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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.

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.

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.

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.

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.

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.

Background: Black men who have sex with men (MSM) in the Southeastern United States are disproportionately affected by HIV. Black MSM are more likely to have unrecognized HIV infection, suggesting that testing may occur later and/or infrequently relative to current recommendations. The objective of this qualitative study was to explore the HIV testing behaviors of Black MSM in Atlanta, Georgia, who were participants in the HIV Prevention Trials Network Brothers Study (HPTN 061). Methods and Findings: We conducted 29 in-depth interviews and four focus groups with a community-recruited sample. Modified grounded theory methodologies were used to guide our inductive analysis, which yielded a typology comprised of four distinct HIV testing patterns. Participants could be categorized as: (1) Maintenance Testers, who tested regularly as part of routine self-care; (2) Risk-Based Testers, whose testing depended on relationship status or sexual behavior; (3) Convenience Testers, who tested irregularly depending on what testing opportunities arose; or (4) Test Avoiders, who tested infrequently and/or failed to follow up on results. We further characterized these groups with respect to age, socioeconomic factors, identity, stigma and healthcare access. Conclusions: Our findings highlight the heterogeneity of HIV testing patterns among Black MSM, and offer a framework for conceptualizing HIV testing in this group. Public health messaging must account for the diversity of Black MSM’s experiences, and multiple testing approaches should be developed and utilized to maximize outreach to different types of testers.

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.

Type I diabetes mellitus afflicts nearly 2 million Americans and is responsible for untold morbidity. Despite significant improvements in monitoring and administration, insulin therapy cannot fully normalize glucose homeostasis at the present time. Therefore, curative therapies for the disease have relied on replacement of the β-cell mass by transplantation. During the last 35 years, whole organ pancreas transplantation (WOP) has evolved gradually into a highly effective therapy for type I diabetic patients who are undergoing simultaneous renal transplantation.1–5 Because the risks of severe complications of this procedure are relatively small in these patients who are already obligated to lifelong immunosuppression, the benefits of the procedure are generally accepted as outweighing the risks.6 In recent years, WOP has also been advocated for type 1 patients with diabetes who have either adequate function of their own kidneys or an established renal transplant. In these cases of pancreas transplant alone or pancreas after kidney transplantation (PAK), very poor glucose control and dangerous episodes of hypoglycemic unawareness are the usual and most persuasive indications for transplantation. These pancreas without kidney transplants remain controversial despite the success of the simultaneous pancreas and kidney transplant procedure (SPK), with at least one recent analysis suggesting that the risks of these procedures may outweigh their benefits.7 IIT offers a less invasive and thus presumably less morbid alternative to WOP for β-cell replacement, although the success of this procedure was considered exceedingly rare until relatively recently.8 By the 1990s, a number of centers using improved methods of islet isolation demonstrated that IIT quite often resulted in sustained insulin secretion. Nevertheless, insulin independence at 1 year post-transplantation remained unusual ( 90% of patients.14 However, in the other 6 centers, success was sporadic (0–50%), probably due to the complexity of the isolation technique and the need for additional experience.15 The success and relative safety of the Edmonton trial has led some to suggest that IIT is ready to supersede WOP as the procedure of choice for replacement of β-cells in type I diabetic patients. Such a contention has important implications in schemas for cadaveric pancreas organ use, because candidates for WOP are currently given priority over potential IIT recipients. Thus, it is important to compare the 2 transplant methods. We have examined a contemporary series of WOP and IIT at our institution to compare relative efficacy, safety, and cost.

Scanning spreading resistance microscopy (SSRM) and scanning capacitance microscopy (SCM) are two different methods for carrier profiling on semiconductor devices based on the atomic force microscope (AFM). The crucial part of these characterization tools is the tip which should have a small radius of curvature and a high electrical conductivity. Therefore, we have developed a process for the fabrication of pyramidal metal tips which are integrated into a silicon cantilever. The fabrication scheme is presented and is discussed in more detail from the point of view of batch fabrication. The fabricated probes were used in the AFM for topography measurements and for electrical measurements. We demonstrate that these probes can be operated in contact mode as well as in tapping mode. The behavior of the metal tips in carrier profiling was extensively studied. Results are presented concerning the application of such probes for 2D SCM measurements on silicon and InP device structures. We demonstrate that silicon cantilevers with integrated metal tips are very well studied for SSRM measurements on InP structures.

We present a biologically inspired actuator exhibiting a novel pumping action. The design of the 'artificial heartbeat' actuator is inspired by physical principles derived from the structure and function of the human heart. The actuator employs NiTi artificial muscles and is powered by electrical energy generated by microbial fuel cells (MFCs). We describe the design and fabrication of the actuator and report the results of tests conducted to characterize its performance. This is the first artificial muscle-driven pump to be powered by MFCs fed on human urine. Results are presented in terms of the peak pumping pressure generated by the actuator, as well as for the volume of fluid transferred, when the actuator was powered by energy stored in a capacitor bank, which was charged by 24 MFCs fed on urine. The results demonstrate the potential for the artificial heartbeat actuator to be employed as a fluid circulation pump in future generations of MFC-powered robots ('EcoBots') that extract energy from organic waste. We also envisage that the actuator could in the future form part of a bio-robotic artwork or 'bio-automaton' that could help increase public awareness of research in robotics, bio-energy and biologically inspired design.

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