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Importance Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low. Objective To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum]). Design, Setting, and Participants This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020. Exposures Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine). Main Outcomes and Measures Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome). Results Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata. Conclusions and Relevance In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.

A comprehensive case study of Keansburg Inlet (New Jersey, USA) is presented with the objective of evaluating inlet management alternatives and assessing the influence of an operational flood gate on channel shoaling. The goal of the research is determining the most effective strategy for minimizing the frequency of maintenance dredging. This study compares the effectiveness of (1) traditional structural solutions, (2) modified dredging templates, and (3) assesses the influence of the flood gate operations during conditions representative of a typical year. Alternative analysis is completed using a coupled hydrodynamic&ndash, wave model (Delft3D-Flexible Mesh (FM)) with Real Time Control to simulate morphological changes. The model was calibrated and evaluated using collected field data. Water levels are reproduced within 6% of the spring tide range with lag times less than 20 min. The model results and observations suggest sediment transport is dominated by wave action with pronounced variations in dominant wave direction. The results indicate that changes to the operational dredging, or what the authors have termed broadly as &ldquo, adaptive dredging techniques&rdquo, appear to deliver the most promising improvement. Model results suggest that the current operational procedures of the flood gate do not significantly alter the channel infilling rates and patterns during typical (i.e., non-extreme event) conditions.

The ethmoidal region of the skull houses one of the most important sense organs of mammals, the sense of smell. Investigation of the ontogeny and comparative anatomy of internal nasal structures of the macrosmatic order Scandentia is a significant contribution to the understanding of the morphotype of Scandentia with potential implications for our understanding of the primate nasal morphological pattern. For the first time perinatal and adult stages of Ptilocercus lowii and selected Tupaia species were investigated by serial histological sections and high-resolution computed tomography (μCT), respectively. Scandentia show a very common olfactory turbinal pattern of small mammals in having two frontoturbinals, three ethmoturbinals, and one interturbinal between the first and second ethmoturbinal. This indicates a moderately developed sense of smell (moderately macrosmatic). The observed septoturbinal is probably an apomorphic character of Scandentia. A general growth in length occurs during postnatal ontogeny; thus the adult ethmoidal region is proportionally longer compared to the rest of the skull. Throughout ontogeny Ptilocercus has a proportionally longer nasal cavity than Tupaia. Major differences exist between Ptilocercus and Tupaia in regard to the proportions of the nasal cavity which correlate with the position of the orbits. Compared to Tupaia, Ptilocercus shows more anteriorly oriented orbits and has a proportionally longer nasal capsule than Tupaia and based on anatomy probably a higher level of olfactory discrimination. Furthermore, Ptilocercus has a platybasic skull base that resembles a derived feature of Ptilocercidae. In contrast, Tupaia has a distinct septum interorbitale leading to a tropibasic skull, a pattern that is a plesiomorphic character of Tupaiidae and Scandentia in general. This finding helps us to understand the septum interorbitale pattern in Primates. Our results indicate that differences among the investigated Scandentia species are correlated with adaptations to foraging and behavioural biology.

Background: Adult patients with diabetes mellitus (DM) have a greater risk of contracting hepatitis B virus (HBV) than the general population, including those ≥ 60 years of age. When infected, patients with DM have more severe HBV-related morbidity and accelerated progression. The CDC recommends HBV vaccination of all adults with DM who are ≥ 60 years of age at the discretion of the treating physician. Due to persistent challenges, including hyporesponsiveness with current 3-dose vaccines, 87% of individuals with DM who are ≥ 60 years of age remain unvaccinated. HBsAg-1018 (Heplisav-BTM) is a 2-dose HBV vaccine with demonstrated higher protection rates than a 3-dose vaccine, particularly in populations known to be hyporesponsive. In this post-hoc analysis of a phase 3 trial, we assessed the safety and efficacy of HBsAg-1018 in patients with type 2 DM (T2DM) who were ≥ 60 years of age. Methods: Patients with T2DM and who were 60-70 years old received either 2-dose HBsAg-1018 at 0 and 4 weeks and placebo at 24 weeks or 3-dose HBsAg-Eng (Engerix-B®) at 0, 4, and 24 weeks. Peak (week 24, HBsAg-1018 vs. week 28, HBsAg-Eng) seroprotection rates (SPRs) and safety were assessed by subgroups (sex, body mass index [BMI], and smoking status). Results: A total of 480 patients (HBsAg-1018, n=327; HBsAg-Eng, n=153) were included in this analysis. Among patients who received all study injections, the peak SPR was significantly higher with HBsAg-1018 at week 24 (88.2% [231/262]) than with HBsAg-Eng at week 28, giving an overall difference of 29.7% (95% CI: 20.5, 39.1; P Conclusion: Two-dose HBsAg-1018 provides better protection against HBV than a 3-dose vaccine (HBsAg-Eng) with a similar safety profile in patients ≥ 60 years of age with T2DM regardless of subgroup. Disclosure R.N. Hyer: Employee; Self; Dynavax Technologies. R.S. Janssen: Employee; Self; Dynavax Technologies.

