cssi/SciSciGPT-SciSciNet huggingface dataset:
Physicians' Perspectives on Increasing the Use of BMI Charts for Young Children

The objective of the study was to explore the barriers and facilitators to using body mass index (BMI) for preschoolers. A survey was administered to a random sample of 600 pediatricians and family physicians in Michigan addressing usual practice for BMI charting, barriers, perceived influence of BMI chart innovations on the likelihood of increasing use of BMI and participating in training regarding obesity management. The response rate was 52%. Few respondents report that they generally use BMI charts for preschoolers (24%). The most frequently endorsed barrier was time and complexity involved in explaining BMI (70%). Respondents endorsed innovations such as color-coded charts (60%), and the inclusion of management recommendations (61%) as strong influences on the likelihood of using BMI more often. Frequently endorsed training modalities were workshops (47%), online (45%), and DVD (43%). Efforts to increase physician use of BMI should address methods to simplify communication of BMI, such as with color-coded charts, and provision of management recommendations based on BMI findings.
adaptive strategies in alpine environments: beyond ecological particularism1

This paper is an attempt to identify some regularities in ecological adaptation and social organization in agricultural-pastoral communities in high altitude environments. Comparisons are made between the Alpine Swiss and Khumbu Sherpas of northern Nepal, and the model which is developed is tested against data drawn from the Andean literature. In spite of the fact that these mountain ranges are in different parts of the world, their inhabitants have made remarkably similar adaptations to their alpine environments.
Nutrition Evaluation of Dietary Fat Substitutes

In response to US dietary guidelines and health goals, the food industry has introduced a variety of innovative food products designed to help the American public lower its fat intake. The physical characteristics and safety considerations of these products are reviewed, as well as their association with chronic disease prevention.
Ultra-reliable communication over unreliable optical networks via lightpath diversity: system characterization and optimization

We propose using diversity via multiple disjoint lightpaths at the optical layer to achieve ultra-reliable communication with low delay between any source-destination pair of all-optical networks. A doubly-stochastic point process model is used to characterize the photo-events of a direct detection receiver. The error probability can be designed to be significantly lower than that of a system without lightpath diversity. System parameters, such as the number of lightpaths used, are optimized to achieve efficient utilization of the limited optical transmitter power.
The Challenge of Managing Mild Parkinson's Disease

Clinicians have a number of options when diagnosing and managing Parkinson's disease. The decision to start pharmacotherapy often depends on the particular needs of the patient and careful weighing of possible benefits, cost, and adverse outcomes. Even mild parkinsonism may require the input of a specialist to obtain the best results.
Optical waveguide formation by ion implantation of Ti or Ag

Ion implantation of Ti into LiNbO/sub 3/ has been shown to be an effective means of producing optical waveguides, while maintaining better control over the resulting concentration profile of the dopant than can be achieved by in-diffusion. While undoped, amorphous LiNbO/sub 3/ can be regrown by solid-phase epitaxy at 400/sup 0/C with a regrowth velocity of 250 A/min, the higher concentrations of Ti required to form a waveguide (approx.10%) slow the regrowth considerably, so that temperatures approaching 800/sup 0/C are used. Complete removal of residual damage requires annealing temperatures of 1000/sup 0/C, not significantly lower than those used with in-diffusion. Solid phase epitaxy of Ag-implanted LiNbO/sub 3/, however, occurs at much lower temperatures. The regrowth is completed at 400/sup 0/C, and annealing of all residual damage occurs at or below 800/sup 0/C. Furthermore, the regrowth rate is independent of Ag concentration up to the highest dose implanted to date, 1 x 10/sup 17/ Ag/cm/sup 2/. The usefulness of Ag implantation for the formation of optical waveguides is limited, however, by the higher mobility of Ag at the annealing temperature, compared to Ti. 7 refs., 4 figs.
Note---A Comment on the Use of Simplex Method for Absolute Value Problems

The linear programming approach to the absolute value problem is to transform the unrestricted variable by the difference of two nonnegative variables. This transformation creates an unbounded feasible region which may lead to erroneous solution. To avoid this, Kaplan [Kaplan, Seymour. 1971. Comment on a precis by Shanno and Weil. Management Sci.17 11, July 778--780.] introduced a new constraint to bound the feasible region and suggested a solution scheme using the simplex method. We shall give two counter examples to the proposed scheme and discuss the difficulties involved with this particular class of problem.
Revision of Ceranisus and the related thrips-attacking entedonine genera (Hymenoptera: Eulophidae) of the world

