cssi/SciSciGPT-SciSciNet huggingface dataset:
Abstract 2609: Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols

Metastasis is responsible for more than 90% of prostate cancer-associated mortality in the United States. Metastasis is facilitated by remodeling of the extracellular matrix by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). These zinc-dependent proteases elicit pivotal role in the proteolytic degradation of structural components of extracellular matrix contributing to the metastatic process. High levels of MMP-2/9 in the plasma and urine has been correlated with metastasis. MMPs are produced in a latent form (pro-MMP) that require activation and are inhibited by tissue inhibitors of matrix metalloproteinases (TIMPs). TIMPs inhibit MMPs by binding in a 1:1 stoichiometry through strong noncovalent interactions. In prostate cancer, low levels of TIMP3 has been associated with aggressive tumor phenotype and poor disease-free survival. Loss of TIMP3 in prostate cancer is attributed to epigenetic silencing tipping the balance towards active MMPs driving metastasis. Green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) has been shown to suppress prostate cancer metastasis, however the mechanism has not been fully elucidated. We determined whether treatment with GTP/EGCG has ability to restore induction of TIMP3 and play a key role in suppressing invasiveness in prostate cancer. Treatment of prostate cancer LNCaP and DUPRO cells with 10μg/mL GTP and 20μM EGCG for 72 h significantly induced TIMP3 mRNA and protein levels. Silencing of enhancer of zeste homolog 2 (EZH2) and class I histone deacetylases (HDACs) significantly increased the expression of TIMP3 which was independent of DNA hypermethylation. Treatment of prostate cancer cells with GTP/EGCG significantly reduced EZH2 and class I HDAC protein levels; H3K27 trimethylation activity; and transcriptional activation of TIMP-3 was found to be associated with decreased EZH2 localization and H3K27 trimethylation enrichment at the TIMP3 promoter with a concomitant increase in histone H3K9/18 acetylation. EGCG/GTP treatment also caused a global reduction in histone methylation thereby increasing histone acetylation to revive and activate TIMP3 levels. Furthermore, EGCG/GTP exposure significantly reduced MMP2/9 gelatinolytic activity and abrogated invasive and migration capabilities in prostate cancer cells. Taken together, our findings suggests that TIMP-3 induction could be a key epigenetic event modulated by GTPs in restoring MMP: TIMP balance to delay prostate cancer invasion and metastasis. Citation Format: Gauri Deb, Vijay S. Thakur, Eswar Shankar, Sanjay Gupta. Epigenetic reactivation of TIMP-3 in human prostate cancer cells by green tea polyphenols. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2609.
Analyzing Winds for Frequency and Duration

Downwash of stack gases near a certain plant occurs when the wind velocity exceeds certain critical values. In order to estimate future occurrences of this phenomenon, it is desirable to know the frequency and duration of those cases in the past in which the critical values have been exceeded. The statistical methods used in selecting and analyzing a typical year’s wind records for purposes of future estimation are discussed. Wind history, valid for the area served by the recording station, is presented in diagrams using a system of probability coordinates. From these data an estimate is made of the frequency and duration of future wind velocities above the critical values. This estimate is valid only for the one plant for which the critical velocities were determined.
Wide Scale Investigation of Protein Interactions by Automation of Fluorescent Polarization and Fluctuation Analysis

Monitoring changes in molecular conformation is essential for studying protein interactions within and between complexes. Methods such as FRET or FCS reveal limited aspects of these changes, which in many cases is insufficient for interpretation. Fluorescent Polarization and Fluctuation Analysis (FPFA), a time-correlated single-photon counting technique that combines homo-FRET and FCS was developed to address this problem. In FPFA changes in protein complex mass and/or shape, the number of fluorescent subunits per complex, as well as subunit proximity (1 – 10 nm), is simultaneously detected. This multimodal approach was validated with series of 6 fluorescent oligomers composed of between 1 and 6 concatenated Venus molecules, and successfully employed to investigate structural dynamics of calcium/calmodulin-dependent protein kinase II (CaMKII) – a multimeric protein kinase that is enriched in synaptic spines and dendrites that is involved in memory and synaptic modulation, as well as microtubule-associated protein 1A/1B-light chain 3 (LC3) – a soluble protein that is a key component of autophagy, a homeostasis process responsible for the turnover of cellular components. Here we have extended FPFA method by developing a robotic microscope that can measure up to 96 samples automatically. This FPFA automation enables wide-scale biophysical analysis of protein-protein interactions, and hence facilitates the identification of drugs that target protein complexes as potential therapeutic sites for diseases of aggregation and abnormal protein-protein interactions.
Targeting deubiquitinases in CLL

In this issue of Blood , Agathanggelou et al demonstrate that inhibition of ubiquitin-specific protease 7 (USP7) compromises homologous recombination DNA repair in part by destabilizing the E3 ligase RAD18 leading to the accumulation of DNA damage which kills chronic lymphocytic leukemia (CLL) cells independently of ataxia telangiectasia mutated (ATM) and p53. 1
Measuring mistreatment of women during childbirth: a review of terminology and methodological approaches

