%, 42%, 50% and 50% at 1, 2, 3, 4 and 5 years, respectively. Two clinical variables on multivariate analysis were associated with increased risk of symptomatic anastomotic POR, namely age17 years at diagnosis [hazard ratio (HR) 2.17, p = 0.019] and gastrointestinal involvement (extent)30 cm (HR 1.85, p = 0.048).This study describes the natural history of POR after ileo-colic resection for Crohn's disease, as defined by endoscopic, radiological and clinical outcomes. Age17 years at diagnosis and gastrointestinal involvement (extent)30 cm were independent risk factors for symptomatic anastomotic POR.

156 Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases (mets) could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment, or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course, and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise > 10% if baseline PSA >20ng/ml, PSA>20 if baseline PSA 1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests, respectively, and univariate Cox regression. Statistical significance was considered at P0.05). Conclusions: First-line use of Ra223 and SBRT to oligomets in hormone-naïve men in this prospective pilot study resulted in a significant delay in ADT use compared to historical control, is well tolerated, and maintains QoL. Clinical trial information: NCT03304418 .

Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

This paper explains equipment related considerations on differences between the lab and field conditions that can lead to variations in resilient modulus (Mr) values of unbound materials as determined in accordance with AASHTO T307 standard. Three different granular materials and an elastic polyurethane (control) sample were tested using commercially available laboratory test equipment. A field test bed was also constructed to measure vehicle (Class 3) induced loading conditions at the bottom of an unbound granular layer underlying new hot-mix asphalt pavement to determine stress pulse duration as a function of vehicle speed. Various interpretation issues were identified within the framework of the testing methods and equipment including: (1) insufficient laboratory sensor sampling rate (per standard); (2) the laboratory specified 0.1 s load-pulse duration and haversine shape are not matching the field stress pulse duration and shape; (3) the need for careful tuning of the load system gain settings; (4) the number of LVDTs used in the vertical strain calculation; (5) limiting quality control and quality assurance to deformation ratio values in the preconditioning sequence; and (6) limiting the load step calculations to the last 5 of 100 load cycles. The goal of this paper is to provide equipment users and specification developers with user knowledge concerning laboratory resilient modulus determination.

Building energy efficiency labeling programs are promising strategies to encourage investments in green buildings. It is necessary to explicitly measure the value of energy efficient labels from an economic perspective that is more understandable to both developers and buyers. This research not only documents evidence on whether a sales premium exists for energy-certified homes but also investigates the effects of market characteristics on the magnitude of the added value of building energy efficiency labeling programs. A hedonic pricing model of 1679 single-family home sales in the metropolitan Atlanta area in the U.S. is developed, with numerous explanatory variables (such as location, time of sale, green features, and other housing characteristics) taken into account. Results indicate that: (i) Homes that earn energy certificates demonstrate a sales price premium of 11.7%, which equates to a dollar value of over $47,000 in Atlanta’s housing market; (ii) The regional energy labels certificated by the EarthCraft House receives higher recognition in the marketplace than that by national Energy Star programs. (iii) The certified homes that are located in the top school districts (i.e., with the top 50 schools) enjoy a substantially higher increase in the home sales premium, compared to green homes in districts with the low-quality schools. A random sampling method is further used to ensure the quality of the regression results with the limited size of the dataset by eliminating stochastic effects of the selected dataset. This research contributes to (i) the body of knowledge by analyzing the market value of building energy efficiency labels in the residential housing market and (ii) the state of practice by shedding light on the information asymmetry problem between home developers and buyers in the housing market to facilitate the adoption of energy labels in building products.

The objective of this pilot project was to evaluate the effectiveness of the FRIENDS program in reducing anxiety and symptoms of depression for children in Regina public schools. The project comprised 461 children in Grades 1, 4, 5, and 6 who participated in the 10-week FRIENDS program between September 2013 and May 2014. Effectiveness of the program was measured using the Revised Children’s Anxiety and Depression Scale, which was administered at the beginning and end of the program. The percentage of children with subclinical or clinical levels of anxiety and depression significantly decreased from 21.8% to 13.4%. This study validated the effectiveness of the FRIENDS program in children in Regina schools.