A world revision of the four entedonine (Hymenoptera: Eulophidae: Entedoninae) genera of larval parasitoids of thrips (Thysanoptera) is presented: Ceranisus Walker, 1841, Entedonomphale Girault, 1915 stat. rev. (reinstated as a valid taxon from previous synonymy under Ceranisus, with type species E. margiscutum Girault, 1915 stat. rev.), Goetheana Girault, 1920, and Thripobius Ferriere, 1938. The following new generic synonymies are proposed: Cryptomphale Girault, 1917, Entedonastichus Girault, 1920, Pirenoidea Girault, 1922, and Thripoctenoides Erdos, 1954 under Entedonomphale. The proposed new combinations are as follows: Entedonomphale bicolorata (Ishii, 1933), E. nubilipennis (Williams, 1916), and Thripobius javae (Girault, 1917) from Ceranisus; Entedonomphale carbonaria (Erdos, 1954), E. dei (Girault, 1922), E. kaulbarsi (Yoshimoto, 1981), and E. mira (Girault, 1920) from Entedonastichus. New synonymies are proposed for the following species: Ceranisus vinctus (Gahan, 1932) under Ceranisus menes (Walker, 1839), Diglyphus aculeo Walker, 1848 under Ceranisus pacuvius (Walker, 1838); Ceranisus maculatus (Waterston, 1930) and Thripobius semiluteus Boucek, 1976 under Thripobius javae (Girault, 1917); Entedonastichus albicoxis (Szelenyi, 1982) under Entedonomphale carbonaria (Erdos, 1954), and Entedonastichus gaussi (Ferriere, 1958) under Entedonomphale bicolorata (Ishii, 1933). Eleven new species are described: Ceranisus barsoomensis and C. votetoda (Australia), C. udnamtak (Nepal); Entedonomphale boccaccioi (USA), E. esenini (Madagascar), E. lermontovi (South Africa), E. quasimodo and E. zakavyka (Australia); Goetheana pushkini (Japan and Republic of Korea) and G. rabelaisi (Australia); and Thripobius melikai (China). Three species are excluded from Ceranisus: C. ancylae (Girault, 1917) (mistakenly listed in Ceranisus) as well as C. nigricornis Motschulsky, 1863 and C. semitestaceus Motschulsky, 1863, both taxa incertae sedis. New data are provided on the distribution and host associations of many of the species included in this review.
COMPARATIVE ANALYSIS OF PIB IN VIVO WITH 6-CN-PIB AND Aβ-IMMUNOHISTOCHEMISTRY POSTMORTEM IN FAMILIAL ALZHEIMER DISEASE ASSOCIATED WITH THE PSEN1 I229F MUTATION

low numbers of participants, relatively long intervals between imaging and death, and low level of detail in terms of the spatial patterns of brain atrophy. The purpose of this investigation was to assess the neuropathologic correlates of regional brainvolumes by combining ex-vivoMRvolumetry and pathology on a large community cohort of older persons. Methods: Cerebral hemispheres were obtained from 166 deceased participants of two longitudinal, epidemiologic clinical-pathologic cohort studies of aging. All hemispheres were imaged ex-vivo, while immersed in 4% formaldehyde solution, on a 3T MRI scanner. A multi-atlas approach was used to segment ex-vivo MRI data intowhite and gray matter, and graymatter into 34 cortical and 8 subcortical regions. The volumes of all regions were normalized by the height of the participants. Following imaging, hemispheres underwent neuropathologic examination. The pathologies that were considered in analyses were: Alzheimer’s disease (AD) pathology, Lewy bodies, hippocampal sclerosis, gross and microscopic chronic infarcts, and cerebral amyloid angiopathy. Multiple linear regression was used to investigate the link between regional volumes and neuropathologies, controlling for age at death, sex, education, postmortem interval to fixation and to imaging. False Discovery Rate (FDR) was used to correct for multiple comparisons.Results: Figure 1 shows brain regions with significant negative correlation (p<0.05, FDR-corrected) between their volume and AD pathology (Fig.1A), and hippocampal sclerosis (Fig.1B). No other pathologies showed significant correlations with the volume of the segmented regions. Conclusions: The present study provides information on the neuropathologic correlates of regional brain volumes in a community cohort of older adults, and may help in the development of imaging biomarkers of AD pathology and hippocampal sclerosis. To our knowledge, this is the largest MR volumetry pathology investigation to date, and the only assessing a high number of brain regions.
Targeting the B Cell Receptor Pathway in Chronic Lymphocytic Leukemia

The B cell receptor (BCR) pathway plays a crucial role in the survival, proliferation and trafficking of chronic lymphocytic leukemia (CLL) cells. Inhibitors of the key kinases in this pathway, including spleen tyrosine kinase (SYK), mammalian target of rapamycin (mTOR), phosphoinositide 3'-kinase (PI3K) and Bruton's tyrosine kinase (BTK), have been found in preclinical models to decrease CLL cell viability both directly and indirectly through modulation of the microenvironment. Recently, oral agents targeting each of these kinases have been explored in early phase clinical trials in patients with CLL. BCR pathway antagonists appear to be highly active in relapsed/refractory CLL, independent of high-risk disease markers such as del(17p). These agents have shown a unique pattern of inducing early transient lymphocytosis, which typically is associated with nodal response. Here, we review the biology of the BCR, the kinases within this pathway and their interaction with the CLL microenvironment. We also discuss data from recent and ongoing clinical trials of BCR antagonists. We address the development of potential biomarkers for response to these agents such as ZAP-70, IGHV status and CCL3, and discuss where these exciting new drugs may fit in the evolving landscape of CLL therapy.
Synthesis of (−)-callicarpenal, a potent arthropod-repellent

