Miracle-dz/UniFAR-FTUs huggingface dataset:
Relative effectiveness assessments of oncology medicines for pricing and reimbursement decisions in European countries.

BACKGROUND There is a debate on the added clinical value of new, expensive, anticancer treatments. Among European decision makers, the relevance of commonly used end points in trials, especially overall survival (OS), progression-free survival (PFS) and quality of life (QoL), varies, leading to the available evidence being valued differently. This research studies the extent to which the value of end points for cancer medicines differs among European decision makers. METHODS We compared guidelines and relative effectiveness assessments (REAs) of medicines for pricing or reimbursement decisions in England, France, Germany, The Netherlands, Poland, and Scotland. Anticancer medicines that received marketing authorization in Europe between 2011 and 2013 with at least four available national REAs were evaluated. A total of 79 REAs were included. RESULTS Health technology assessment (HTA) guidelines indicate a preference for clinically and patient relevant end points such as OS and QoL above surrogate end points. Most guidelines do not specify whether PFS is considered a surrogate or patient-relevant end point. The number of REAs included per jurisdiction varied between 7 (The Netherlands) and 18 (Germany). OS data were included in all REAs and were the preferred end point by HTA agencies, but these data were not always mature or robust. QoL data are included in only 54% of the REAs, with a limited impact on the recommendations. PFS data are included in 70% of the REAs, but the extent to which HTA agencies find PFS relevant varies. CONCLUSIONS European decision-making on relative effectiveness of anticancer medicines is affected by a gap in requested versus available clinical evidence, mainly because the regulator is willing to accept some degree of clinical uncertainty. A multi-stakeholder debate would be essential to align concrete robust evidence requirements in oncology and a collectively shared definition for relevant clinical benefit, which will benefit patients and society in general.
Gamma-glutamyl transpeptidase-dependent iron reduction and LDL oxidation--a potential mechanism in atherosclerosis.

BACKGROUND gamma-Glutamyl transpeptidase (gamma-GT) is found in serum and in the plasma membranes of virtually all cell types. Its physiologic role is to initiate the hydrolysis of extracellular glutathione (GSH), a tripeptide in which cysteine lies between alpha-glycine and gamma-glutamate residues. Cysteine and other thiol compounds are known to promote LDL oxidation by reducing Fe(III) to redox active Fe(II); therefore, we sought to determine whether similar reactions can be sustained by GSH and influenced by gamma-GT. METHODS Fe(III) reduction and LDL oxidation were studied by monitoring the formation bathophenanthroline-chelatable Fe(II) and the accumulation of thiobarbituric acid-reactive substances, respectively. Human atheromatous tissues were examined by histochemical techniques for the presence of oxidized LDL and their colocalization with cells expressing gamma-GT activity. RESULTS A series of experiments showed that the gamma-glutamate residue of GSH affected interactions of the juxtaposed cysteine thiol with iron, precluding Fe(III) reduction and hence LDL oxidation. Both processes increased remarkably after addition of purified gamma-GT, which acts by removing the gamma-glutamate residue. GSH-dependent LDL oxidation was similarly promoted by gamma-GT associated with the plasma membrane of human monoblastoid cells, and this process required iron traces that can be found in advanced or late stage atheromas. Collectively, these findings suggested a possible role for gamma-GT in the cellular processes of LDL oxidation and atherogenesis. Histochemical analyses confirmed that this may be the case, showing that gamma-GT activity is expressed by macrophage-derived foam cells within human atheromas, and that these cells colocalize with oxidized LDL. CONCLUSIONS Biochemical and histochemical correlates indicate that gamma-GT can promote LDL oxidation by hydrolyzing GSH into more potent iron reductants. These findings may provide mechanistic clues to the epidemiologic evidence for a possible correlation between persistent elevation of gamma-GT and the risk of fatal reinfarction in patients with ischemic heart disease.
Interoceanic Differences in the Reproduction of Coral-Reef Fishes

Eggs of demersal spawning coral-reef fishes of the tropical western Atlantic are smaller than those of related species in the western Pacific. Decreased egg volume may result in increased fecundity per unit body weight of Atlantic species, a factor that may underlie apparent differences in the stability of the respective coral-reef fish communities.
COP1 Functions as a FoxO1 Ubiquitin E3 Ligase to Regulate FoxO1-mediated Gene Expression*