Reducing surface roughness is critical for improving the mechanical properties of metal 3D printed components. As produced laser sintered metal 3D printed components suffer from high surface roughness. This problem is enormously big for the 3D printed components with intricate geometries involving a large internal surface area. To address this issue, we performed chemical polishing of the 3D printed 316 steel components. After 30 minutes of chemical polishing the color of 3D printed steel components’ surface became dull grey to bright lustrous. According to optical profilometer study, the surface morphology improved dramatically. The Rq roughness parameter changed from ∼8 um to ∼0.6 um. We also applied chemical polishing on cubical metal 3D printed components with internal surfaces. This surface finishing method was equally effective for the internal and external surfaces.

Purpose: Medical gender confirmation therapy (GCT) plays an important role in transgender health; however, its prevalence and determinants constitute an area of uncertainty. Methods: Data for this cross-sectional study were obtained from an online survey distributed from October 2012 through the end of 2013 among persons who visited the social media sites of a transgender education and social networking meeting. Eligible respondents (n=280) were persons whose gender identity was different from their sex assigned at birth and who responded to questions about previously received or planned hormonal therapy (HT), chest reconstruction, or genital surgery. Multivariable logistic regression models examined how receipt and plans to receive different GCT types were associated with participants' characteristics and gender identity. Results: The respective percentages of ever and current HT were 58% and 47% for transwomen and 63% and 57% for transmen. Genital surgery was reported by 11 participants; all transwomen. Relative to transmen, transwomen were thrice more likely to report plans to undergo genital surgery. By contrast, transmen were more than 10 times as likely as transwomen to have had or planned chest surgery. Older participants and those who were in a committed relationship were less likely to plan future GCT. Having health insurance was not associated with GCT receipt. Treatment cost was named as the main problem by 23% of transwomen and 29% of transmen. Accessing a qualified healthcare provider for transgender-related care was listed as the primary reason for not receiving surgery by 41% of transmen and 2% of transwomen. Conclusions: Prevalence of GCT differed across subgroups of participants and was lower than corresponding estimates reported elsewhere. The variability of results may reflect differences in recruitment procedures and response rates; however, it is also possible that it may be driven by geographic, socioeconomic, and health-related heterogeneity of the transgender population.

Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.

The vehicle-miles-traveled (VMT) fee has been widely suggested as an alternative funding mechanism to the current state of practice, the fuel tax per gallon. The VMT fee has drawn researchers' and policy makers' attention, particularly regarding its equity performance in various social groups. With the introduction of the concept of vulnerable households, and with the use of socioeconomic-, geographic-, and vehicle-specific attributes from the 2009 National Household Travel Survey, the social groups in the United States that were most likely to be affected under each funding mechanism were identified through the estimation of three-stage least squares models at the national level. The results showed that households located in states with lower fuel taxation operated vehicles of lower fuel efficiency and thus contributed a larger portion of revenues generated by the fuel tax. In contrast, households with higher fuel-efficiency vehicles or with a higher average income generated more trips annually and thus would pay higher VMT fees at the household level. The study also examined whether the identified vulnerable households at the national level were different at the state level. With the use of the state of Iowa as a case study, the results suggested that, despite some similarities in the characteristics of the vulnerable households at the two levels of analysis, the development of state-specific models was statistically supported.