Abstract Callicarpenal (1), a natural terpenoid isolated from American beautyberry (Callicarpa americana), has shown significant repellent activities against mosquitoes, ticks, and imported fire ants. Here we report our efficient synthetic approach to this natural product, and preliminary results of the mosquito biting-deterrent effects of callicarpenal as well as its synthetic precursors and related C8-epimers. The synthetic strategy allows rapid access to various epimers and analogues of the natural product that can be used to explore its structure–activity relationship and optimize its biological properties.
OPTIMAL TRANSDUCER PLACEMENT FOR OUTPUT FEEDBACK CONTROL OF BROADBAND STRUCTURAL ACOUSTIC RADIATION

This work outlines a procedure for optimizing the locations of colocated transducers for active structural acoustic control of broadband disturbances using output feedback control with static compensators. A constrained optimization algorithm was used to select the locations of colocated transducer pairs for static output feedback control of sound radiation from a plate confined within an infinite baffle. The development of the appropriate cost function and optimization algorithm is discussed in detail. Case studies optimizing a control system with one colocated sensor-actuator pair and a system with three pairs are presented. The initial locations of the sensor-actuator pairs were arbitrarily selected. Results indicate that the closed-loop performance of the system can be increased when a constrained optimization algorithm is used to determine the optimal transducer locations. The most significant increase in controller active insertion loss for the system investigated was 13.6 dB in a single, 1/3 octave-band when using an optimally located sensor-actuator pair versus a non-optimally located pair.
Climate Change Regionalism in North America

lobal institutions and debates about climate change governance attract consid-erable academic and media attention. The main multilateral forums are arenas forhigh-proﬁle political negotiations, inter-state conﬂicts, and thousands of nongov-ernmental actors. Similarly, national climate change politics and policy are signiﬁ-cant to decision makers and scholars, and local and urban climate change activismand planning also draw notable interest. However, outside the European Union(EU), much less analytical and political attention is paid to issues and possibilities ofregional-level climate change governance—despite the fact that regional coopera-tion and institutional arrangements offer a multitude of political, economic, andenvironmental beneﬁts not readily available in local, national, or global settings(Balsiger & VanDeveer, 2010; Jordan, Huitema, Van Asselt, Rayner, & Berkhout,2010; Patt, 2009). Furthermore, regional policy making around economic integra-tion and trade has proliferated in recent decades, resulting in scholarly and politicaldebates about the complementarities and conﬂicts between global and regionaltrade initiatives, state sovereignty, and democratic governance (Kuhnhardt, 2010;Laursen, 2003).Even as North American trade and economic integration deepened signiﬁcantlyover the last 20 years, little public debate about regional options for better climatechange and energy governance has followed. In fact, few leading North Americannationalpoliticians—someinCanadaandMexicobutpracticallynoneintheUnitedStates—have paid serious attention to continental alternatives for reducing green-house gas (GHG) emissions and addressing adaptation needs, even as the dynamicnature of multilevel climate change governance driven by subnational policy lead-ership across the continent is growing (Selin & VanDeveer, 2009a, 2009b) However,it is possible to identify potential beneﬁts for North American countries of morecoordinated action across Canadian, U.S., and Mexican public and private sectorentities. Furthermore, global GHG emissions cannot be adequately reduced—andthe goal of keeping average global temperatures from increasing more than 2°Cover preindustrial levels cannot be met—without signiﬁcant cuts in North Americanemissions.This viewpoint article intends to stimulate both scholars and practitioners toengage in more serious reﬂection and critical debate about opportunities forfurther coordinated North American responses to climate change. It draws atten-
Ins and Outs of Major Facilitator Superfamily Antiporters

The major facilitator superfamily (MFS) represents the largest group of secondary active membrane transporters, and its members transport a diverse range of substrates. Recent work shows that MFS antiporters, and perhaps all members of the MFS, share the same three-dimensional structure, consisting of two domains that surround a substrate translocation pore. The advent of crystal structures of three MFS antiporters sheds light on their fundamental mechanism; they operate via a single binding site, alternating-access mechanism that involves a rocker-switch type movement of the two halves of the protein. In the sn-glycerol-3-phosphate transporter (GlpT) from Escherichia coli, the substrate-binding site is formed by several charged residues and a histidine that can be protonated. Salt-bridge formation and breakage are involved in the conformational changes of the protein during transport. In this review, we attempt to give an account of a set of mechanistic principles that characterize all MFS antiporters.
Nationwide Satellite Training for Public Health Professionals: Web-Based Follow-Up.