COP1 is a Ring-Finger E3 ubiquitin ligase that is involved in plant development, mammalian cell survival, growth, and metabolism. Here we report that COP1, whose expression is enhanced by insulin, regulates FoxO1 protein stability. We found that in Fao hepatoma cells, ectopic expression of COP1 decreased, whereas knockdown of COP1 expression increased the level of endogenous FoxO1 protein without impacting other factors such as C/EBPα and CREB (cAMP-response element-binding protein). We further showed that COP1 binds FoxO1, enhances its ubiquitination, and promotes its degradation via the ubiquitin-proteasome pathway. To determine the biological significance of COP1-mediated FoxO1 protein degradation, we have examined the impact of COP1 on FoxO1-mediated gene expression and found that COP1 suppressed FoxO1 reporter gene as well as FoxO1 target genes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two key targets for FoxO1 in the regulation of gluconeogenesis, with corresponding changes of hepatic glucose production in Fao cells. We suggest that by functioning as a FoxO1 E3 ligase, COP1 may play a role in the regulation of hepatic glucose metabolism.
An Application of Improved PageRank in Focused Crawler

The focused crawler of a special-purpose search engine aims to selectively seek out pages that are relevant to a pre-defined set of topics, rather than to exploit all regions of the Web. The PageRank algorithm is often used in ranking web pages, and it is also used in URL ordering for focused crawler. It estimates the page's authority by taking into account the link structure of the Web. However, it assigns each outlink the same weight and is independent of topics, resulting in topic-drift. In this paper, we propose an improved PageRank algorithm, which we called "To-PageRank", and then we present a crawling strategy using the To-PageRank algorithm combining with the topic similarity of the hyperlink metadata. The experiment in focused crawler shows that the new improved crawling strategy has better performance than the Breath-first and PageRank algorithms.
TÜRKİYE’DE TİCARİ AÇIKLIK, FİNANSAL AÇIKLIK VE EKONOMİK BÜYÜME ARASINDAKİ İLİŞKİLER: SINIR TESTİ YAKLAŞIMI

Ozet Bu calismada, ticari aciklik, finansal aciklik ve ekonomik buyume arasindaki iliski Turkiye icin 1989-2014 donemi kapsaminda ucer aylik veriler yardimiyla analiz edilmistir. Serilerin duraganligi, Carrion-i-Silvestre vd. (2009) coklu yapisal kirilmali birim kok testi ile analiz edilmis ve ticari aciklik ile finansal aciklik degiskenlerinin duzeyde ve ekonomik buyume degiskenin ilk farkinda duragan oldugu gozlenmistir. Degiskenler arasindaki nedensellik iliskisini belirlemek amaciyla Toda-Yamamoto nedensellik testi uygulanmistir. Test sonuclari, finansal aciklik ile ekonomik buyume arasinda cift yonlu ve buyumeden ticari acikliga dogru olan tek yonlu nedensellik iliskisinin varligini gostermistir. Degiskenler arasindaki esbutunlesme iliskisi sinir testiyle incelenmis ve degiskenler arasinda esbutunlesme iliskisi tespit edilmistir. Uzun ve kisa donemli analiz sonuclari ise, ekonomik buyumenin ticari acikliktan negatif, finansal acikliktan pozitif ve istatistiki olarak anlamli etkilendigini gostermistir. Anahtar Kelimeler: Ticari Aciklik, Finansal Aciklik, Ekonomik Buyume, Toda-Yamamoto Nedensellik Testi, Sinir Testi. JEL Siniflandirmasi : C32, F15, F21, F43.
Influence of Gravity Waves on the Internal Rotation and Li Abundance of Solar-Type Stars

The Sun's rotation profile and lithium content have been difficult to understand in the context of conventional models of stellar evolution. Classical hydrodynamic models predict that the solar interior must rotate highly differentially, in disagreement with observations. It has recently been shown that internal waves produced by convection in solar-type stars produce an asymmetric, shear layer oscillation, similar to Earth's quasi-biennial oscillation, that leads to efficient angular momentum redistribution from the core to the envelope. We present results of a model that successfully reproduces both the rotation profile and the surface abundance of lithium in solar-type stars of various ages.
Osler meets the marketplace--speculations on the future of internal medicine in the 21st century.