Although mistreatment of women during facility-based childbirth has received increasing recognition as a critical issue throughout the world, there remains a lack of consensus on operational definitions of mistreatment and best practices to assess the issue. Moreover, only minimal research has focused on mistreatment in Latin America and the Caribbean, a region notable for social inequalities and inequitable access to maternal health care. In this article, we discuss the results of a literature review that sought to contribute to the determination of best practices in defining and measuring the mistreatment of women during childbirth, particularly within Latin America and the Caribbean. The review includes a total of 57 English, Spanish, and Portuguese-language research publications and eight legal documents that were published between 2000 and 2017. While the typologies of “disrespect and abuse” and “mistreatment during facility-based childbirth” are most frequently employed in global studies, “obstetric violence” remains the most commonly operationalized term in Latin America and the Caribbean in both research and policy contexts. Various researchers have advocated for the use of those three different typologies, yet the terms all share commonalities in highlighting the medicalization of natural processes of childbirth, roots in gender inequalities, parallels with violence against women, the potential for harm, and the threat to women’s rights. For measuring mistreatment, half of the research publications in this review use qualitative methods, such as in-depth interviews and focus groups. After analyzing the strengths and limitations of quantitative, qualitative, and mixed methods approaches to assessing mistreatment, we recommend mixed methods designs as the optimal strategy to evaluate mistreatment and advocate for the inclusion of direct observations that may help bridge the gap between observed measures and participants’ self-reported experiences of mistreatment. No matter the conceptual framework used in future investigations, we recommend that studies seek to accomplish three objectives: (1) to measure the perceived and observed frequencies of mistreatment in maternal health settings, (2) to examine the macro and micro level factors that drive mistreatment, and (3) to assess the impact of mistreatment on the health outcomes of women and their newborns.
Energy Situation and Fossil Energy

The world continues to indulge its dangerous addiction to Middle East oil, but things seem to be somewhat better in the past 10 years. Now, journalists are saying, “What if we never run out of oil?” A combination of events are positive: Fracked oil and gas, perhaps methane hydrate as flammable ice, doubled CAFE standards, improved buildings and appliance standards, and the diversification of energy supplies with renewable energy. But, will poisonous fluids from fracking leak into the water table? And China now uses more energy and imported oil than the U.S.
Migrating to the City in North West China: Young Rural Women’s Empowerment

China has one of the largest internal migrant populations of the world today, one third of them are estimated to be women. This paper, part of a long-term study, reports on young women migrants fro...
Career Paths in Psychiatry: Some Antecedents and Concomitants

Factors preceding and accompanying the career paths of 111 psychiatrists who graduated from the Stanford University residency program during the years 1965–1975, were studied through a survey, using multiple regression as main analytic technique. Antecedent variables predicting the path of the full-time academic psychiatrist included having had a research residency, perceiving the residency program as relevant, being a foreign medical school graduate, and being male; while associated concomitant variables included number of journal articles and book chapters published, no formal continuing education reported, not living in California, and living in the South. The career paths of the clinical faculty psychiatrist, the non-academically affiliated clinician and the administratively oriented psychiatrist were similarly studied.
Mixed-granular architectural diversity for device security in the Internet of Things

With the emergence of the Internet of Things (IoT) regime, the security of microprocessor-based systems is a rapidly growing concern. It is estimated that within a few years, there will be billions of connected IoT devices, many of which will be controlled by the same off-the-shelf hardware. This hardware homogeneity creates a major security risk, since a vulnerability in one system can affect millions more which are based on the same underlying hardware. Similarities between instruction set architecture (ISAs) of processors enable malicious software to propagate among networked devices, often leading to large-scale attacks, as shown in recent reports. To effectively counter such software attacks, we present a novel solution based on diversifying the hardware, so that finding and exploiting a vulnerability in one device does not put millions more at risk. We achieve this using low-overhead, mixed-granular architectural modifications, which enable device manufacturers to make every instance of the hardware unique, with architectures that can evolve over time. Using the OpenRISC 1200 CPU as a case study, we show how low-overhead diversification can improve system security for area- and power-constrained IoT devices. Results show a high level of security with area and power overheads of 1.3% and 3.8%, respectively, and negligible effect on CPU performance.
Shifting DOC concentration and quality in the freshwater lakes of the Kangerlussuaq region: An experimental assessment of possible mechanisms