INTRODUCTION Few studies have rigorously evaluated the effectiveness of health-related continuing education using satellite distribution. This study assessed participants' professional characteristics and their changes in knowledge, attitudes, and actions taken after viewing a public health preparedness training course on mass vaccination broadcast nationally by satellite. METHODS A three-part survey design was used to evaluate training effectiveness. Paper-based questionnaires were distributed at a stratified sample of downlink facilities to collect knowledge and attitude responses before and after the broadcast. Six weeks later, willing participants were invited by e-mail to complete a Web-based follow-up questionnaire to assess actions taken as a result of viewing the broadcast. Paired t-tests and McNemar's chi-square were used to compare changes in attitude from before to after the broadcast, after the broadcast to follow-up, and before the broadcast to follow-up. RESULTS A total of 544 paper-based questionnaires were received from 59 of 70 sampled sites. The pre- and post assessments administered the day of the broadcast demonstrated statistically significant knowledge gain (p < .001) and an increased belief immediately following the broadcast that mass vaccination clinics are important to their organizations' public health activities (p < .001). Of the 291 respondents who completed the follow-up online questionnaire, 44% (n = 128) reported they implemented or planned some form of action after the broadcast. Reported actions were higher among public health workers most likely to be directly involved in preparedness and immunization activities. DISCUSSION This evaluation assessed (1) participants' professional characteristics, (2) knowledge gain, (3) self-reported actions taken following the broadcast, (4) program satisfaction, and (5) suggested improvements for future satellite broadcast programs. The study's methodology of using a Web-based survey for follow-up is a relatively economical tool for assessing longer-term continuing education program objectives.
The power of collaboration: integrating a preventive medicine-public health curriculum into a pediatric residency.

Abstract This is one of six short papers that describe additional innovations to help integrate public health into medical education; these were featured in the “Patients and Populations: Public Health in Medical Education” conference. They represent relatively new endeavors or curricular components that had not been explored in prior publications. Although evaluation data are lacking, it was considered to be of value to medical educators to share a brief description of the collaboration between the Division of Preventive, Occupational, and Aerospace Medicine and the Department of Pediatrics at Mayo Clinic to integrate a preventive medicine–public health curriculum into the pediatric residency.
Food Security in Nigeria and South Africa: Policies and Challenges

This paper highlights food security situation and reflects on the challenges of food security in two sub-Saharan African countries: Nigeria and South Africa. Over the years, Nigeria and South Africa ha ve made several attempts to address the issue of increased affordable food production in both quantity and quality. Some of these attempts have cumulated into several programmes and projects aimed at boosting agricultural production. Commendable as some of these policies and programs are, it would appear that the goal of food security might not be achieved with these initiatives alone in the respective countries. A number of challenges appear to limit effective implementation of these strategies. Therefore, in order to exploit the benefit of food security policies in the two countries, there may be need to share experiences between Nigeria and South Africa with the overall purpose of reducing food insecurity.
Premalignancy of the testis and paratestis

Summary There has been great progress in the understanding of the molecular events involved in normal germ cell maturation and testicular tumour pathobiology. Identification of the molecules involved in these processes has provided a number of new immunohistochemical markers for intratubular germ cell neoplasia, unclassified (IGCNU) and germ cell tumours. OCT4, the most important of the newer markers, is highly sensitive and specific for IGCNU and is superior to older immuno-histochemical markers for this purpose. However, germ cell maturation delay is a potential pitfall in the application of this marker. In contrast to the type II testicular germ cell tumours, relatively little is known about premalignant lesions of testicular sex cord-stromal tumours, malignancies of the rete testis and epididymis, and paratesticular malignancies.
Neutronics Design for a Spherical Tokamak Fusion-Transmutation Reactor (In Chinese)

Based on studies of the spherical tokamak fusion reactors, a concept of fusion-transmutation reactor is put forward. By using the one-dimension transport and burn-up code BISON3.0 to process optimized design, a set of plasma parameters and blanket configuration suitable for the transmutation of MA (Minor Actinides) nuclear waste is selected. Based on the one-dimension calculation, two-dimension calculation has been carried out by using two-dimension neutronics code TWODANT. Combined with the neutron flux given by TWODANT calculation, burn-up calculation has been processed by using the one-dimension radioactivity calculation code FDKR and some useful and reasonable results are obtained.
An Off-DiagonalT1 Theorem and Applications

Abstract We give a general boundedness criterion, analogous to the T 1 Theorem, for singular integrals mapping L p to L q , q p . As an easy corollary of this result, we deduce the Kato–Ponce “Leibniz Rule” for fractional order derivatives. We also study commutators of parabolic singular integrals and deduce pointwise a.e. convergence of truncations of a class of parabolic singular integrals which includes the caloric double-layer potential on the boundary of a non-cylindrical domain.
Interventions to improve hospital patient satisfaction with healthcare providers and systems: a systematic review