In this century, medicine has become a preoccupation of American society. Biology has replaced engineering and physics as the dominant science. The American public, stimulated by the media, is obsessed with health care issues, both personal and societal. Health care is a significant component of the American economy and medical technology has become an important American export. Despite this success, medicine has recently been gripped by a siege mentality. American business and government have unleashed economic forces which have shaken the foundation which medicine has erected over the past four decades. Hospitals are failing, physician reimbursement is falling and federal support for medical education is under attack. Therefore, as we stand on the threshold of the twentyfirst century, the future ofAmerican medicine appears uncertain, if not perilous. This feeling of uncertainty is not new for medicine and must be placed in the context oftwo historical perspectives. The first is that the profession of medicine, by its very nature, is an instrument of change. Medicine's quest for improving health has led to scientific advances which civilization now takes for granted. The second historical perspective is that healing is a fundamental human preoccupation. Over millennia, physicians have had important roles ranging from mystic priests to social activists and from beloved country doctor to high tech wizard. Therefore, medicine has a permanent but constantly evolving position in society. At any point in time, medicine's role reflects the science and beliefs of its era.
Delays in protease inhibitor use in clinical practice

AbstractOBJECTIVE: To determine the clinical factors associated with delayed protease inhibitor initiation. DESIGN: Chart review and telephone survey. SETTING: General medicine practice at an academic medical center in Boston, Mass. PATIENTS: One hundred ninety patients living with HIV and a viral load of more than 10,000 copies/ml. MEASUREMENTS AND MAIN RESULTS: The main outcome measurement was time to first protease inhibitor prescription after first elevated HIV viral load (>10,000 copies/ml). In this cohort, 190 patients had an elevated viral load (median age 39; 87% male; 12% history of injection drug use; 63% AIDS; 53% with depression; 17% history of pneumocystis pneumonia; 54% CD4 <200). In Cox proportional hazards modeling, significant univariate correlates for delayed protease inhibitor initiation were higher CD4 cell count (hazard ratio [HR] 2.38 for CD4 200–500 compared with <200, 95% confidence interval [CI] 1.59, 3.57; and HR 8.33 for CD4 >500; 95% CI 2.63, 25.0), higher viral load (HR 0.43 for each 10-fold increase; 95% CI 0.31, 0.59), injection drug use (HR 2.08; 95% CI 1.05, 4.17), AIDS (HR 0.24; 95% CI 0.15, 0.36), and history of pneumocystis pneumonia (HR 0.32; 95% CI 0.21, 0.49). In multivariate models adjusted for secular trends in protease inhibitor use, factors significantly associated with delay of protease inhibitor initiation (p<.05) were higher CD4 cell count (for CD4 200–500, HR 2.63; 95% CI 1.61, 4.17; for CD4 >500, HR 11.11; 95% CI 3.57, 33.33), higher viral load (HR 0.66 for each 10-fold increase; 95% CI 0.45, 0.98), history of pneumocystis pneumonia (HR 0.57; 95% CI 0.37, 0.90), history of depression (HR 1.49; 95% CI 1.03, 2.13), and history of injection drug use (HR 2.70; 95% CI 1.35, 5.56). CONCLUSIONS: HIV-infected patients with higher CD4 cell counts or a history of depression or history of injection drug use have significant and lengthy delays of protease inhibitor therapy. Although some delays may be clinically appropriate, enhancement of provider and patient education might prove beneficial. Further research should examine reasons for delays in protease inhibitor initiation and their appropriateness.
Midlatency Auditory Evoked Potentials Predict Movements During Anesthesia with Isoflurane or Propofol