In this study, a combination of synchronized high-speed video (HSV) and infrared (IR) thermography was used to characterize the nucleation, growth and detachment of bubbles generated during nucleate boiling inside the nanoemulsion fluid. The Ethanol/Polyalphaolefin nanoemulsion fluid was formed by dispersing ethanol nanodroplets into base fluid Polyalphaolefin, in which these nanodroplets can serve as the pre-seed boiling nuclei. With this unique combination, it allows controlled nucleation, time-resolved temperature distribution data for the boiling surface and direct visualization of the bubble cycle to track bubble nucleation and growth. Data gathered included measurements of bubble growth versus time, as well as 2D temperature history of the heater surface underneath the bubbles. Our findings demonstrate a significant difference of bubble dynamics between the nanoemulsion fluid and pure ethanol, which may also account for the substantial increase in heat transfer coefficient and critical heat flux of nanoemulsion fluid. It is also observed here that the bubbles occurred inside the nanoemulsion fluid appear to be more uniform and two orders-of-magnitude larger in size. While the growth rate of the bubbles inside pure ethanol was found to be heat diffusion controlled at a coefficient around ½, which however, dropped to be around 0.3 for nanoemulsion fluid. Further study on this unique system will help reveal its heat transfer mechanisms.

The aim of this study was to identify the set of welding parameters that yields the highest weld strengths in six different triple-layer, coextruded polyolefin films. The parameters investigated include weld forces, energy delivery, and amplitude. Welds were made using an ultrasonic plunge welding system. Weld performance was determined by peel and shear strength and tearing force. It was observed that energy and weld force had a significant effect on peel strength for the majority of the materials and the highest peel strength was found at high weld forces and high energies for all materials. Low weld energy and low weld force were observed to produce high-shear strength welds for all materials. However, the results for tearing force were inconsistent among all six materials. The highest tear resistance was found with welds created with the highest force and amplitude and at mid-range energy levels.

INTRODUCTION Document management covers the preparation, review, approval, issue, change, withdrawal and storage of documents. Good practice (GxP)—for example, as described in GAMP15 Appendix M9 (1)—must be applied consistently throughout the full document life cycle for a regulated organization to be able to demonstrate the level of control now demanded by regulatory bodies. Electronic document management systems (EDMS) are a class of applications specifically developed to support these requirements. This paper describes an approach to successful implementation of such systems.

Many serious bacterial infections are difficult to treat due to biofilm formation, which provides physical protection and induces a sessile phenotype refractory to antibiotic treatment compared to the planktonic state. A key structural component of biofilm is extracellular DNA, which is held in place by secreted bacterial proteins from the DNABII family: integration host factor (IHF) and histone-like (HU) proteins. A native human monoclonal antibody, TRL1068, has been discovered using single B-lymphocyte screening technology. It has low-picomolar affinity against DNABII homologs from important Gram-positive and Gram-negative bacterial pathogens. The disruption of established biofilm was observed in vitro at an antibody concentration of 1.2 μg/ml over 12 h. The effect of TRL1068 in vivo was evaluated in a murine tissue cage infection model in which a biofilm is formed by infection with methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43300). Treatment of the established biofilm by combination therapy of TRL1068 (15 mg/kg of body weight, intraperitoneal [i.p.] administration) with daptomycin (50 mg/kg, i.p.) significantly reduced adherent bacterial count compared to that after daptomycin treatment alone, accompanied by significant reduction in planktonic bacterial numbers. The quantification of TRL1068 in sample matrices showed substantial penetration of TRL1068 from serum into the cage interior. TRL1068 is a clinical candidate for combination treatment with standard-of-care antibiotics to overcome the drug-refractory state associated with biofilm formation, with potential utility for a broad spectrum of difficult-to-treat bacterial infections.

Summary This article presents activities appropriate for the first half of a general introductory statistics course. All activities revolve around the same data set collected early in the course. The activities require students to make decisions about how they should proceed.

Our previous studies showed that both Sae and Fur are required for the induction of eap and emp expression in low iron. In this study, we show that expression of sae is also iron-regulated, as sae expression is activated by Fur in low iron. We also demonstrate that both Fur and Sae are required for full induction of the oxidative stress response and expression of non-covalently bound surface proteins in low-iron growth conditions. In addition, Sae is required for the induced expression of the important virulence factors isdA and isdB in low iron. Our studies also indicate that Fur is required for the induced expression of the global regulators Agr and Rot in low iron and a number of extracellular virulence factors such as the haemolysins which are also Sae- and Agr-regulated. Hence, we show that Fur is central to a complex regulatory network that is required for the induced expression of a number of important S. aureus virulence determinants in low iron.