We investigate Titan's low-latitude and midlatitude surface using spectro-imaging near-infrared data from Cassini/Visual and Infrared Mapping Spectrometer. We use a radiative transfer code to first evaluate atmospheric contributions and then extract the haze and the surface albedo values of major geomorphological units identified in Cassini Synthetic Aperture Radar data, which exhibit quite similar spectral response to the Visual and Infrared Mapping Spectrometer data. We have identified three main categories of albedo values and spectral shapes, indicating significant differences in the composition among the various areas. We compare with linear mixtures of three components (water ice, tholin-like, and a dark material) at different grain sizes. Due to the limited spectral information available, we use a simplified model, with which we find that each albedo category of regions of interest can be approximately fitted with simulations composed essentially by one of the three surface candidates. Our fits of the data are overall successful, except in some cases at 0.94, 2.03, and 2.79 μm, indicative of the limitations of our simplistic compositional model and the need for additional components to reproduce Titan's complex surface. Our results show a latitudinal dependence of Titan's surface composition, with water ice being the major constituent at latitudes beyond 30°N and 30°S, while Titan's equatorial region appears to be dominated partly by a tholin-like or by a very dark unknown material. The albedo differences and similarities among the various geomorphological units give insights on the geological processes affecting Titan's surface and, by implication, its interior. We discuss our results in terms of origin and evolution theories. ©2018. American Geophysical Union. All Rights Reserved.

Background Immunologic response to a complete vaccine regimen of currently licensed alum-adjuvanted hepatitis B vaccines is reduced in several subpopulations, including older adults, men, obese persons, and smokers. Two phase 3 trials in healthy adults demonstrated that 2 doses over 1 month of an investigational hepatitis B vaccine (HBsAg-1018) induced superior seroprotection rates (SPRs) to 3 doses over 6 months of the licensed vaccine Engerix-B ® (HBsAg-Eng). Methods An exploratory analysis of immunogenicity was conducted in subpopulations from pooled data for the 2 phase 3 trials. Results In each subpopulation, the peak SPR in the HBsAg-1018 group was statistically significantly higher than the peak SPR in the HBsAg-Eng group. Peak HBsAg-1018 SPRs ranged from 91.6% to 99.7%, while peak HBsAg-Eng SPRs ranged from 67.7% to 92.9%. Conclusion In these exploratory analyses, 2 doses of HBsAg-1018 induced statistically significantly higher rates of seroprotection than 3 doses of HBsAg-Eng across all subpopulations.

study question: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? summaryanswer: Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. what is known already: AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. study design, size, duration: The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010– 2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. participants/materials, setting, methods: Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was ,13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N ¼ 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N ¼ 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant’s age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. main results and the role of chance: Three metabolites of DEHP were significantly and inversely associated with both measures of boys’ AGD. Associations (b, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: 21.12 (22.16, 20.07) for mono-2-ethylhexyl phthalate (MEHP), 21.43, (22.49, 20.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and 21.28 (22.29, 20.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. limitations, reasons for caution: Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. wider implications of the findings: Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical.

Many patients with chronic kidney disease (CKD) are hyporesponsive to currently licensed alum-adjuvanted hepatitis B vaccines, including Engerix-B(®) (HBsAg-Eng). Seroprotection rates (SPRs) are further reduced in CKD patients with diabetes mellitus. Three doses of an investigational hepatitis B vaccine (HBsAg-1018) that uses a Toll-like receptor 9 agonist demonstrated superior SPRs to 4 double doses of HBsAg-Eng in a large phase 3 trial of CKD patients.A prespecified subgroup analysis of immunogenicity was conducted in CKD participants with type 2 diabetes in the phase 3 trial.In 328 participants, the peak SPR in the HBsAg-1018 group met criteria for noninferiority and superiority to the peak SPR in the HBsAg-Eng group. The peak geometric mean concentration of antibody against hepatitis B surface antigen in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group.HBsAg-1018 induced significantly higher seroprotection than HBsAg-Eng in CKD patients with diabetes.

