Miracle-dz/UniFAR-FTUs huggingface dataset:
Health economic issues in rheumatoid arthritis

The objectives of treatment in rheumatoid arthritis (RA) are to reduce temporary symptoms due to inflammatory activity and, more importantly, to preserve function. The introduction of potent disease‐modifying anti‐rheumatic drugs (DMARDs) in recent years has increased the opportunities for effective treatment. However, these treatments come at a substantially higher cost than traditional DMARDs and therefore compete with other essential interventions for limited resources. They have triggered a debate on whether they represent an efficient use of resources, which patients should be treated, when, and for how long. Cost‐effectiveness analysis attempts to estimate the trade‐offs involved in these decisions and to provide information that can help in making them. However, in chronic progressive diseases, health gains and any potential associated economic benefits are often most evident in the long term. As a consequence, the impact of new treatments has to be estimated using models that can project available knowledge, such as results from clinical trials or short‐term follow‐up studies in clinical practice, into the future. These models also allow scenarios to be explored that provide the best value for money, for example by defining subgroups for which treatment is most effective, or criteria that define when treatment should be stopped. Economic evaluation in RA has a long tradition, with the first study performed about 20 years ago. However, with the recent drug introductions, the field has witnessed an explosion of economic studies. Modelling techniques have become more sophisticated to overcome concerns about their validity. At the same time, they may appear less transparent, making it difficult for non‐specialists to understand the details. This article, rather than reviewing all published models and comparing them, attempts to illustrate the inputs required for such studies, and the influence that different approaches and datasets can have on the results.
Multicenter phase II study of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same leucovorin and fluorouracil regimen.

PURPOSE To evaluate the objective tumor response rates and toxicities of leucovorin (LV) plus fluorouracil (5-FU) cancer regimen combined with oxaliplatin (85 mg/m(2)) every 2 weeks on metastatic colorectal cancer patients with documented proof of progression while on bimonthly LV and 5-FU alone. PATIENTS AND METHODS One hundred patients were enrolled onto this study and 97 received the study drugs between October 1995 and December 1996. Eighty-nine patients were eligible for per-protocol efficacy analysis with documented proof of progression on one of the following two treatments: LV 500 mg/m(2) and continuous 5-FU infusion 1.5 to 2 g/m(2)/22 hours, days 1 through 2 every 2 weeks (FOLFUHD); or LV 200 mg/m(2), bolus 5-FU 400 mg/m(2), and continuous 5-FU infusion 600 mg/m(2)/22 hours, days 1 through 2 every 2 weeks (LV5FU2). In our study, 40 patients received FOLFUHD + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX3) and 57 patients received LV5FU2 + 85 mg/m(2) of oxaliplatin day 1 (FOLFOX4). RESULTS Of the 97 patients treated, 20 partial responses were observed (FOLFOX3/4: response rate, 20.6%; 95% confidence interval, 13% to 31.1%; FOLFOX3: response rate,18.4%; FOLFOX4: response rate, 23.5%). For patients treated with FOLFOX3/4, the median response duration for was 7.5 months, and the major toxicities were peripheral neuropathy and neutropenia. The incidence of grade 3 (National Cancer Institute common toxicity criteria) peripheral neuropathy was 20.6%; whereas the overall incidence of grade 3 to 4 neutropenia was 27.8%, 15%, and 36.9% for FOLFOX3/4, FOLFOX3, and FOLFOX4, respectively (P =.02). From the start of treatment, median progression-free survival was 4. 7, 4.6, and 5.1 months for FOLFOX3/4, FOLFOX3, FOLFOX4, respectively, and median overall survival was 10.8, 10.6, and 11.1 months, respectively. CONCLUSION This phase II study of oxaliplatin at 85 mg/m(2) in combination with bimonthly LV plus 5-FU in patients with colorectal cancer resistant to LV plus 5-FU alone confirms the enhanced antitumor activity of oxaliplatin in combination with 5-FU.
A harmony search algorithm for the no-wait flow shop optimization scheduling

This paper proposes an effective method for the no-wait flow-shop scheduling optimization based on harmony search (HS). Flow-shop scheduling problem (FSSP) is a typical NP-hard combinational optimization. The purpose of this paper is the total flow time criterion. Firstly, the HS-based optimization mechanism and framework is presented. Secondly, the total flow time is calculated by a novel method. Thirdly, a largest-order-value rule is used to transform harmony in harmony memory from real vectors to job sequence so that the harmony search can be applied for FSSP. Improvising rule of new harmony is expatiated and high effective algorithm parameters are set for optimization object. At last, simulations and comparisons demonstrate the efficiency, effectiveness and robustness of harmony search algorithm for no-wait FSSP.
Morphometric and cytogenetic characteristics of testicular germ cells and Sertoli cell secretory function in men with non-mosaic Klinefelter's syndrome.