ABSTRACTSince 2003, concentrations of dissolved organic carbon (DOC) in lakes in the Kangerlussuaq region declined by 14–55 percent, with these decreasing DOC concentrations potentially altering lake ecology and reflecting changes in regional carbon (C) cycling. To evaluate possible mechanisms responsible for this shift, we performed experiments to test the effects of dust addition, bacterial activity, or photodegradation on DOC concentration and two DOC quality metrics: the specific ultraviolet absorbance (SUVA254) and the chromophoric DOC spectral slope coefficient (S275–295). Lake-water DOC concentrations did not decline in any treatments, but there were changes in DOC quality. Dust addition increased SUVA254 and decreased the magnitude of S275–295 in one lake, the impacts of bacterial activity were variable, and sunlight exposure elicited a decline in SUVA254 and an increase in the magnitude of S275–295 in all lakes. These results suggest that DOC pools in the study lakes are photoreactive, even thoug...
Disparities in substance use behaviors and disorders among adult sexual minorities by age, gender, and sexual identity

Abstract Background Sexual minorities (SMs) experience elevated rates of substance use behaviors and disorders relative to heterosexuals; minority stress is theorized to contribute to these disparities. As SMs are not a homogenous group, analyses that aggregate SMs across sexual identity, age, or gender obscure important variation among this population. To date, age- and gender-specific disparities have not been rigorously examined using a large national sample. Methods Using data on 67,354 adults (ages 18–49) from the 2015 and 2016 National Survey of Drug Use and Health we examined age- and gender-specific disparities in smoking, heavy episodic drinking, marijuana use, illicit drug use, and alcohol/substance use disorder. Age groups were ages 18–25, 26–34, and 35–49. Using logistic regression, we estimated age- and gender-specific odds ratios for gay/lesbian and bisexual individuals, relative to heterosexuals; analyses adjusted for demographic characteristics. Results Bisexual women had significantly elevated odds of all outcomes at all ages, relative to heterosexual women. Gay/lesbian individuals had significantly elevated odds for nearly all outcomes compared to same-gender heterosexuals at ages 18–25, but not consistently at older ages. For bisexual men, significant disparities compared to heterosexual men were only observed at ages 35–49 for marijuana use and alcohol/substance use disorder. Conclusions We found notable within-group differences regarding SM disparities. While disparities were most pronounced in young adulthood for gay/lesbian individuals and mid-adulthood for bisexual men, bisexual women uniquely experienced disparities across all ages. Minority stress experiences may vary with respect to gender, age/cohort, and sexual identity, resulting in differential risk for substance use.
Latest Findings on the Photoionization of Met-Cars

An overview of our latest findings on the photoionization of metallocarbohedrene clusters (Met-Cars) is presented. The ionization potentials (IPs) of titanium and zirconium Met-Cars of the stoichiometry Ti8−x Zr x C12 (x=0–4, 8) were determined by studying their photoionization efficiency spectra near threshold. It was found that the IPs are about 4 eV and decrease smoothly as the Ti/Zr ratio decreases. Comparison of the determined IPs with those predicted by theoretical calculations by other groups suggests that the geometry of the Met-Cars is that of the tetrahedral cage structure with T d symmetry, assuming a high degree of accuracy in the IP calculations. In another experiment, we investigated the mechanism of the delayed ionization of both single- and binary-metal Met-Cars. Using a reflectron time-of-flight mass spectrometer with a modified Wiley–McLaren double acceleration region, we measured ionization rates arising from the electron emission of Met-Cars composed of various transition metals under different photoionization conditions, which led to the conclusion that a thermionic emission mechanism dominantly contributes to the delayed ionization.
Nature, Feeling, and Disclosure in the Poetry of Wallace Stevens

In Wallace Stevens’ phenomenological poetry, Nature and the human respons to Nature are inseparable components of a single experience of a “world.” is human feeling for the things of the world that makes them “things,” bi that feeling has its basis in what is already there. This fundamental phenom enological idea is expressed with particular vividness in one of Stevens’ la poems, entitled ‘An Old Man Asleep’: The two worlds are asleep, are sleeping now. A dumb sense possesses them in a kind of solemnity. The self and the earth — your thoughts, your feelings, Your beliefs and disbeliefs, your whole peculiar plot; The redness of your reddish chestnut trees, The river motion, the drowsy motion of the river R.1
Severe Periprosthetic Cortical Atrophy in the Skeletally Immature: A Report of Three Cases

We describe three patients who developed cortical bone atrophy around cemented endoprostheses used for partial femur reconstructions after resection of Ewing's sarcoma. We believe this to be related to remodeling secondary to stress-shielding. Rather than increased porosity and decreased mineral density, the stress-shielding in these skeletally immature patients resulted in altered morphology of the cortical bone, with apparent maintenance of density.
Electrocautery ablation of anal HSIL: correlation of treatment outcomes with histological features and HPV genotypes