In flood protection, the dominant paradigm of ‘building hard structures’ is being challenged by approaches that integrate ecosystem dynamics and are ‘nature-based’. Knowledge development and policy ambitions on greening flood protection (GFP) are rapidly growing, but a deficit remains in actual full-scale implementation. Knowledge is a key barrier for implementation. To analyse conditions for the implementation of GFP, a knowledge-arrangement perspective is developed. The knowledge-arrangement perspective is applied on a case study of successful implementation of GFP in the Netherlands, the pilot Sand Engine Delfland, a large-scale (21.5 Mm3) sand nourishment project. This project confirms that an integrated knowledge arrangement enables GFP as it allows for multifunctionality. Effectiveness of the integrated arrangement in this project is explained by its ‘flexible’ nature providing ample design space. This was possible because core values in flood protection and nature were not part of the integrated arrangement. More generally the case study demonstrates the difficulties of implementing GFP in existing mainstream flood protection routines. These are not (yet) geared to incorporate uncertainty, dynamics and multifunctionality, characteristics associated with GFP. The Sand Engine project can be regarded as a ‘field laboratory’ of physical and institutional learning and an innovation for mainstream flood protection.

Next-generation sequencing is radically changing how DNA diagnostic laboratories operate. What started as a single-gene profession is now developing into gene panel sequencing and whole-exome and whole-genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, WGS will soon become the standard and be routinely offered. Here, we focus on the critical steps involved in performing WGS, with a particular emphasis on points where WGS differs from WES, the important variables that should be taken into account, and the quality control measures that can be taken to monitor the process. The points discussed here, combined with recent publications on guidelines for reporting variants, will facilitate the routine implementation of WGS into a diagnostic setting. © 2017 Wiley Periodicals, Inc.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology

Using a large-capacity-on-chip preconcentrator device for selective ethylene measurement leads to some challenges. The dramatic increase of the water influence and the gas chromatography effect of the preconcentrator must be known and compensated before a good measurement with this new device can be performed. Nevertheless, after facing these challenges the small gas chromatograph presented in this paper was for the first time able to detect an ethylene concentration of 170 ppbv. Deduced from this measurement a detection limit below 50 ppbv can be reached, which is absolutely mandatory for shelf life prediction of climacteric fruits. New stationary phases were tested. The used packed gas chromatography column is now capable of separating vaporized water and ethylene gas from each other, which was a breakthrough in the analysis of ethylene concentrations in ambient air. It can be predicted that the system will be available at a price under 1000 €.

In this work, we present a miniaturized sensor for detecting pH changes in agar-gel culture medium during fungal growth. For the first time an integrated approach of impedance and colorimetric principles for real-time monitoring of pH changes (7.6 to 2.0) in agar-gels on-chip is demonstrated. The designed sensor comprises a 7 mm diameter chamber with pre-loaded agar-gel medium which promotes the growth of the fungi. Detection of pH change in the medium is carried out by measuring changes in the impedance of the culture medium with integrated electrodes. As a second measurement principle, a pH indicator dye is added to the agar-gel which changes the color of the gel with respect to the pH change. The colorimetric principle serves as a reference measurement that indicates a pH change after which further pH shifts can be determined using impedance measurement.

Background HEPLISAV-B® [hepatitis B vaccine (recombinant), adjuvanted] uses a cytidine phospho-guanosine (CpG) oligonucleotide or “1018,” a Toll-like receptor 9 agonist, as an adjuvant. Engerix-B® [hepatitis B vaccine (recombinant)], as well as other hepatitis B vaccines, use alum. HEPLISAV-B, a 2-dose vaccine given at Weeks 0 and 4, was recently approved for use in adults ≥18 years for the prevention of hepatitis B. Approval of HEPLISAV-B was based on three pivotal phase 3 noninferiority trials, comparing it with Engerix-B, a 3-dose vaccine given at Day 0, Day 30, and 6 months. Immunogenicity and safety results for these trials, HBV-10, HBV-16 and HBV-23, have been published previously; the safety of HEPLISAV-B was generally similar to Engerix-B. Methods The 3 randomized trials were observer-blinded and collectively included subjects aged 18–70 years. Immunogenicity analysis based on antibody against hepatitis B surface antigen (anti-HBs) levels were based on the per-protocol analysis. Presented here are reverse cumulative frequency plots of anti-HBs serum concentrations for the 3 trials. Results Across the trials, reverse cumulative frequency plots of anti-HBs concentrations showed a higher proportion (>90%) of HEPLISAV-B subjects developed a seroprotective antibody level (anti-HBs levels ≥10 mIU/mL) compared with Engerix-B subjects (80% to ~90%). A higher proportion of HEPLISAV-B subjects had anti-HBs levels between 10 mIU/mL and 1,000 mIU/mL. While a higher proportion of Engerix-B subjects had anti-HBs levels >1,000 mIU/mL, a significantly higher proportion of Engerix-B subjects did not develop seroprotective antibody levels. The response curves indicate a more consistent immune response with a higher percentage of subjects achieving seroprotection with less variability for HEPLISAV-B compared with Engerix-B, which showed a more variable response and fewer subjects achieving seroprotection. Conclusion HEPLISAV-B, using a CpG adjuvant, results in a higher percentage of persons achieving seroprotection and produces a more uniform and consistent induction of protective antibody levels than Engerix-B, an alum-adjuvanted vaccine. Disclosures R. N. Hyer, Dynavax Technologies Corporation: Employee and Shareholder, Salary and Stock options. R. Janssen, Dynavax Technologies Corporation: Employee and Shareholder, Salary and Stock options.