BACKGROUND Klinefelter's syndrome is the most frequent chromosomal abnormality in infertile men. In this study, the chromosomes of round spermatids and spermatogonia/primary spermatocytes from men with non-mosaic Klinefelter's syndrome were examined, together with the Sertoli cell secretory function and sperm morphometry. METHODS Twenty-four men with non-mosaic Klinefelter's syndrome and nine men with obstructive azoospermia underwent therapeutic testicular biopsy. When spermatozoa in the final filtrate were present, they were processed for sperm morphometry or ICSI. Sperm morphometry was evaluated by the maximal length and width of the sperm head, the length of the midpiece and the ratio of the acrosomal region to the total surface area of the head. When round spermatids were present, they were processed for fluorescent in-situ hybridization (FISH). FISH was also applied to fragments of seminiferous tubules. Sertoli cell secretory function was measured by the amount of androgen binding protein (ABP) secreted in vitro. RESULTS More than 93% of the evaluated round spermatids were normal. The proportions of 24,XY and of 24,XX round spermatids to the total number were significantly larger in men with Klinefelter's syndrome than in obstructed azoospermic men. Men with Klinefelter's syndrome who had spermatozoa in their testicular tissue (n = 12) were positive for both 46,XY and 47,XXY spermatogonia in their seminiferous tubules. In contrast, men with Klinefelter's syndrome without spermatozoa in their testicular tissue (n = 12) were positive for 47,XXY spermatogonia but negative for 46,XY spermatogonia in their seminiferous tubules. ABP profiles were significantly smaller in men with Klinefelter's syndrome who were negative for spermatozoa compared with men who were positive. Four pregnancies were achieved and five healthy babies were born. CONCLUSIONS This study suggests that few 46,XXY spermatogonia undergo meiosis with an XX pairing and a Y univalent type of pairing. Hyperhaploid round spermatids (24,XY and 24,XX) may be produced by meiosis of 47,XXY spermatogonia. Men with Klinefelter's syndrome who are negative for testicular spermatozoa have a greater degree of Sertoli cell secretory dysfunction compared with men with Klinefelter's syndrome who are positive for spermatozoa. There are several defects in sperm morphometry with functional significance in men with Klinefelter's syndrome.
Prediction of protein retention times in hydrophobic interaction chromatography by robust statistical characterization of their atomic‐level surface properties

The correlation between the dimensionless retention times (DRT) of proteins in hydrophobic interaction chromatography (HIC) and their surface properties were investigated. A ternary atomic‐level hydrophobicity scale was used to calculate the distribution of local average hydrophobicity across the proteins surfaces. These distributions were characterized by robust descriptive statistics to reduce their sensitivity to small changes in the three‐dimensional structure. The applicability of these statistics for the prediction of protein retention behaviour was looked into. A linear combination of robust statistics describing the central tendency, heterogeneity and frequency of highly hydrophobic clusters was found to have a good predictive capability (R2 = 0.78), when combined a factor to account for protein size differences. The achieved error of prediction was 35% lower than for a similar model based on a description of the protein surface on an amino acid level. This indicates that a robust and mathematically simple model based on an atomic description of the protein surface can be used for the prediction of the retention behaviour of conformationally stable globular proteins with a well determined 3D structure in HIC. © 2016 American Institute of Chemical Engineers Biotechnol. Prog. , 32:372–381, 2016
Comparison of sustained attention assessed by auditory and visual psychomotor vigilance tasks prior to and during sleep deprivation