To determine threshold values, sensitivity, and specificity of midlatency auditory evoked potentials (MLAEP) for prediction of spontaneous intraoperative movements, 40 patients undergoing elective laparotomy were studied.Continuous epidural analgesia was used in all patients. To maintain general anesthesia, the patients in Group 1 (n = 20) received isoflurane (0.4-1.2 vol%), and the patients in Group 2 (n = 20) received propofol (3-5 mg [centered dot] kg-1 [centered dot] h-1 intravenously). Spontaneous movements were documented intraoperatively. Auditory evoked potentials were recorded continuously until the end of anesthesia. Latencies of the peaks V, Na, Pa, Nb, and P1 (ms) and amplitudes Na/Pa, Pa/Nb, and Nb/P1 (micro V) were measured. Changes of MLAEP latencies and amplitudes during anesthesia were similar in both groups. Anesthesia led to statistically significant increases in the latencies of Na, Pa, Nb, and P1 and decreases in the amplitudes of Na/Pa, Pa/Nb, and Nb/P1 compared with the awake state. Before and during spontaneous movement observed intraoperatively or during emergence from anesthesia, the latencies of the peaks Na, Pa, Nb, and P1 decreased, and the amplitudes Na/Pa, Pa/Nb, Nb/P1 increased significantly. A threshold value of 60 ms of Nb proved to be most predictive of movement during anesthesia. MLAEP recording seems to be a promising method to monitor the level of anesthesia as defined by spontaneous movement during anesthesia. (Anesth Analg 1997;85:164-73)
Low-Dose Mucosal Simian Immunodeficiency Virus Infection Restricts Early Replication Kinetics and Transmitted Virus Variants in Rhesus Monkeys

ABSTRACT Defining the earliest virologic events following human immunodeficiency virus type 1 (HIV-1) transmission may be critical for the design of vaccine strategies aimed at blocking acquisition of HIV-1 infection. In particular, the length of the eclipse phase and the number of transmitted virus variants may define the window in which a prophylactic vaccine must act. Here we show that the dose of the virus inoculum affects these key virologic parameters following intrarectal simian immunodeficiency virus (SIV) infection of rhesus monkeys. Low-dose SIV infection resulted in a lengthened eclipse phase, fewer transmitted virus variants, and decreased innate immune activation compared with these parameters in high-dose SIV infection. These data suggest a mechanism by which it may be considerably easier for a vaccine to protect against low-risk HIV-1 transmission than against high-risk HIV-1 transmission. These findings have implications for the design and interpretation of HIV-1 vaccine efficacy studies.
Mitochondrial Cytochrome c Release Mediates Ceramide-induced Activator Protein 2 Activation and Gene Expression in Keratinocytes*

The intracellular signaling pathway(s) through which second messenger ceramides induce gene expression in human cells has not yet been characterized. In the present study, ceramide-induced expression of intercellular adhesion molecule-1 (ICAM-1), which requires activation of transcription factor activator protein 2 (AP-2), was found to be mediated through a mitochondrial pathway. Inhibitors of mitochondrial electron transport chain (e.g. rotenone, thenoyltrifluoroacetone, and antimycin A) reduced ceramide-induced ICAM-1 expression. Stimulation of human keratinocytes with cell-permeant ceramides at concentrations that did not induce apoptosis (no activation of caspases 3, 8, and 9 and no nucleosomal fragmentation) but caused AP-2 activation and ICAM-1 induction released cytochrome c (cyt c) from mitochondria into the cytoplasm of cells. This cyt c release was an indispensable prerequisite for effective ceramide signaling, because its inhibition by modulating the mitochondrial megachannel with bonkrekic acid or carboxyatractyloside prevented ceramide-induced AP-2 activation and ICAM-1 expression. Analysis of the interaction between cyt c and AP-2 revealed that cyt c oxidized AP-2 and that this redox regulation greatly enhanced the DNA binding capacity of AP-2. Mitochondria thus have a previously unrecognized function in signaling ceramide-induced transcription factor activation and gene regulation.
Relevancy and Measurement of Religiosity in Consumer Behavior Research

Although culture and subcultural norms have been subjected to increased scrutiny in recent years as explanatory constructs for various dimensions of consumer behavior, religion as an element of culture has received only slight attention in the marketing literature. This study seeks to examine the influence of religiosity on one aspect of consumer behavior - shopping orientation. The findings revealed that three shopping orientation factors, namely quality consciousness, impulsive shopping and price consciousness were related to religiosity. It is suggested that religiosity should be included as a possible determinant of shopping orientations in consumer behavior models.
Mutations in HIV-1 Envelope That Enhance Entry with the Macaque CD4 Receptor Alter Antibody Recognition by Disrupting Quaternary Interactions within the Trimer