Background Less than 1 in 3 US adults who initiated the 3-dose (0, 1, 6 months) hepatitis B vaccine series have completed it. HepB-CpG (Heplisav-B; Dynavax) is a new licensed adjuvanted vaccine that requires only 2 doses (0, 1 month). As part of a cluster study performed at Kaiser Permanente Southern California, we compared compliance with second dose and series completion for HepB-CpG vs. comparator vaccine (Engerix-B; GlaxoSmithKline) recipients. Methods The cohort included adults not on dialysis who received their first dose of hepatitis B vaccine in family or internal medicine departments from 8/7/2018 to 2/1/2019. Second dose compliance was assessed for the full cohort, but series completion was assessed for a subset vaccinated from August 7, 2018 to September 30, 2018 to allow at least 6 months’ follow-up. Compliance rates were estimated using the Kaplan Meier method. Adjusted hazard ratios (aHR) were estimated using Cox proportional hazard regression with robust variance to account for within medical center correlation, adjusting for age, race/ethnicity, census block income and education, prior healthcare utilization, and factors that trigger alerts for hepatitis B vaccination (diabetes and testing for sexually transmitted infections). Results There were 6500 HepB-CpG and 7733 comparator vaccine recipients (1,442 and 2,604 prior to September 30, 2018). Rates of second dose compliance at 60 days were 32.9% for HepB-CpG and 29.1% for comparator vaccine, and rates of series completion at 210 days were 56.9% and 20.6%. There was no significant difference in second dose compliance (aHR 1.14, 95% CI: 0.91, 1.47), but HepB-CpG recipients were 5 times more likely to complete the series (aHR 5.17; 95% CI: 3.84, 6.98). Second dose compliance and series completion were significantly less likely among Blacks compared with Whites and significantly more likely among Asians, adults ≥60 years compared with those < 30 years, and adults living in census blocks with a median annual income of $40,000–69,000 compared with < $40,000. Conclusion Overall, second dose compliance was similar, but series completion was better for HepB-CpG recipients than comparator vaccine recipients, suggesting that the 2-dose vaccine could lead to improvements in coverage and protection against hepatitis B virus. Disclosures All authors: No reported disclosures.

The combined glucose-lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single-dose or 4-week dosing) in diabetic ob/ob mice. Vehicle-corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post-dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

Background Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2 × 20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng). Methods An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18–75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg + 3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2 × 20 mcg rHBsAg + 500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year. Results Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs ≥ 10 mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs ≥ 100 mIU/mL in theHBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1 mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5 mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response toHBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng. Conclusion In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ‘kra’ monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1,2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ‘hypnozoite’ in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6,7,8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry., Nature, 455, ISSN:0028-0836, ISSN:1476-4687

Gallstone disease has a high incidence, and most common presentations are well known and recognized. Particulalry in the elderly population though, uncommon presentations of gallstone disease are more frequent, and can easily be missed or misinterpreted. In this article we present 5 such patients with an atypical presentation of gallstone disease. We will then discuss atypical gallstone disease in more detail.

Rationale: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. Objectives: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. Methods: Retrospective analysis of the Colorado CF Database (1992–2008), CF Foundation Registry (1992–2007), and Multiple Cause of Death Index (1992–2005). Measurements and Main Results: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV1 decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV1 declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV1 decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV1 improvement in response to CF center care. Conclusions: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Anhand der Nitrierung von Benzol wird die Steigerung von Umsatz und Selektivitat in mehreren Mikroreaktorstufen mit unterschiedlicher Konzentrationsfuhrung untersucht. Im Gegenstrom wird im Vergleich zum Gleichstrom ein hoherer Umsatz des Benzols bei stochiometrischem Verhaltnis erzielt. Durch Verschaltung der Nitriersaure im Kreuzstrom wird eine erhebliche Verminderung der Dinitrobenzole beobachtet.