Background Electrocautery ablation (EA) is a widely used treatment modality for HPV-induced anal high-grade squamous intraepithelial lesions (HSIL). Roughly half of the targeted HSILs persist or recur following ablation. Several clinical characteristics have been linked to EA resistance; however, there is little data on whether and how ablation outcomes are affected by lesional histology and HPV genotypes. Methods Among lesions that responded to EA and those that recurred, we compared mitotic activity, type of dysplasia (classic vs. keratinized) and degree of dysplasia (AIN2 vs. AIN3). HPV genotypes were tested using cytology samples. Results 97 HIV-infected patients with HSIL underwent EA and surveillance. Upon follow-up (median 10 months, range 5–37), 44 (45%) patients revealed benign or LSIL at the prior ablation site (EA-sensitive group), whereas 53 (55%) revealed HSIL (EA-resistant group). Age, gender, and race distribution were similar regardless of ablation outcomes. The EA-sensitive group tended to have solitary lesions (60%), non-16/18 h-HPV infection (68%), and HPV clearance (18%), whereas the EA-resistant group had multiple synchronous lesions (81%) and HPV16/18 infection (57%). Compared to EA-sensitive lesions, resistant ones were characterized by higher mitotic activity (mean 7 vs. 3/HPF), a higher percentage of AIN3 (70% vs. 36%), as well as the keratinized dysplasia (74% vs. 48%). Conclusions Anal HSIL ablation resistance is associated with multiple synchronous lesions, HPV16/18 infection, high mitotic activity, AIN3, and keratinized dysplasia. Patients with these types of lesions are at high risk of recurrence and warrant careful surveillance.
Calling Out Fake News on Social Media: A Comparison of Literature in Librarianship and Journalism

This study compared 475 scholarly journal articles in librarianship and journalism on social media published between 2006 and early 2017. Though articles from these two information professions are ...
Lives of Writing

Studying development of writing across the lifespan contains many challenges, but research is now emerging, starting to fill in a dynamic picture of trajectories of development. The study is necessarily complex, multidisciplinary, and collaborative. This special issue contributes to this emerging research focus.
Prevalence of depressive symptoms among older adults who reported medical cost as a barrier to seeking health care: findings from a nationally representative sample.

Older adults aged 65 and over will make up more than 20% of U.S. residents by 2030, and in 2050, this population will reach 83.7 million. Depression among older adults is a major public health concern projected to be the second leading cause of disease burden. Despite having Medicare, and other employer supplements, the burden of out of pocket healthcare expenses may be an important predictor of depression. The current study aims to investigate whether delay in seeing a doctor when needed but could not because of medical cost is significantly associated with symptoms of current depression in older adults. Cross-sectional data from the 2011 Behavioral Risk Factor Surveillance System (BFRSS) from 12 states and Puerto Rico were used for this study (n = 24,018). The prevalence of symptoms of current depression among older adults who reported medical cost as a barrier to seeking health care was significantly higher (17.8%) when compared to older adults who reported medical cost not being a barrier to seeking health care (5.5%). Older adults who reported medical cost as a barrier to seeking health care were more likely to report current depressive symptoms compared to their counterparts [Adjusted Odds Ratio (AOR): 2.2 [95% CI: 1.5–3.3]). Older adults (≥ 65 years of age) who experience the burden of medical cost for health care are significantly more likely to report symptoms of depression. Health care professionals and policymakers should consider effective interventions to improve access to health care among older adults.
Nanoscale vacuum channel transistors fabricated on silicon carbide wafers

Vacuum tubes were central to the early development of electronics, but were replaced, decades ago, by semiconductor transistors. Vacuum channel devices, however, offer inherently faster operation and better noise immunity due to the nature of their channel. They are also stable in harsh environments such as radiation and high temperature. However, to be a plausible alternative to solid-state electronics, nanoscale vacuum channel devices need to be fabricated on the wafer scale using established integrated circuit manufacturing techniques. Here, we show that nanoscale vacuum channel transistors can be fabricated on 150 mm silicon carbide wafers. Our devices have a vertical surround-gate configuration and we show that their drive current scales linearly with the number of emitters on the source pad. The silicon carbide vacuum devices are also compared to identically sized silicon vacuum channel transistors, which reveals that the silicon carbide devices offer superior long-term stability. Nanoscale vacuum channel transistors, which have a vertical surround-gate configuration, can be fabricated on 150 mm silicon carbide wafers using conventional integrated circuit processing technology.
Design of a focused collimator for proton therapy spot scanning using Monte Carlo methods