To date, no detailed examination of the pattern of change in reaction time performance for different sensory modalities has been conducted across the circadian cycle during sleep deprivation. Therefore, we compared sustained auditory and visual attention performance during 40 h of sleep deprivation assessing multiple metrics of auditory and visual psychomotor vigilance tasks (PVT). Forty healthy participants (14 women) aged 30.8 ± 8.6 years were studied. Subjects were scheduled for an ∼8 h sleep schedule at home prior to three–six laboratory baseline days with an 8 h sleep schedule followed by 40 h sleep deprivation. Visual and auditory PVTs were 10 min in duration, and were administered every 2 h during sleep deprivation. Data were analysed with mixed‐model anova. Sleep deprivation and circadian phase increased response time, lapses, anticipations, standard deviation of response times and time on task decrements for visual and auditory PVTs. In general, auditory vigilance was faster and less variable than visual vigilance, with larger differences between auditory and visual PVT during sleep deprivation versus baseline. Failures to respond to stimuli within 10 s were four times more likely to occur to visual versus auditory stimuli. Our findings highlight that lapses during sleep deprivation are more than just long responses due to eye closure or visual distraction. Furthermore, our findings imply that the general pattern of change in attention during sleep deprivation (e.g. circadian variation, response slowing, lapsing and anticipations, time on task decrements and state instability) is similar among sensory–motor behavioral response modalities.
TetX Is a Flavin-dependent Monooxygenase Conferring Resistance to Tetracycline Antibiotics*

The tetracycline antibiotics block microbial translation and constitute an important group of antimicrobial agents that find broad clinical utility. Resistance to this class of antibiotics is primarily the result of active efflux or ribosomal protection; however, a novel mechanism of resistance has been reported to be oxygen-dependent destruction of the drugs catalyzed by the enzyme TetX. Paradoxically, the tetX genes have been identified on transposable elements found in anaerobic bacteria of the genus Bacteroides. Overexpression of recombinant TetX in Escherichia coli followed by protein purification revealed a stoichiometric complex with flavin adenine dinucleotide. Reconstitution of in vitro enzyme activity demonstrated a broad tetracycline antibiotic spectrum and a requirement for molecular oxygen and NADPH in antibiotic degradation. The tetracycline products of TetX activity were unstable at neutral pH, but mass spectral and NMR characterization under acidic conditions supported initial monohydroxylation at position 11a followed by intramolecular cyclization and non-enzymatic breakdown to other undefined products. TetX is therefore a FAD-dependent monooxygenase. The enzyme not only catalyzed efficient degradation of a broad range of tetracycline analogues but also conferred resistance to these antibiotics in vivo. This is the first molecular characterization of an antibiotic-inactivating monooxygenase, the origins of which may lie in environmental bacteria.
Functional conservation of the lncRNA NEAT1 in the ancestrally diverged marsupial lineage: Evidence for NEAT1 expression and associated paraspeckle assembly during late gestation in the opossum Monodelphis domestica

ABSTRACT Long non-coding RNAs (lncRNAs) are widely expressed and play various roles in cell homeostasis. However, because of their low conservation at the sequence level, recapitulating lncRNA evolutionary history is often challenging. While performing an ultrastructural analysis of viral particles present in uterine glands of gestating opossum females, we serendipitously noticed the presence of numerous structures similar to paraspeckles, nuclear bodies which in human and mouse cells are assembled around an architectural NEAT1/MENϵ/β lncRNA. Here, using an opossum kidney (OK) cell line, we confirmed by immuno-electron microscopy the presence of paraspeckles in marsupials. We then identified the orthologous opossum NEAT1 gene which, although poorly conserved at the sequence level, displays NEAT1 characteristic features such as short and long isoforms expressed from a unique promoter and for the latter an RNase P cleavage site at its 3′-end. Combining tissue-specific qRT-PCR, in situ hybridization at the optical and electron microscopic levels, we show that (i) NEAT1 is paraspeckle-associated in opossum (ii) NEAT1 expression is strongly induced in late gestation in uterine/placental extracts (iii) NEAT1 induction occurs in the uterine gland nuclei in which paraspeckles were detected. Finally, treatment of OK cells with proteasome inhibitors induces paraspeckle assembly, as previously observed in human cells. Altogether, these results demonstrate that paraspeckles are tissue-specific, stress-responding nuclear bodies in marsupials, illustrating their structural and functional continuity over 200 My of evolution throughout the mammalian lineage. In contrast, the rapid evolution of the NEAT1 transcripts highlights the relaxed constraint that, despite functional conservation, is exerted on this lncRNA.
High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia

Depending on its expression level, RUNX1 can act as a tumor promoter or suppressor in hematological malignancies. The clinical impact of RUNX1 expression in cytogenetically normal acute myeloid leukemia (CN-AML) remained unknown, however. We evaluated the prognostic significance of RUNX1 expression using several public microarray datasets. In the testing group (n = 157), high RUNX1 expression (RUNX1high) was associated with poorer overall survival (OS; P = 0.0025) and event-free survival (EFS; P = 0.0025) than low RUNX1 expression (RUNX1low). In addition, the prognostic significance of RUNX1 was confirmed using European Leukemia Net (ELN) genetic categories and multivariable analysis, which was further validated using a second independent CN-AML cohort (n = 162, OS; P = 0.03953). To better understand the mechanisms of RUNX1, we investigated genome-wide gene/microRNAs expression signatures and cell signaling pathways associated with RUNX1 expression status. Several known oncogenes/oncogenic microRNAs and cell signaling pathways were all up-regulated, while some anti-oncogenes and molecules of immune activation were down-regulated in RUNX1high CN-AML patients. These findings suggest RUNX1high is a prognostic biomarker of unfavorable outcome in CN-AML, which is supported by the distinctive gene/microRNA signatures and cell signaling pathways.
A Prospective Randomized Trial of Laparoscopic Gastric Bypass Versus Laparoscopic Adjustable Gastric Banding for the Treatment of Morbid Obesity: Outcomes, Quality of Life, and Costs

Background:Gastric bypass and adjustable gastric banding are the 2 most commonly performed bariatric procedures for the treatment of morbid obesity. The aim of this study was to compare the outcomes, quality of life, and costs of laparoscopic gastric bypass versus laparoscopic gastric banding. Study Design:Between 2002 and 2007, 250 patients with a body mass index of 35 to 60 kg/m2 were randomly assigned to gastric bypass or gastric banding. After exclusion, 111 patients underwent gastric bypass and 86 patients underwent gastric banding. Outcome measures included demographic data, operative time, blood loss, length of hospital stay, morbidity, mortality, early and late reoperation rate, weight loss, changes in quality of life, and cost. Treatment failure was defined as losing less than 20% of excess weight or conversion to another bariatric operation for failure of weight loss. Results:There were no deaths at 90 days in either group. The mean body mass index was higher in the gastric bypass group (47.5 vs. 45.5 kg/m2, respectively, P < 0.01) while the mean age was higher in the gastric band group (45 vs. 41 years, respectively, P < 0.01). Compared with gastric banding, operative blood loss was higher and the mean operative time and length of stay were longer in the gastric bypass group. The 30-day complication rate was higher after gastric bypass (21.6% vs. 7.0% for gastric band); however, there were no life-threatening complications such as leaks or sepsis. The most frequent late complication in the gastric bypass group was stricture (14.3%). The 1-year mortality was 0.9% for the gastric bypass group and 0% for the gastric band group. The percent of excess weight loss at 4 years was higher in the gastric bypass group (68 ± 19% vs. 45 ± 28%, respectively, P < 0.05). Treatment failure occurred in 16.7% of the patients who underwent gastric banding and in 0% of those who underwent gastric bypass, with male gender being a predictive factor for poor weight loss after gastric banding. At 1-year postsurgery, quality of life improved in both groups to that of US norms. The total cost was higher for gastric bypass as compared with gastric banding procedure ($12,310 vs. $10,766, respectively, P < 0.01). Conclusions:Laparoscopic gastric bypass and gastric banding are both safe and effective approaches for the treatment of morbid obesity. Gastric bypass resulted in better weight loss at medium- and long-term follow-up but was associated with more perioperative and late complications and a higher 30-day readmission rate. There was a wide variation in weight loss after gastric banding with a small proportion of patients considered as treatment failure, and male gender was a predictive factor for poor weight loss.
Quantitative Expression of Hepatobiliary Transporters and Functional Uptake of Substrates in Hepatic Two-Dimensional Sandwich Cultures: A Comparative Evaluation of Upcyte and Primary Human Hepatocytes