To determine the status of the HIV epidemic in the United States and Canada.We used data on AIDS and HIV diagnoses for 1996-2005 reported to the United States and Canadian national surveillance systems to determine trends in AIDS and HIV (33 US states only) diagnoses and to identify population groups most affected by HIV. HIV incidence for Canada was determined using back-calculation methods. We also determined the proportion of persons diagnosed late (HIV diagnosis within 12 months before AIDS diagnosis).AIDS diagnosis rates were higher in 2005 among blacks (54.1 per 100,000) and Hispanics (18.0) compared with whites (5.9) in the United States and among blacks (4.7) and aboriginal peoples (4.9) compared with whites (0.7) in Canada. Since 2001, HIV diagnoses increased among men who have sex with men in both countries and in Canada, increased among persons from HIV-endemic countries and where heterosexual contact was the only identified risk of transmission. Overall, HIV incidence remained relatively stable in Canada during that period. A large proportion of persons were diagnosed late in the disease process (United States, 54.3%; Canada, 64.2%).Rates of HIV transmission remain a challenge in both the United States and Canada as overall diagnosis rates have not decreased in recent years. Renewed prevention efforts are needed to further reduce the high HIV diagnosis rates among racial/ethnic minorities and to decrease HIV transmission among men who have sex with men.

(CHEST 2008; 134:1074–1079) A 33-year-old man was brought to the emergency department with dyspnea, chest pain, and confusion. His symptoms began 2 weeks prior, with intermittent mild anterior chest pain, palpitations, exertional breathlessness, and diaphoresis. The symptoms gradually worsened, and on the morning of presentation he complained of severe chest pain and dyspnea at rest. Several hours later, he was found by his wife on the floor, confused and tremulous. His wife called emergency services and he was transported to the emergency department. In the emergency department, the patient was unresponsive to verbal and tactile stimuli. He was orotracheally intubated for airway protection. The patient’s wife said that he was healthy before his recent symptoms began. Although he was not taking any medications, she thought he was told in the past that he should take a thyroid medication. He had no allergies, no family history of heritable disease, and never used tobacco, alcohol, or recreational drugs. He had emigrated from Mexico at age 23 years and worked as a carpenter. He lived at home with his wife and two children.

New approaches are needed to fight the human immunodeficiency virus (HIV) epidemic, now in its third decade in the United States. The epidemiology of HIV in the past decades illustrates these new challenges. Annual incident cases of acquired immunodeficiency syndrome (AIDS) declined 38% and deaths from AIDs declined 63% between 1995 and 1998, due primarily to the introduction of combination antiretroviral therapy (ART).1,2 However, the annual number of incident AIDS cases and deaths remained stable from 1999 through 2006, and the estimated number of new HIV infections occurring annually in the U.S. has remained stable since 2000.1,3 This article seeks to put the current emphasis of the Centers for Disease Control and Prevention (CDC) on HIV testing programs in the context of the epidemiology of the U.S. HIV epidemic; to describe major CDC prevention initiatives that involve HIV testing, focusing on the Advancing HIV Prevention (AHP) initiative;4 and to describe what has been learned in the first five years since new strategies for preventing HIV infection were outlined in the AHP initiative.

Purpose: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor–selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis. Experimental Design: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes. Results: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis. Conclusions: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-γ, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.

The recommendations for human immunodeficiency virus (HIV) testing in the United States were recently revised. An important goal of these revisions is to reduce the proportion of individuals infected with HIV who are unaware of their infection. In the new guidelines, screening is recommended for all individuals aged 13-64 years in any health care setting, provided that they are notified that testing will be performed and do not decline testing. It was further recommended that individuals at high risk for HIV infection be screened annually. Through wider screening, the identification of persons with unrecognized HIV is expected to facilitate treatment and allow better targeting of HIV prevention strategies.

b d Public health departments collect a vast array of identifiable information in the course of mandatory reporting efforts and other surveillance activities. These undertakings span a range of conditions from infectious threats and chronic diseases including cancer, to immunization status and birth defects. Advocates for expanded surveillance extended the practice to occupational diseases and, most ambitiously, to profiles of childhood health status. Syndromic surveillance is also increasingly undertaken in the new post-September 11 security environ - ment. In the one Supreme Court case addressing public health surveillance, a unanimous tribunal upheld the right of the state to conduct surveillance. 1