Purpose When designing a collimation system for pencil beam spot scanning proton therapy, a decision must be made whether or not to rotate, or focus, the collimator to match beamlet deflection as a function of off-axis distance. If the collimator is not focused, the beamlet shape and fluence will vary as a function of off-axis distance due to partial transmission through the collimator. In this work, we quantify the magnitude of these effects and propose a focused dynamic collimation system (DCS) for use in proton therapy spot scanning. Methods This study was done in silico using a model of the Miami Cancer Institute's (MCI) IBA Proteus Plus system created in Geant4-based TOPAS. The DCS utilizes rectangular nickel trimmers mounted on rotating sliders that move in synchrony with the pencil beam to provide focused collimation at the edge of the target. Using a simplified setup of the DCS, simulations were performed at various off-axis locations corresponding to beam deflection angles ranging from 0° to 2.5°. At each off-axis location, focused (trimmer rotated) and unfocused (trimmer not rotated) simulations were performed. In all simulations, a 4 cm water equivalent thickness range shifter was placed upstream of the collimator, and a voxelized water phantom that scored dose was placed downstream, each with 4 cm airgaps. Results Increasing the beam deflection angle for an unfocused trimmer caused the collimated edge of the beamlet profile to shift 0.08-0.61 mm from the baseline 0° simulation. There was also an increase in low-dose regions on the collimated edge ranging from 14.6% to 192.4%. Lastly, the maximum dose, D max , was 0-5% higher for the unfocused simulations. With a focused trimmer design, the profile shift and dose increases were all eliminated. Conclusions We have shown that focusing a collimator in spot scanning proton therapy reduces dose at the collimated edge compared to conventional, unfocused collimation devices and presented a simple, mechanical design for achieving focusing for a range of source-to-collimator distances.
Controller Inhalers: Overview of Devices, Instructions for Use, Errors, and Interventions to Improve Technique

Inadequate inhaler technique in persistent asthma is frequently reported. However, there is little consensus on inhaler checklists, and critical elements of technique are not uniformly described. In addition, inhaler error rates and risk factors for poor technique are variable across studies. This Clinical Commentary Review summarizes the literature on inhaler design, use, and interventions to improve technique. Our aim is to help clinicians identify patients with poor inhaler technique, recognize the most important errors, and correct technique using evidence-based interventions.
Augmenting propulsion demands during split-belt walking increases locomotor adaptation of asymmetric step lengths

Promising studies have shown that the gait symmetry of individuals with hemiparesis due to brain lesions, such as stroke, can improve through motor adaptation protocols forcing patients to use their affected limb more. However, little is known about how to facilitate this process. Here we asked if increasing propulsion demands during split-belt walking (i.e., legs moving at different speeds) leads to more motor adaptation and more symmetric gait in survivors of a stroke, as we previously observed in subjects without neurological disorders. We investigated the effect of propulsion forces on locomotor adaptation during and after split-belt walking in the asymmetric motor system post-stroke. To test this, 12 subjects in the chronic phase post-stroke experienced a split-belt protocol in a flat and incline session so as to contrast the effects of two different propulsion demands. Step length asymmetry and propulsion forces were used to compare the motor behavior between the two sessions because these are clinically relevant measures that are altered by split-belt walking. The incline session resulted in more symmetric step lengths during late split-belt walking and larger after-effects following split-belt walking. In both testing sessions, subjects who have had a stroke adapted to regain speed and slope-specific leg orientations similarly to young, intact adults. Importantly, leg orientations, which were set by kinetic demands, during baseline walking were predictive of those achieved during split-belt walking, which in turn predicted each individual’s post-adaptation behavior. These results are relevant because they provide evidence that survivors of a stroke can generate the leg-specific forces to walk more symmetrically, but also because we provide insight into factors underlying the therapeutic effect of split-belt walking. Individuals post-stroke at a chronic stage can adapt more during split-belt walking and have greater after-effects when propulsion demands are augmented by inclining the treadmill surface. Our results are promising since they suggest that increasing propulsion demands during paradigms that force patients to use their paretic side more could correct gait asymmetries post-stroke more effectively.
"We go to Tijuana to double check everything": The contemporaneous use of health services in the U.S. and Mexico by Mexican immigrants in a border region.

Abstract Research in 2009 showed that hundreds of thousands of Mexican immigrants in the U.S. return to Mexico for healthcare annually. Existing studies on the cross-border healthcare behaviors of this group are dominated by two related questions: 1) Why do Mexican immigrants go to Mexico for care? and 2) What are individual-level predictors of seeking care in Mexico? While this research has identified people's motivations for crossing the border for care and key characteristics associated with this behavior, it has underemphasized an important feature of cross-border healthcare seeking, namely that some immigrants contemporaneously use healthcare in the U.S. and Mexico. Drawing on qualitative interviews with Mexican immigrants in San Diego, CA, located on the U.S.-Mexico border, I show that for some, seeking care in Mexico is a way to supplement the care they receive in the U.S. In this region, some people combine care in the two countries in attempts to achieve what they believe to be optimal care results. Their cross-border behaviors include seeking care in the U.S. for a health condition and, if dissatisfied, going to Mexico for care; getting care in the U.S for certain health problems and Mexico for others; going to Mexico for specialist care when their U.S. doctors will not refer them to specialists; and going to Mexico for pharmaceuticals their U.S. doctors will not prescribe. For these individuals, proximity to the border changes the meanings and behaviors associated with being a patient, in that it enables them to be more actively engaged in their care. At the same time, findings raise questions about the quality of care that results from mixing care in the two countries. These findings suggest a need to understand cross-border healthcare seeking among some border residents as embedded in a larger repertoire of healthcare practices.
FDA Approval Summary: Pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma

The FDA approved pembrolizumab on June 29, 2020, for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) colorectal cancer with no prior systemic treatment for advanced disease. The approval was based on data from Study Keynote-177, which randomly allocated patients to receive either pembrolizumab or standard of care (SOC) with chemotherapy. Overall survival (OS) and independently assessed progression-free survival (PFS) were the primary endpoints. At the time of the final PFS analysis and second prespecified interim OS analysis, the estimated median PFS was 16.5 months (95% CI: 5.4-32.4) versus 8.2 months (95% CI: 6.1-10.2) in the pembrolizumab and SOC arms, respectively [HR: 0.60 (95% CI: 0.45-0.80); two-sided P = 0.0004]. FDA assessed unblinded OS data during the review of the application and identified no safety concerns that would preclude approval of this supplement. Adverse reactions occurring in >30% of patients receiving pembrolizumab were diarrhea, fatigue/asthenia, and nausea. Adverse reactions occurring in >30% of patients receiving SOC were diarrhea, nausea, fatigue/asthenia, neutropenia, decreased appetite, peripheral neuropathy (high-level term), vomiting, abdominal pain, constipation, and stomatitis. Duration of treatment in the pembrolizumab arm was almost double (median 11.1 months, range 0-30.6 months) than the duration of treatment in patients receiving SOC (median, 5.7 months). Approval of pembrolizumab is likely to change the treatment paradigm for first-line treatment with MSI-H advanced colorectal cancer given the study results and different safety profile.
Impact of Rapid Medical Evaluation on Patient Flow in an Urban Emergency Department

Rapid Medical Evaluation (RME) is a new Emergency Department (ED) process that initiates testing while patients are in the Waiting Room. Primary goal of this study is to assess the effectiveness of RME pathway on the patient flow through the ED. This was a retrospective, single site, cohort study of patients presenting to the ED 12 months before (PRE group) and 12 months after (POST group) RME implementation. The POST group was divided into those that underwent RME and those managed using standard care pathway (SCP). Data was collected from Electronic Health Record (EHR) database using SQL and consisted of time stamp data for discrete ED patient events. The following metrics were calculated for all ED encounters: Active ED Room Time, Boarding Time, Total ED Room Time, Total ED Time, and Door-to-Provider Time. Patients undergoing RME on average spent 90-min less in ED Treatment Room compared to SCP group and were evaluated by a provider 151 min earlier than if they had waited for an available ED Treatment Room. Implementation of RME helped reduce time patients spend in ED Treatment Room, improved patient throughput, and decreased Door-to-Provider time during the busiest times in the ED.
Protein Dynamics and Substrate Protonation States Mediate the Catalytic Action of trans-4-Hydroxy-l-Proline Dehydratase.

The enzyme trans-4-hydroxy-l-proline (Hyp) dehydratase (HypD) is among the most abundant glycyl radical enzymes (GREs) in the healthy human gut microbiome and is considered a promising antibiotic target for the prominent antibiotic-resistant pathogen Clostridium difficile. Although an enzymatic mechanism has been proposed, the role of the greater HypD protein environment in mediating radical reactivity is not well understood. To fill this gap in understanding, we investigate HypD across multiple time- and length-scales using electronic structure modeling and classical molecular dynamics. We observe that the Hyp substrate protonation state significantly alters both its enzyme-free reactivity and its dynamics within the enzyme active site. Accurate coupled-cluster modeling suggests the deprotonated form of Hyp to be the most reactive protonation state for C5-Hpro-S activation. In the protein environment, hydrophobic interactions modulate the positioning of the Cys434 radical to enhance the reactivity of C5-Hpro-S abstraction. Long-time dynamics reveal that changing Hyp protonation states triggers the switching of a Leu643-gated water tunnel, a functional feature that has not yet been observed for members of the GRE superfamily.
Indirect Screening: Enhancing Identification of Illicit Drug Use during Pregnancy

INDIRECT SCREENING: ENHANCING IDENTIFICATION OF ILLICIT DRUG USE DURING PREGNANCY By Courtney E. Smith, M.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2012 Major Director: Dace S. Svikis, Ph.D. Professor Department of Psychology OBJECTIVE: Most drug use screening measures rely on and are validated against self-report. Fear of negative consequences often promotes denial of drug use. For pregnant women, social stigma and fear of legal consequences make underreporting of drug use even more likely. An indirect screener that could effectively identify pregnant women at risk for illicit drug use without reliance on disclosure would be clinically significant. The purpose of the current study was to develop and validate an indirect measure of prenatal drug use by comparing correlates of prenatal drug use to urinalysis results. METHOD: Pregnant women attending an OB appointment at the VCUHS Women’s Health Clinic were recruited and consented to participate in an anonymous, two-phase study. In Phase 1, women completed a 20-minute computerized assessment which included a true/false index of items known to tap behavioral, medical, psychological, experiential and demographic correlates of drug abuse and dependence. In Phase 2, participants were asked to provide a urine sample for drug testing. Women received a $20 gift card after they participated in each phase. RESULTS: Two hundred and thirty-one women completed both Phase 1 and 2 (94% completion rate). Participants were primarily AfricanAmerican (66%), single (75%) and receiving public assistance (70%). Urinalysis revealed that 16% of the sample tested positive for recent drug use, while only 5% of women self-reported past month drug use. After examining the univariate and multivariate relationships between each indirect item and drug status (i.e., positive or negative urinalysis), six indirect items were chosen to comprise the Wayne Indirect Drug Use Screener-Pregnancy (WIDUS-P). Cross-validation analyses resulted in a sensitivity of .90, specificity of .75, and AUC of .85. In comparison to direct screening approaches, the WIDUS-P was superior in identifying pregnant women who had used drugs recently. CONCLUSIONS: Findings support the use of an indirect screening tool to identify prenatal drug use, especially over currently-used direct methods. Such a measure could easily be implemented into regular clinic practice and result in more cost-effective and better identification of prenatal drug use.
The Two of us Together