ABSTRACT Chimeric simian immunodeficiency virus (SIV)/human immunodeficiency virus (HIV) (SHIV) infection of macaques is commonly used to model HIV type 1 (HIV-1) transmission and pathogenesis in humans. Despite the fact that SHIVs encode SIV antagonists of the known macaque host restriction factors, these viruses require additional adaptation for replication in macaques to establish a persistent infection. Additional adaptation may be required in part because macaque CD4 (mCD4) is a suboptimal receptor for most HIV-1 envelope glycoprotein (Env) variants. This requirement raises the possibility that adaptation of HIV-1 Env to the macaque host leads to selection of variants that lack important biological and antigenic properties of the viruses responsible for the HIV-1 pandemic in humans. Here, we investigated whether this adaptation process leads to changes in the antigenicity and structure of HIV-1 Env. For this purpose, we examined how two independent mutations that enhance mCD4-mediated entry, A204E and G312V, impact antibody recognition in the context of seven different parental HIV-1 Env proteins from diverse subtypes. We also examined HIV-1 Env variants from three SHIVs that had been adapted for increased replication in macaques. Our results indicate that these different macaque-adapted variants had features in common, including resistance to antibodies directed to quaternary epitopes and sensitivity to antibodies directed to epitopes in the variable domains (V2 and V3) that are buried in the parental, unadapted Env proteins. Collectively, these findings suggest that adaptation to mCD4 results in conformational changes that expose epitopes in the variable domains and disrupt quaternary epitopes in the native Env trimer. IMPORTANCE These findings indicate the antigenic consequences of adapting HIV-1 Env to mCD4. They also suggest that to best mimic HIV-1 infection in humans when using the SHIV/macaque model, HIV-1 Env proteins should be identified that use mCD4 as a functional receptor and preserve quaternary epitopes characteristic of HIV-1 Env.
Designing for Sharing in Local Communities

The Sharing Economy has brought new attention to the everyday practice of sharing. Digital tools are changing both what we can do together across neighbourhoods and how we think about sharing our time, materials and skills. It is possible to design to boost resource management, economic wellbeing and social resilience by fostering sharing practices, but do different designs speak to different priorities in design for sharing?
Copper and zinc concentrations in atherosclerotic plaque and serum in relation to lipid metabolism in patients with carotid atherosclerosis.

BACKGROUND/AIM Some oligoelements are now investigated as possibly having a role in atherosclerosis. The aim of this study was to compare the concentrations of copper and zinc in the serum and carotid plaque and parameters of lipid metabolism in patients with different morphology of carotid atherosclerotic plaque. METHODS Carotid endarterectomy due to the significant atherosclerotic stenosis was performed in 91 patients (mean age 64 ± 7). The control group consisted of 27 patients (mean age 58 ± 9), without carotid atherosclerosis. Atheroscletoric plaques were divided into four morphological groups, according to ultrasonic and intraoperative characteristics. Copper and zinc concentrations in the plaque, carotid artery and serum were measured by atomic absorption spectrophotometry. RESULTS Serum copper concentrations were statistically significantly higher in the patients with hemorrhagic in comparison to those with calcified plaque (1.2 ± 0.9 µmol/L vs 0.7 ± 0.2 µmol/L, respectively; p = 0.021). Zinc concentrations were statistically significantly lower in plaques of the patients with fibrolipid in comparison to those with calcified plaques (22.1 ± 16.3 g/g vs 38.4 ± 25.8 µg/g, respectively; p = 0.024). A negative significant correlation was found for zinc and triglycerides in the serum in all the patients (r = -0.52, p = 0.025). In the control group we also demonstrated a positive significant correlation for low-density lipoprotein cholesterol and copper in the serum (r = 0.54, p = 0.04). CONCLUSION The data obtained in the current study are consistent with the hypothesis that high copper and lower zinc levels may contribute to atherosclerosis and its sequelae as factors in a multifactorial disease. Further studies are necessary in order to conclude whether high concentration of copper and zinc in the serum could be risk factors for atherosclesrosis.
Improved robust controller design for dynamic IPT system under mutual-inductance uncertainty

A robust controller is designed based on the generalized mixed sensitivity with regard to the mutual-inductance uncertainty between coupling coils in dynamic inductive power transfer system to fulfill an output tracking control. A generalized state-space averaging model for a nominal series-series resonance IPT system is firstly established and the characteristic of mutual-inductance is obtained in FEM software. A linear fractional transformation of the nominal model and its uncertainty is discussed to generate a standard optimized problem. Simulation and practical experiment results are conducted to verify the performance of a closed-loop IPT system with the designed robust controller.