Short-term effects of therapeutic claw trimming in acutely lame cows (n=21) with nonadvanced claw horn lesions on the endocrine, metabolic, and behavioral stress responses were investigated in comparison to regular claw trimming in nonlame control cows (n=21). Controls were matched to lame cows by parity and stage of lactation. Lame cows suffering from typical sole ulcers or white line disease were blinded and randomly assigned to 2 treatments, receiving 15 min before interventions either ketoprofen (n=11; 3mg/kg of BW intramuscularly; Romefen, Merial, Lyon, France) or placebo (n=10; saline in equivalent amount and route of administration). All cows underwent functional claw trimming in lateral recumbency on a surgical tipping table, and claw horn lesions in lame cows were conventionally treated (removal of loose horn, block on opposing claw, bandaging of affected claw). Blood samples collected 15 min before, at the end, and 24h after claw trimming were analyzed for concentrations of cortisol, fatty acids, lactate, and glucose, and fecal samples (collected before treatment and after 24 h) for cortisol metabolites. Behavioral stress responses during functional and therapeutic claw trimming were recorded. Concentrations of blood cortisol, fatty acids, glucose, and fecal cortisol metabolites were higher in lame than in nonlame cows after treatment. During claw treatment, more leg movements were recorded for lame cows than nonlame cows. Pre-emptive administration of ketoprofen had no obvious effects on stress responses to therapeutic claw trimming. Treatments of claw horn lesions caused a significant stress and pain reaction in acutely lame cows, demonstrating the necessity of adequate pain management protocols for such interventions.

In this work, we present a new miniaturized culture medium based sensor system where we apply an optical reference in an impedance measurement approach for the detection of mold in archives. The designed sensor comprises a chamber with pre-loaded culture medium which promotes the growth of archive mold species. Growth of mold is detected by measuring changes in the impedance of the culture medium caused due to increase in the pH (from 5.5 to 8) with integrated electrodes. Integration of the reference measurement helps in determining the sensitivity of the sensor. The colorimetric principle serves as a reference measurement that indicates a pH change after which further pH shifts can be determined using impedance measurement. In this context, some of the major archive mold species Eurotium amstelodami, Aspergillus penicillioides and Aspergillus restrictus have been successfully analyzed on-chip. Growth of Eurotium amstelodami shows a proportional impedance change of 10 % (12 chips tested) per day, with a sensitivity of 0.6 kΩ/pH unit.

A small-angle detector will complete the performance of the cold time-of-flight spectrometer FOCUS at the Swiss Spallation Source SINQ of the Paul Scherrer Institute, Villigen, Switzerland. It is constructed from position-sensitive 3He tubes located 2.5 m away from the sample, and covers an area of about 95 × 70 cm2 with a spatial resolution of approximately 1.5 cm. The 2D detector is located within a vacuum chamber, next to the argon chamber of the existing large angle detectors, and covers an angular range from 2 to 22°. Commissioning of the 2D small angle detector will start in spring 2006.

Background: New HIV infections stem from people who are aware they are HIV positive (approximately 75% of infected persons in the USA) and those who are unaware of their HIV-positive status (approximately 25%). Objective: We estimated the relative contribution of these two groups in sexually transmitting new HIV infections to at-risk (HIV-negative or unknown serostatus) partners in the USA. Methods: The parameters in the estimation included: number of people aware and unaware they are infected with HIV; 33% of the aware group are at low risk of transmitting HIV because of low/undetectable viral load; 57% relative reduction in the prevalence of unprotected anal and vaginal intercourse (UAV) with at-risk partners in persons aware (compared to unaware) they have HIV; and assumed differences in the average number of at-risk UAV partners in each awareness group (ranging from equal to twice as many in the unaware group). Results: The proportion of sexually transmitted HIV from the HIV-positive unaware group was estimated to range from 0.54 (assuming no difference in average number of at-risk UAV partners between groups) to 0.70 (assuming twice as many at-risk UAV partners in the unaware group). Using the lower bounds, the transmission rate from the unaware group was 3.5 times that of the aware group after adjusting for population size differences between groups. Conclusion: The results indicate that the HIV/AIDS epidemic can be lessened substantially by increasing the number of HIV-positive persons who are aware of their status.