The Xavante depend on the cerrado [savannah in Portuguese] and the cerrado depends on the Xavante. The animals depend on the cerrado and the cerrado depends on the animals. The animals depend on the Xavante and the Xavante depend on the animals.
Pharmacological dissociation of heart rate and somatomotor components of the orienting response

In response to a discrete auditory stimulus, rats exhibit a quick, lateral head jerk and a 40-50-bpm deceleration in heart rate (HR). Both the head jerk and the bradycardia are components of the orienting response (OR), which is presumed to reflect stimulus-directed attention. The present research examined the effects of cholinergic and dopaminergic blockade on the OR to an 80-dB tone. In Experiment 1, scopolamine hydrobromide was found to inhibit the HR OR in a dose-dependent manner ranging from little effect at 0.05 mg/kg to complete inhibition of the cardiac OR at 0.5 mg/kg. The head-jerk response, unlike the cardiac response, was undiminished by scopolamine. In the second experiment, haloperidol, administered at dosages ranging from 0 to 10 mg/kg, attenuated the behavioral response (head jerk) in a dose-dependent fashion but had no effect on the cardiac component of the OR. These results demonstrate that the autonomic and behavioral components of the OR are independent representations of a common central process unaffected by cardiosomatic coupling. The results also demonstrate that neither the cardiac nor the somatomotor component of the OR is dependent upon the integrity of central cholinergic or dopaminergic neurotransmission.
The stress intensity factors and interaction between cylindrical cracks in fiber-matrix composites

Publisher Summary Advances in the field of material science have led to the development of a class of unconventional materials, such as fibrous composites. In general, composites are composed of strong, lightweight fibers embedded in a matrix. As the development of composites has progressed, the utilization of these materials in industry has become increasingly more common. The elastic interaction between two cylindrical cracks in an infinite, homogeneous, isotropic, elastic medium is examined in the chapter. The cylindrical cracks represent a case of fiber–matrix debonding. This chapter examines the effect of the cracks spacing and size on the stress intensity factors, KI and KII, which result from a pressure loading. Each crack is modeled as a pile-up of Somigliana ring dislocations. The solution is based on analytical expressions obtained earlier for the ring dislocation. The continuous distributions of dislocation densities, modeling the two cracks, are obtained numerically using a piecewise quadratic approximation and an iterative scheme to evaluate the interaction between the two cracks. The interaction among the superdislocations also provides a closed form expression for the stress intensity factor.
Poisson integrals and nontangential limits

A new result is established for nontangential limits of the Poisson integral of an f ∈ L P (R N ) for N ≥ 2. This is accomplished by showing for N = 2,∃f such that the σ-set of f strictly contains the Lebesgue set of f. A similar theorem is also proved for Gauss-Weierstrass integrals, giving a new result for solutions of the heat equation.
Meta-Therapeutic Processes and the Affects of Transformation: Affirmation and the Healing Affects

When successful therapeutic experiences themselves become the focus of therapeutic inquiry and work, it becomes possible to deepen and broaden the treatment's effectiveness. The systematic exploration of phenomena associated with therapeutic change—through exploring the patient's experience of having a therapeutic experience—activates meta-therapeutic processes associated with characteristic affects of transformation. The aim is to raise the consciousness of therapists of all orientations, a fortiori those interested in integration, of the therapeutic potential inherent in the exploration of such nondenominational processes. First, three meta-therapeutic processes—acknowledging mastery, mourning-the-self, and receiving affirmation—and their respective affective markers—joy, emotional pain, and the healing affects—are identified. Then, the focus is on the dynamics of the affirmation process and the phenomenology of the healing affects. Therapeutic benefits and possible sources of resistance to receiving affirmation—in both patients and therapists—are discussed. In the last part of the paper, a transcript of a clinical vignette illustrates integrative therapeutic work with the response to affirmation and the experience of the healing affects.
The Fiction of Reconciliation: Creating Dialogue through Verbal and Performance Arts in South Africa