Background Many hospital systems seek to improve patient satisfaction as assessed by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys. A systematic review of the current experimental evidence could inform these efforts and does not yet exist. Methods We conducted a systematic review of the literature by searching electronic databases, including MEDLINE and EMBASE, the six databases of the Cochrane Library and grey literature databases. We included studies involving hospital patients with interventions targeting at least 1 of the 11 HCAHPS domains, and that met our quality filter score on the 27-item Downs and Black coding scale. We calculated post hoc power when appropriate. Results A total of 59 studies met inclusion criteria, out of these 44 did not meet the quality filter of 50% (average quality rating 27.8%±10.9%). Of the 15 studies that met the quality filter (average quality rating 67.3%±10.7%), 8 targeted the Communication with Doctors HCAHPS domain, 6 targeted Overall Hospital Rating, 5 targeted Communication with Nurses, 5 targeted Pain Management, 5 targeted Communication about Medicines, 5 targeted Recommend the Hospital, 3 targeted Quietness of the Hospital Environment, 3 targeted Cleanliness of the Hospital Environment and 3 targeted Discharge Information. Significant HCAHPS improvements were reported by eight interventions, but their generalisability may be limited by narrowly focused patient populations, heterogeneity of approach and other methodological concerns. Conclusions Although there are a few studies that show some improvement in HCAHPS score through various interventions, we conclude that more rigorous research is needed to identify effective and generalisable interventions to improve patient satisfaction.
S06-3 Us cohort study of uranium miners on the colorado plateau: what new information can we learn?

Since the 1950s, the U.S. Public Health Service (and subsequently the National Institute for Occupational Safety and Health) has conducted a cohort study of more than 4000 uranium miners on the Colorado Plateau (CP) in the southwest United States. These miners were obtaining raw uranium to supply the U.S. nuclear weapons industry from the 1940s to the late 1980s. Initially, researchers administered questionnaires and physical examinations among the miners (both white and American Indian), who are a subset of a much larger group of miners employed during the cold war era. Thousands of measurements were made of radon progeny in hundreds of mines over a period of decades. Since the 1970s, the CP cohort has been followed for mortality and morbidity outcomes and smoking assessment. The unique features of the CP cohort include its high doses, extensive dosimetry, near-complete smoking information, and long follow-up. The cohort has contributed extensively to knowledge of lung cancer risk from radon exposure, including understanding of inverse dose-rate effects, changes in risk with time since exposure, and the form of interaction with smoking. As of the last follow-up in 2005, 75% of the cohort was deceased. Despite the anticipation that lung cancer rates would decline in the late follow-up, published findings suggest that attributable risk of lung cancer continues to be high in the cohort, particularly for miners who smoked little or not at all. The form of interaction of radon dose with smoking appears to remain sub-multiplicative but super-additive. Outcomes other than lung cancer, such as idiopathic pulmonary fibrosis, and some forms of renal disease, have shown associations with radon exposure. With a final wave of follow-up, the CP cohort continues to provide key information to support the development of protective standards to minimise lifetime lung cancer risk from occupational radon exposure.
The Differential Effects of Neonatal Androgen, Estrogen and Progesterone on Adult Rat Prostate Growth

AbstractPhysiologic surges of serum androgen, estrogen and progesterone normally occur in both rat and human males during the neonatal periods. The effect of these hormone surges on the sex accessory tissues is not known. This study demonstrates that neonatal dihydrotestosterone, 17β-estradiol, or progesterone can permanently alter the androgen sensitivity of adult rat sex accessory tissues. Neonatal dihydrotestosterone or progesterone can permanently increase the androgen sensitivity of the adult prostate above normal while neonatal estradiol permanently decreases adult prostate androgen sensitivity below normal. The results of this preliminary study suggest that normally occurring neonatal hormone surges may permanently mark, or imprint, the prostate and determine its future growth in adulthood.
FcμR in human B cell subsets in primary selective IgM deficiency, and regulation of FcμR and production of natural IgM antibodies by IGIV.

IgMFcR (FcμR) are expressed on B cell and B cell subsets. Mice deficient in secreted IgM and FcμR share properties of impaired specific antibody response and autoimmunity with patient with selective IgM deficiency (SIGMD). Intravenous immunoglobulin (IGIV) regulates immune response, including modulation of IgGFc receptors. However, there are no data on the expression of FcμR in patients with SIGMD, and the effects of IGIV on FcμR. In this study, we investigated FcμR expression in naive marginal zone (MZ), IgM memory, and class-switched memory B cells in patients with selective IgM deficiency and healthy controls. Furthermore, we examined the direct effect of IGIV on FcμR expression and on the upregulation of FcμR by TLR2 agonist (Pam3). Finally, we examined the effect of IVIG on spontaneously produced IgM and natural IgM anti-phosphorylcholine (PC) antibodies by B cells and B1 cells. FcμR expression is significantly decreased in MZ B cells in patients with SIGMD as compared to control. IGIV, at immunomodulatory concentrations, inhibited FcμR upregulation by Pam3 in MZ B cells, and IgM-depleted IGIV inhibited spontaneous secretion of natural IgM anti-PC antibodies and not total IgM by B1 cells. These data suggest that decreased FcμR expression on MZ B cells may play a role in the pathogenesis of SIGMD, and an inhibition of TLR-2-induced upregulation of FcμR by IGIV may be one of the mechanisms of its anti-inflammatory action. IGIV-induced inhibition of natural IgM antibodies may be one of the mechanisms of IGIV-induced immunoregulation.
ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin- Free Method] Post-Authorization Safety Surveillance (PASS): Safety and Efficacy Following Product Switch in Routine Clinical Practice.