Summary This article shows that when applying resampling methods to the problem of comparing two proportions, students can discover that whether you resample with or without replacement can make a big difference.

Laminin-5, a major adhesive ligand for epithelial cells, undergoes processing of its gamma2 and alpha3 chains. This study investigated the mechanism of laminin-5 processing by keratinocytes. BI-1 (BMP-1 isoenzyme inhibitor-1), a selective inhibitor of a small group of astacin-like metalloproteinases, which includes bone morphogenetic protein 1 (BMP-1), mammalian Tolloid (mTLD), mammalian Tolloid-like 1 (mTLL-1), and mammalian Tolloid-like 2 (mTLL-2), inhibited the processing of laminin-5 gamma2 and alpha3 chains in keratinocyte cultures in a dose-dependent manner. In a proteinase survey, all BMP-1 isoenzymes processed human laminin-5 gamma2 and alpha3 chains to 105- and 165-kDa fragments, respectively. In contrast, MT1-MMP and MMP-2 did not cleave the gamma2 chain of human laminin-5 but processed the rat laminin gamma2 chain to an 80-kDa fragment. An immunoblot and quantitative PCR survey of the BMP-1 isoenzymes revealed expression of mTLD in primary keratinocyte cultures but little or no expression of BMP-1, mTLL-1, or mTLL-2. mTLD was shown to cleave the gamma2 chain at the same site as the previously identified BMP-1 cleavage site. In addition, mTLD/BMP-1 null mice were shown to have deficient laminin-5 processing. Together, these data identify laminin-5 as a substrate for mTLD, suggesting a role for laminin-5 processing by mTLD in the skin.

Today's courses in statistical methods, for the most part, focus on the same methods that were taught 30 years ago. The actual practice of statistics has moved beyond these traditional statistical methods. Modern methods—including dynamic graphics, nonlinear estimation, resampling, and other simulation-based inference methods—are being used by many scientists and engineers. However, these methods generally are not included in courses in statistical methods, especially at the undergraduate level. This article discusses the development of a collection of instructional modules, built around actual applications from science and engineering. Each module is self-contained and includes instructional materials such as: objectives, examples, lecture materials, computer implementation of the methodology, homework, class/discussion exercises, and assignments. The modules are intended as a resource for instructors to experiment with and explore the use ofmodern statistical methodology inundergraduate statistics metho...

Dynamic modulus testing and the development of master curves is an essential test used to characterize asphalt mixes. The dynamic modulus values are used in the mechanisitic-emprical pavement design guide that is being implemented by many state agencies. To compare dynamic modulus values, most researchers use master curves to analyze the values; however, the log-log scale of the master curve masks the differences between the mixes, requiring the use of an appropriate and reliable statistical data analysis approach to make accurate comparisons between mixes. In this paper, a full experimental plan is designed to investigate the effect of three different factors on the dynamic modulus, namely (1) type of mix: hot mix asphalt versus warm mix asphalt, (2) impact of reheating, and (3) moisture conditioning of specimens. An open-access statistical software package, “R,” is used for the analysis. The data showed that the type of mix and moisture conditioning were statistically significant factors. The statistical analyses presented in this paper begin with a simplified approach and then become increasingly comprehensive. The simplified approach considers a single temperature and frequency only. A more encompassing approach, with the aid of split-plot repeated measures (SPRM) analysis, is then performed in which each of the three factors is considered separately. This is followed by a full analysis on the entire data set that takes into account the interaction between all factors. The benefits of performing a full analysis in lieu of a simplified analysis are highlighted and a detailed interpretation of the results is given.