Except for a small number of novels and short stories, South African writers have shied away from narrating reconciliation, and from creating work that draws its inspiration from the Truth and Reconciliation Commission (TRC). Publishers, in their gate-keeping role, have played a crucial role in the dearth of literature that responds to the TRC. In South Africa today it is difficult for a new writer to get narratives that are set in the apartheid era published due to commercial considerations. Theater, on the other hand, goes through profoundly different gate-keeping processes than works of prose fiction. Theater is highly subsidized by the state or private grants and foundations. Profitability or lack thereof is often not the ultimate determining factor as to whether a play is produced or not—except in the purely commercial performances spaces. As a result playwrights and other creators of the theater have narrated reconciliation, sometimes in the context of the TRC, quite extensively. There are still vas...
New Arguments that Philosophers don't Treat Intuitions as Evidence

According to orthodox views of philosophical methodology, when philosophers appeal to intuitions, they treat them as evidence for their contents. Call this “descriptive evidentialism.” Descriptive evidentialism is assumed both by those who defend the epistemic status of intuitions and by those, including many experimental philosophers, who criticize it. This article shows, however, that the idea that philosophers treat intuitions as evidence struggles to account for the way philosophers treat intuitions in a variety of philosophical contexts. In particular, it cannot account for philosophers' treatment of a priori intuitions, for nonpropositional uses of intuition, and for philosophers' failure to use intuition to exclude the counterintuitive. The article concludes that alternatives to descriptive evidentialism (some of which are sketched) must be developed, and that much of the recent debate between traditionalists and skeptics from, for example, experimental philosophy is probably based on a false presupposition.
Synthesis and Biochemical Characterization of an Analogue of CheY-Phosphate, a Signal Transduction Protein in Bacterial Chemotaxis†

CheY is a signal transduction protein of the bacterial chemotaxis system that acts as a molecular switch to alter the swimming behavior of the bacterium. When CheY becomes phosphorylated at Asp57, CheY-Pi interacts with flagellar motor proteins, including FliM, to increase the likelihood that the flagellar motor will change its sense of rotation, increasing the frequency of tumbling. The structure of CheY in its dephosphorylated (inactive) state has been intensively investigated. The short lifetime ( approximately 20 s) of the aspartyl phosphate has precluded the complete structural determination of CheY-Pi. We have synthesized an analogue of CheY-Pi by alkylating an aspartate-to-cysteine mutant at position 57 of CheY to add a phosphonomethyl group at Cys57. This analogue, phosphono-CheY, is stable for months. Phosphono-CheY binds to two of the targets of CheY-Pi, FliM and CheZ, in a manner similar to that of CheY-Pi and much better than either unphosphorylated CheY or the unmodified form of D57C CheY. Phosphono-CheY also binds Mg(II) with a dissociation constant of approximately 6 mM at neutral pH and moderate salt level. These observations indicate that phosphono-CheY is a good biochemical analogue of CheY-Pi.
Performance and application of serial-scan FLIRs

Infrared imaging systems have increased in number rapidly since the early 1960's; however, system insertion has been almost entirely in military and paramilitaryapplications. In the future, infraredimaging systems wilifind increasedacceptance in commercial applications provided that system costs are reduced. FLIR Systems, Inc. was founded in response to a recognized world wide need for high quality, affordable infrared systems. In this paper we present the salient features of a serial scan forward looking infrared (FUR) system which has been developed to achieve high sensitivity and resolution in systems which are less complex and are inherently less expensive to manufacture, operate and maintain. Specifically our systems utilize an 8 to 12 micron band HgCdTe detector array consisting of two or more rows of detectors in parallel with four to six detector elements in series summed in Time Delay and Integration (TDI). The serial scan approach greatly reduces the complexity and cost of the amplification and scan conversion when compared to parallel scanned systems while a small amount ofparallel scanning reduces the scan rate to a practical level. Design considerations and manufacturing methods are reviewed with emphasis on high performance and system affordability.
The production and oxidation of uranium nanoparticles produced via pulsed laser ablation

Abstract Depleted uranium samples were ablated using five nanosecond pulses from a Nd:YAG laser and produced films of ∼1600 A thickness that were deposited with an angular distribution typical of a completely thermal ablation (cos1 θ). The films remained contiguous for many months in vacuum but blistered due to tensile stress induced in the films several days after being brought into air. While under vacuum (2 × 10−10 Torr base pressure) the films were allowed to oxidize from the residual gases, of which water vapor was found to be the primary oxidizer. During the oxidation, the samples were monitored with both X-ray and ultraviolet photoemission spectroscopy (XPS and UPS) and were found to oxidize following Langmuir kinetics. That a 2D-surface growth model described the oxidation indicates that, even at these low pressures, oxygen accumulation on the surface is a much faster process than diffusion into the bulk. While bulk diffusion did occur, the oxygen present at the surface saturated the measurements taken using photoemission and diffusion was difficult to observe. A method for determining oxide concentration via photoemission from the valence level, as opposed to the more conventional core levels, is also presented.