Abstract A prospective, non-interventional Post-Authorization Safety Surveillance (PASS) program was initiated in 2004 to document ADVATE safety and efficacy in routine clinical practice. More than 900 subjects newly prescribed ADVATE have been enrolled in the US, EU and Japan alone. Herein, we present final US and interim EU results comprising 506 treated subjects, 451 of which have completed the 1-year observation period and 20 ongoing. Age cohorts were as follows: 27 neonates/infants (0- 50 previous EDs). Eight subjects had unknown exposure history. Twenty-nine PUPs/MTPs reported exact exposure history prior to ADVATE: 5 reported 0 ED; 7 reported 1 to 3 EDs; and 17 reported 4 to 50 EDs. Most study subjects had FVIII ≤2%; 46 of which were PUPs/MTPs and 389 were PTPs. Among PTPs with FVIII ≤2%, 331 had no known history of inhibitor; 58 reported having a history of inhibitor prior to receiving ADVATE. At enrollment, 58% of subjects were prescribed prophylaxis, while 42% were treated on-demand. A total of 4848 bleeds in 343 subjects were treated. The on-demand efficacy was rated only as excellent/good in 94% of subjects. Subjects who were prescribed ADVATE prophylaxis (N=291) received a mean of 3 infusions per week at 29 IU/kg/ infusion. The median annual bleed rate on prophylaxis was 2.4 bleeds per year. Prophylactic efficacy assessments were provided for 268 subjects; 92% received only excellent/good ratings. Similar efficacy results were seen for the various populations with or without history of inhibitor. No unusual or unexpected AEs were seen in the study. One de novo, low-titer (1.4 BU), transient inhibitor was reported in 331 PTPs with FVIII ≤2% and no prior inhibitor history, providing a de novo inhibitor incidence estimate of 0.3% (95% CI, 0.01% – 1.67%). Two recurrent, low-titer inhibitors (≤1.5 BU) were reported in PTPs with FVIII ≤2%. One de novo, high-titer and 1 de novo, low-titer inhibitor were reported in PTPs with FVIII >2%. Two high-titer inhibitors were reported among 61 PUPs/MTPs. Other SAEs included 1 headache, 2 allergic reactions, 1 ineffective drug response in a subject with inhibitor and ITI history, and 1 hemarthrosis secondary to trauma. Results from the US and EU PASS registries validate the ADVATE safety and efficacy profile in the general hemophilia A population, in real-world clinical settings. Consistent with the formal clinical study findings ADVATE continues to demonstrate low risk for inhibitor development in PTPs.
High-resolution mass spectrometry confirms the presence of a hydroxyproline (Hyp) post-translational modification in the GGGGP linker of an Fc-fusion protein

ABSTRACTFlexible and protease resistant (G4S)n linkers are used extensively in protein engineering to connect various protein domains. Recently, several groups have observed xylose-based O-glycosylation at linker Ser residues that yield unwanted heterogeneity and may affect product quality. Because of this, an engineering effort was implemented to explore different linker sequence constructs. Here, we demonstrate the presence of an unexpected hydroxylation of a prolyl residue in the linker, made possible through the use of high-resolution mass spectrometry (HR-MS) and MSn. The discovery started with the detection of a poorly resolved ∼+17 Da mass addition at the reduced protein chain level of an Fc-fusion construct by liquid chromatography-MS. Upon further investigation at the peptide level using HR-MS, the mass increase was determined to be +15.99 Da and was localized to the linker peptide SLSLSPGGGGGPAR [210–223]. This peptide corresponds to the C-terminus of Fc [210–216], the G4P linker [217–221], and ...
The Oppenheimer tragedy

Back in the 1950s, during the oral part of the qualifying exam at the University of Wisconsin, a student was once asked what Robert Oppenheimer had contributed to physics. "I don't know,"the student confessed – and was informed that this was the correct answer.
Simultaneous integrated boost (SIB) for treatment of gynecologic carcinoma: Intensity-modulated radiation therapy (IMRT) vs volumetric-modulated arc therapy (VMAT) radiotherapy.