Cdc7 is a serine-threonine kinase that phosphorylates components of the pre-replication complex during DNA replication initiation. Cdc7 is highly conserved, and Cdc7 orthologs have been characterized in organisms ranging from yeast to humans. Cdc7 is activated specifically during late G1/S phase by binding to its regulatory subunit, Dbf4. Drosophila melanogaster contains a Dbf4 ortholog, Chiffon, which is essential for chorion amplification in Drosophila egg chambers. However, no Drosophila ortholog of Cdc7 has yet been characterized. Here, we report the functional and biochemical characterization of a Drosophila ortholog of Cdc7. Co-expression of Drosophila Cdc7 and Chiffon is able to complement a growth defect in yeast containing a temperature-sensitive Cdc7 mutant. Cdc7 and Chiffon physically interact and can be co-purified from insect cells. Cdc7 phosphorylates the known Cdc7 substrates Mcm2 and histone H3 in vitro, and Cdc7 kinase activity is stimulated by Chiffon and inhibited by the Cdc7-specific inhibitor XL413. Drosophila egg chamber follicle cells deficient for Cdc7 have a defect in two types of DNA replication, endoreplication and chorion gene amplification. However, follicle cells deficient for Chiffon have a defect in chorion gene amplification but still undergo endocycling. Our results show that Cdc7 interacts with Chiffon to form a functional Dbf4-dependent kinase complex and that Cdc7 is necessary for DNA replication in Drosophila egg chamber follicle cells. Additionally, we show that Chiffon is a member of an expanding subset of DNA replication initiation factors that are not strictly required for endoreplication in Drosophila.

To determine whether fibrin sealant injected into the tract created by liver biopsy can be used to decrease postprocedural bleeding. An innovative delivery system was used to deploy the fibrin sealant.Fibrin sealant is a hemostatic agent consisting of a suspension of fibrinogen and thrombin. A delivery system was devised whereby fibrin sealant could be injected into the tract created by liver biopsy. Thirty swine were randomized into three groups: control (n = 10), heparin (n = 10), and warfarin (n = 10). Each swine underwent laparotomy and was randomized to undergo three to five open liver biopsies with either a 14-gauge cutting needle in conjunction with the fibrin sealant device or a standard 14-gauge cutting needle alone. Forty-seven biopsy procedures were performed with the device; 64 biopsy procedures were performed without the device. Immediate blood loss per biopsy (mL) was estimated based on the size of the blood stain on a sponge. Specimens were assessed for sample size.Immediate blood loss with and without the device, respectively, was: control, 0.1 mL, 5.4 mL; heparin, 0 mL, 7 mL; warfarin, 0.1 mL, 9.3 mL. These differences were significant (P.01) for each group of swine. In 43 of 47 biopsies (91%), the device functioned without difficulty. There was no difference in sample size when the device was used.The fibrin sealant device is effective in reducing bleeding after open liver biopsy in anticoagulated and nonanticoagulated swine. The promising results suggest that a trial of percutaneous liver biopsy in swine should be considered.

lacZ fusion strains were constructed using the promoters of five cell wall stress stimulon genes: pbp2 , tcaA , vraSR , sgtB , and lytR . All fusion strains were induced only in the presence of cell wall-active antibiotics, suggesting the potential of these strains for use in high-throughput screening for new cell wall-active agents.

Appendicitis among liver transplant recipients has not been described in the current literature. We report 8 recipients who experienced appendicitis three weeks to 181 months after liver transplantation (LT). Initial presenting findings differed from the nonimmunosuppressed population in that a majority of the patients did not have leukocytosis (>10,000 cells/mm3). Four patients experienced perforation, three of whom presented three days after the development of abdominal pain. All patients recovered after surgery without untoward sequela.

Graduate teaching assistants at Iowa State University develop their teaching skills through an apprenticeship-like process. First-year graduate students start out as laboratory instructors/graders. After the first year, some graduate teaching assistants teach a section of an introductory statistics course. This article describes this apprenticeship-like process and the mentoring and resources provided to graduate teaching assistants.

As a part of an opening course survey, data on eye color and gender were collected from students enrolled in an introductory statistics course at a large university over a recent four year period. ...

This is a case study that focuses on the renovation of Maplewood market apartments in Georgia.

This report will summarize the home energy improvements performed in the Atlanta, GA area. In total, nine homes were retrofitted with eight of the homes having predicted source energy savings of approximately 30% or greater based on simulated energy consumption.