Molecular dynamics of the ferroelectric compound triglycine sulphate (TGS) was studied by quasi-elastic neutron scattering. From among the three glycine molecules forming the unit cell the non-planar GI molecule is responsible for the polarisation which occurs in crystal and for the order–disorder ferroelectric phase transition at T c = 49 °C. This molecule also shows a complex dynamics much faster than that performed by the other glycine molecules. The key group of this molecule is the amino group that, on one hand, seems to be responsible for the phase transition and, on the other hand, performs motional processes spread on a wide time scale. These motions have been detailed studied by means of different energy resolution windows within the quasi-elastic scattering range. We found that the dynamics of this group develops in a restricted spatial volume and consists in a faster rotational diffusion around the molecular axis of the group and a slower flipping dynamics between two symmetrical positions on both sides of a mirror plane containing the molecular axis of GI molecule.

Recent outbreaks of syphilis among men who have sex with men (MSM) in major cities in the United States and reported increases in sexual risk behavior have raised concerns about potential increases in human immunodeficiency virus (HIV) transmission. The majority of MSM who have early syphilis are HIV infected; in preliminary studies, rates of recent HIV infection among them are also high. Data from San Francisco, Los Angeles, and Seattle-King County, however, suggest no temporal increases in HIV incidence among MSM seeking HIV testing at select large public sites during the syphilis outbreaks. Because most HIV incidence and behavioral data are from large metropolitan areas with large gay populations and well-established HIV epidemics, we do not know whether, nationally, incidence of HIV infection among MSM has been increasing, decreasing, or stable during syphilis outbreaks. Further studies of HIV incidence in larger and smaller cities with different maturities of HIV epidemic are warranted. Comprehensive and integrated HIV/STD prevention and control efforts are also needed to halt the spread of syphilis and reduce HIV transmission among gay and bisexual men.

This study evaluated the magnitude and distribution of unrecognized HIV infection among young men who have sex with men (MSM) and of those with unrecognized infection, the prevalence and correlates of unprotected anal intercourse (UAI), perceived low risk for infection, and delayed HIV testing. MSM aged 15-29 years were approached, interviewed, counseled, and tested for HIV at 263 randomly sampled venues in 6 US cities from 1994-2000. Of 5649 MSM participants, 573 (10%) tested positive for HIV. Of these, 91% of black, 69% of Hispanic, and 60% of white MSM (77% overall) were unaware of their infection. The 439 MSM with unrecognized infection reported a total of 2253 male sex partners in the previous 6 months; 51% had UAI; 59% perceived that they were at low risk for being infected; and 55% had not tested in the previous year. The HIV epidemic among MSM in the United States continues unabated, in part, because many young HIV-infected MSM are unaware of their infection and unknowingly expose their partners to HIV. To advance HIV prevention in the third decade of HIV/AIDS, prevention programs must reduce unrecognized infection among young MSM by increasing the demand for and availability of HIV testing services.

Photoproduction of neutral pions from nuclei (carbon, calcium, niobium, lead) has been studied for incident-photon energies from 200 MeV to 800 MeV with the TAPS detector using the Glasgow photon tagging spectrometer at the Mainz MAMI accelerator. Data were obtained for the inclusive photoproduction of neutral pions and the, partial channels of quasifree single-pi(0), double-pi(0), and pi(0)pi(+/-) photoproduction. They have been analyzed in terms of the in-medium behavior of nucleon resonances and the pion-nucleus interaction. They are compared to earlier measurements from the deuteron and to the predictions of a Boltzmann-Uehling-Uhlenbeck (BUU) transport model for photon-induced pion production from nuclei.

SANS-II facility at SINQ (Paul Scherrer Institute)—the reinstalled former Riso small-angle neutron scattering instrument—is presented. Its operational characteristics are listed. Approaches for precise determination of wavelength, detector dead time and attenuation factors are described as well.

The low-temperature magnetic properties of the rare-earth intermetallic compound system R3Pd20Si6(R = rare earth) were studied by elastic and inelastic neutron scattering. The compounds show due to the two rare-earth sublattices built from the 4a and 8c sites in the cubic crystal structure (space group Fm-3m) successive magnetic ordering with two different propagation vectors. In this report, we give an overview of the results obtained for the magnetic structures and the crystalline electric fields in the 3-20-6-system.

FOCUS is a cold neutron time-of-flight spectrometer at the swiss spallation neutron source SINQ (Paul Scherrer Institute). Various quasielastic and inelastic neutron scattering experiments have been performed so far using a pyrolithic graphite monochromator with incident wavelengths between 2 and 6 A. Recently, the instrument has been complementarily equipped with a new mica monochromator. This device is mechanically identical to the graphite monochromator but it covers the wavelength range from 6 to 15 A. With that new monochromator an energy resolution below 10 μeV (FWHM) is feasible on FOCUS which is a factor of 5 below the former value accessible with the graphite monochromator. The design as well as first experiences with the new monochromator will be discussed. One of the first measurements using the mica monochromator, which investigated the dynamics of Na 4 B(OH) 4 3+ clusters confined in pores of a zeolite is presented.