The aim of this study was to quantitatively compare dosimetric criteria between intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) plans for patients undergoing radiation treatment of gynecologic carcinoma with a simultaneous integrated boost (SIB) technique. IMRT and VMAT plans were retrospectively analyzed for 20 patients. The elective volume was planned to receive 45 Gy in 25 fractions of 1.8 Gy, with the integrated boost volume (involved nodes) receiving 55 Gy simultaneously. The same dose constraints were employed during the optimization of both techniques. IMRT plans consisted of 9 to 11 fields at equally spaced gantry angles. VMAT plans consisted of 3 full arcs of 360°. A large variety of dose metrics across planning target volume (PTV)45, PTV55, bladder, rectum, sigmoid, bowel, kidneys, and femoral heads were extracted per patient, per plan. Conformity and homogeneity indices were also calculated and compared for each target volume. The total number of monitor units as well as the integral dose was also compared between IMRT and VMAT. The Wilcoxon signed rank test was performed to evaluate any significant differences between parameters, with an applied Bonferroni correction to account for multiple testing (significance level, p < 0.0006). The results demonstrate the equivalence of the 2 planning techniques across all studied parameters, with the exception of the expected decrease in monitor units that VMAT is capable of achieving. The findings of this study suggest that IMRT and VMAT are both acceptable options for applying simultaneous integrated boost techniques for the treatment of gynecologic cancers. The technique of choice will be dependent on departmental resources and should be considered on a case-by-case basis.
Abstract LB-318: Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation

Lung cancer is the most common tumor cancer worldwide and approximately 15-25% of the patients with lung adenocarcinoma have KRAS driven tumors. These malignancies involve, in the majority of cases, a constitutive activation of KRAS signaling pathway (1,2) and are associated with poor prognosis in patients with advanced disease (metastatic setting). Currently there is no specific therapy to target KRAS driven tumors approved by FDA (3), then finding alternative targeted therapies is a need to cover for this disease. Pharmacological inhibition of CDK4 was been suggested as a beneficial therapy to treat NSCLC patients carrying K-RAS oncogenes; and researchers base the potential efficacy of this approach on a synthetic lethal interaction between K-ras and CDK4 in in this type of tumors (4). Hence, CDK4/6 inhibitors appear as promising therapy to treat this type of tumors. Abemaciclib is a cell cycle inhibitor with selective activity against CDK4 and CDK6 and is being evaluated in advanced clinical trials for its potential to reduce NSCLC cancer growth. Here we describe studies towards the in-vitro mechanism of action of abemaciclib to reduce tumor cells growth in NSCLC cell lines harboring mutations in KRAS. Overall, abemaciclib reduces NSCLC cell growth as indicated by a reduction of cell number and proliferation biomarker Ki67 upon treatment. This tumor growth inhibition is mediated by arrest of cell cycle in G1 phase as a direct consequence of Rb phosphorylation blockade. In this study we are further reporting a phenotypic characterization of sensitive cell lines monitoring cell proliferation, senescence, and apoptosis markers using flow cytometry and high content imaging approaches as well as metabolic profiling. . Bibliography (1) Schubbert S, Shannon K and Bollang G (2007) Nature Rev. Cancer 7(4) 295-308. (2) Ihle NT et al (2012) J Natl Cancer Inst. 104(3): 228-239. (3) Roberts PJ et al (2010) J Clin Oncol. 28(31):4769-77 (4) Puyol M et al (2010) Cancer Cell 1(13): 63-73. Citation Format: Raquel Torres-Guzman, Carmen Baquero, Carlos Marugan, Cecilia Mur, Severine I. Gharbi, Sandra Gomez, Joaquin Amat, Karsten Boehnke, Philip W. Iversen, Alfonso deDios, Xueqian Gong, Sean Buchanan, Richard P. Beckman, Maria Jose J. Lallena. Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-318. doi:10.1158/1538-7445.AM2017-LB-318
A Brain Phenotype for Stressor‐Evoked Blood Pressure Reactivity

Background Individuals who exhibit large‐magnitude blood pressure (BP) reactions to acute psychological stressors are at risk for hypertension and premature death by cardiovascular disease. This study tested whether a multivariate pattern of stressor‐evoked brain activity could reliably predict individual differences in BP reactivity, providing novel evidence for a candidate neurophysiological source of stress‐related cardiovascular risk. Methods and Results Community‐dwelling adults (N=310; 30–51 years; 153 women) underwent functional magnetic resonance imaging with concurrent BP monitoring while completing a standardized battery of stressor tasks. Across individuals, the battery evoked an increase systolic and diastolic BP relative to a nonstressor baseline period (M ∆systolic BP/∆diastolic BP=4.3/1.9 mm Hg [95% confidence interval=3.7–5.0/1.4–2.3 mm Hg]). Using cross‐validation and machine learning approaches, including dimensionality reduction and linear shrinkage models, a multivariate pattern of stressor‐evoked functional magnetic resonance imaging activity was identified in a training subsample (N=206). This multivariate pattern reliably predicted both systolic BP ( r =0.32; P r =0.25; P Conclusions A novel multivariate pattern of stressor‐evoked brain activity may comprise a phenotype that partly accounts for individual differences in BP reactivity, a stress‐related cardiovascular risk factor.
Cancer immunotherapy using checkpoint blockade