Deficient functional expression of drug transporters incapacitates most hepatic cell lines as a reliable tool for evaluating transporter-mediated drug-drug interactions. Recently, genetically modified cells (referred to as upcyte hepatocytes) have emerged as an expandable, noncancerous source of human hepatic cells. Herein, we quantified mRNA and protein levels of key hepatobiliary transporters and we assessed associated uptake activity in short- and long-term cultures of upcyte human hepatocytes (UHH) in comparison to cryopreserved primary human hepatocytes (cPHH). Expression of canalicular efflux pumps, such as MRD1/ABCB1, MATE1/SLC47A1, and MRP2/ABCC2, was relatively well preserved in UHH. By contrast, long-term cultivation of UHH in a two-dimensional sandwich configuration [sandwich-cultured upcyte human hepatocytes (SCUHH)] was required to upregulate organic anion-transporting polypeptide OATP1B1/SLCO1B1, OATP2B1/SLCO2B1, NTCP/SLC10A1, and OCT1/SLC22A1 mRNA expression, which correlated well with respective protein abundances. However, mRNA and protein levels of sinusoidal solute carrier transporters, except for NTCP and OATP2B1, remained low in SCUHH compared to sandwich-cultured cPHH. OCT1- and NTCP-mediated uptake of N-methyl-4-phenylpyridinium acetate and taurocholate was demonstrated in both hepatic models, whereas active uptake of OATP1B1/1B3-selective marker substrates, paralleled by markedly reduced SLCO1B1/1B3 expression, were not detectable in SCUHH. Uptake studies under Na+-depletion and excess of taurocholate confirmed the presence of functional NTCP protein and indicated that NTCP, apart from OATP2B1, contributed substantially to the overall hepatic uptake of rosuvastatin in SCUHH. In conclusion, our data suggest that SCUHH, despite their limitation for evaluating OATP1B1/1B3-mediated transport processes, retain NTCP, OATP2B1, and OCT1 transport activities and thus may be considered as a tool for elucidating compensatory uptake pathways for OATP1B1/1B3 substrates.
Wide FOV displays for Digital Museum

In this research, we introduce digital technology to museum environment by providing spherical image contents. This research built two systems. First, we introduce binocular-type system providing visitors with information about exhibits such as historical backgrounds and surrounding environment when used, and then projection device that creates full-image space by scanning. According to evaluation experiment in a museum, the systems received positive opinion for introduction to the museum.
Validating Three-Dimensional Imaging of the Breast

The potential to extrapolate accurate data from 3-dimensional (3D) images of the breast is enormous and will greatly improve our ability to qualitatively determine differences in shape, size, and contour. The validity of these calculated measurements is important and needs to be determined before any meaningful data can be evaluated. Part I:Premastectomy 3D images (3dMD patient) were obtained on 19 breasts (14 patients). The volume of the mastectomy specimen was determined intraoperatively using water displacement. Two independent raters then calculated breast volumes using the 3D images and software, and these were compared with the intraoperative volume. Inter- and intrarater reliability was determined. Part II: Surface measurements (nipple to notch) were then evaluated on 20 breasts (10 patients) by comparing the 3D image determined distance to the known measurements. Part I:The average breast volume was 500 mL, compared with 489 mL for rater 1 and 490 mL for rater 2. The relative difference between the measured volume and the calculated volume for rater 1 and rater 2 was about −2%, with a standard deviation of ± 13% to 16%. The coefficient of reproducibility for each reader was excellent, at 0.80 for rater 1 and 0.92 for rater 2. The level of agreement between the readers was also high at 0.975. Part II: The average nipple to notch measurement for each patient was 27.1 cm, compared the calculated average of 25.1 cm for rater 1 and 26.1 cm for rater 2. The mean relative difference between the measured and calculated distances for raters 1 and 2 was about −6%, with a standard deviation of ± 6% to 7%. The level of agreement between readers was high, at 0.975. The ability to objectively determine breast volume and surface measurements using 3D imaging technology is now available with consistent and reproducible accuracy. Measurements are typically underestimated, with more variability when calculating volumes. Although inherent subjectivity will always exist when evaluating breast measurements, 3D technology provides invaluable information, particularly in the longitudinal evaluation of results.