Less sensitive (LS) HIV-1 enzyme immunoassays (EIAs) have significantly improved the quantity and quality of HIV surveillance data. The first LS-HIV-1 EIA, the Abbott 3A11-LS, provided reliable incidence data, but the assay required specialized equipment, and the lack of available reagents made testing difficult. This study evaluated the use of an alternate assay, a modified version of the Vironostika HIV-1 EIA (Vironostika-LS), to be used for LS testing. The Vironostika-LS has similar performance characteristics to the Abbott 3A11-LS with additional advantages. This 96-well formatted assay is commonly found in public health laboratories for routine HIV-1 testing and can be used with both serum and dried blood spot specimens. The estimated mean time from seroconversion (defined using a standardized optical density cutoff of 1.0) with the Vironostika-LS was 170 days (95% CI, 145-200 days). When the Vironostika-LS was applied to a matched serum set previously tested with the Abbott 3A11-LS, the Vironostika-LS accurately identified 97% of specimens with recent or long-standing HIV infection. The paper also reports Vironostika-LS quality control guidelines and the results from 3 rounds of proficiency testing.

We report on the magnetic properties of the tetranuclear metallic cluster [Mn4O2(O2CPh)6(dpm)2]. Using susceptibility, magnetization and inelastic neutron scattering (INS) spectroscopy we have determined the exchange and anisotropy parameters. The four Mn3+ (S=2) form a tetranuclear cluster with butterfly-type geometry. The two core Mn3+ ions are strongly antiferromagnetically coupled with Jb=−4.8±0.1 meV. The outer Mn3+ ions are loosely coupled to the core spins via two different weak interactions, ferromagnetic and antiferromagnetic, respectively: Jw1=+0.1±0.01 meV and Jw2=−0.1±0.01 meV. In addition, the octahedrally coordinated outer Mn3+ ions experience a large single-ion anisotropy DS2z with D=−0.47±0.01 meV due to a strong distortion of the MnO6 octahedra. The Lande g-factor is g=1.94±0.03. Frustration effects and competitive interactions lead to remarkable magnetic properties which cannot be unambiguously interpreted without the additional information from INS.

The sensitive/less-sensitive (S/LS) enzyme immunoassay (EIA) testing strategy for discriminating "early" from "longstanding" HIV infection has been widely applied for detecting recent seroconverters and estimating HIV incidence rates. The originally developed assay (3A11-LS EIA; Abbott Laboratories, Abbott Park, IL) involved performance of LS EIAs using a bead-based assay that required specialized equipment and reagents of limited availability. In contrast, 96-microwell-based EIAs are more universally applied for HIV serodiagnosis throughout the world. The authors report development and preliminary validation of an LS protocol using an EIA in a 96-well format: the Vironostika HIV-1 MicroElisa System (Vironostika-LS EIA; Bio Merieux, Raleigh, NC). The results with samples from recent HIV-1 seroconverters, persons with longstanding HIV-1 asymptomatic infection, patients on highly active antiretroviral therapy, and AIDS patients show a high degree of correlation between the Vironostika-LS EIA and 3A11-LS EIA. The authors also demonstrate that the Abbott 3A11-LS EIA and Vironostika-LS EIA performed comparably on HIV-1-positive samples from persons infected with non-B HIV-1 subtypes. These results support the potential use of the Vironostika-LS EIA for detection of recent HIV-1 infections for incidence projections and for other epidemiologic, clinical, and molecular surveillance applications.

The crystal fields (CFs) of the binary rare-earth compounds PrAl3 and NdAl3 have been examined at ambient pressure by means of inelastic neutron scattering. The CF of the latter compound has also been measured under hydrostatic pressure (p = 0.84 GPa). The observed substantial changes of the CF under pressure are discussed within the framework of first-principles density functional theory calculations.

Inelastic neutron scattering studies of the relaxation rate of crystal-field excitations have provided evidence for large oxygen and copper isotope effects on the pseudogap in high-temperature superconductors. Existing experiments in the slightly underdoped HoBa2Cu4O8 compound will be reviewed, as well as possible implications of such findings on the microscopic mechanism of high-temperature superconductivity. New relevant experiments performed in the La1-xSrxCuO4 family will also be presented.