The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial

The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization. The FLOURISH study is designed to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. The FLOURISH study is a double-blind, placebo-controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one-time IC administration of RT-100 (1012 vp) or placebo in a 1:1 ratio. Subjects will be 18-80 years of age, on optimal standard of care HF therapy with LVEF ≥10% and ≤35% by echocardiogram, and will undergo IC administration of RT-100 vs. placebo on Day 1. Follow-up study visits will be performed at Weeks 1 and 4, and Months 3, 6, and 12. Patients will be followed for an additional 36 months for safety assessments with telephone contact at Months 24, 36, and 48. The primary objective is to determine the efficacy of IC RT-100 vs. placebo in reducing the event rate of all (first and repeat) HF hospitalizations occurring from baseline to 12 months. The secondary objectives are to determine the efficacy of IC RT-100 on CV death, all cause death, and all HF events and in improving NYHA functional classification. Exploratory endpoints will include echocardiographic parameters of left ventricular systolic and diastolic function, HF symptoms and physical limitations, 6-minute walking distance, Borg dyspnea score, and NT-proBNP levels. The FLOURISH study, which received fast track designation from the Food and Drug Administration in December 2017, will further investigate the role of a one-time intracoronary injection of RT-100 in reducing HF hospitalizations and will serve as a registration trial (potentially pivotal investigation) for RT-100 as a treatment for HFrEF.
Energy modeling framework for optimizing heat recovery in a seasonal food processing facility

Abstract Societal, cultural and economic factors are driving food processors to reduce energy consumed per unit mass of food. This presents a unique problem because time variant batch processing using low to medium grade heat is common in food production facilities. Heat recovery methods may be implemented by food processors to reduce energy consumption; however, temporal variance in the process and utility flow require the development of a robust, easily implemented energy model to accurately determine system effectiveness and economic incentive. A bottom-up modular computational framework is proposed to model the energy consumption of a cannery. The model predicts that the cannery will require 612 kJ gas/kg product produced, which is within the ranges provided in previous literature. Results show that adding a globally optimized indirect heat recovery system will reduce the gas consumption by 6% annually. The proposed framework, used here to represent a cannery, may be adapted to many different types of food processing facilities. With a clear picture of energy consumption by device, and the ability to predict the impact of process modification or heat recovery, plant-level energy usage for food processing may be significantly reduced.
Hearing Loss: Effect on Hospice and Palliative Care Through the Eyes of Practitioners

Abstract Context Discussions regarding values and goals of care are central to providing quality palliative care. An inability to hear during these sensitive discussions may significantly impair the quality of care provided, yet hearing loss (HL) is not formally addressed in these settings or in programs designed to assist practitioners gain advanced communication skills. Objective To gain an understanding of hospice and palliative care practitioners' experiences with HL and its impact on the care provided. Method SurveyMonkey questionnaire eliciting whether and how HL impacted care provided with an open-ended question asking for descriptions of a situation where HL created a problem in communication with an older patient. Responses were analyzed using constant comparative techniques. Results Of 510 respondents, 464 (91%) reported HL had some or great impact on the quality of care provided, 449 (88%) noted encountering a situation where HL impaired communication with an older adult, and 99 of these participants (22%) provided a specific example. The overarching theme was “Diagnostic and Treatment Uncertainty.” Nonmutually exclusive categories underpinning this theme included the following: unable to get needed information, misinterpreting level of understanding, patient misunderstanding of instructions, and goals-of-care errors. Conclusion HL impacts the quality of care provided to persons with serious illness by disrupting the identification, assessment, and treatment of the physical, psychosocial, and spiritual symptoms an individual is experiencing. HL should be formally addressed in programs designed to develop skills in conducting sensitive conversations. Practitioners should screen for HL, use practices that facilitate comprehension, and use assistive listening devices as needed.
Google Earth Virtual Reality and expository writing for young English Learners from a Funds of Knowledge perspective

The purpose of this study is to examine the incorporation of Google Earth Virtual Reality (VR) into English Learners’ (ELs) expository writing experiences from a Funds of Knowledge perspective util...
Building Teachers’ Trust in Principals: Exploring the Effects of the Match Between Teacher and Principal Race/Ethnicity and Gender and Feelings of Trust:

Trusting relationships play a crucial role in all aspects of school life. This study builds on this understanding by exploring the role gender and race/ethnicity plays in establishing trust between...
Board Structure and Audit Committee Monitoring: Effects of Audit Committee Monitoring Incentives and Board Entrenchment on Audit Fees

Our study addresses two research questions. First, are audit fees related to the presence of common members in audit and compensation committees (committee overlap)? Second, are audit fees related to whether board membership is protected by the use of a staggered voting system (board classification)? Using a treatment effects model to control for endogeneity, we find a negative relationship between audit fees and committee overlap, which is consistent with the argument that committee overlap is associated with weak corporate governance and that in an environment with weak governance, monitoring efforts by the audit committee are similarly weak. We find a positive relationship between audit fees and board classification, indicating that firms with classified boards seek greater monitoring, which is consistent with the prior literature which suggests that such firms seek the “quiet life” and wish to avoid reporting-related problems.