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Partially fluorinated oxo-alkoxide tungsten complexes bearing β-diketonate or ketoesterate ligands have been synthesized and their thermal and physical properties have been evaluated for Aerosol Assisted Chemical Vapor Deposition (AACVD) of WOx. Volatility and thermal stability of the complexes have been shown to depend on the bidentate ligand and the degree of fluorination of the alkoxides. Growth of tungsten oxide from the precursor WO(OC(CH3)2CF3)3(tbac) (tbac = tert-butyl acetoacetate) has been demonstrated. Deposits grown at temperatures from 150 to 300 °C are amorphous thin films of substoichiometric WOx. Deposition at temperatures from 350 to 500 °C produced either polycrystalline films or crystalline nanorods of W18O49.

Introduction As part of a study to assess the impact of the COVID-19 pandemic on the sleep of patients of a multidisciplinary sleep clinic, we surveyed how they accessed healthcare for sleep problems. Methods Patients were invited to complete an online survey in October 2020. Results 74 patients completed the survey (mean age 50.2 years, range 21–83 years, 56.8% female). 26/74 (35%) reported at least one delay in accessing healthcare for sleep problems. In particular, 7/49 (14.3%) had delays seeing a general practitioner whilst 16/43 (37.2%) experienced delays accessing a sleep physician. 7/26 (26.9%) reported delays booking a sleep study and 4/15 (26.7%) had delays hiring continuous positive airway pressure equipment. 11/31 (35.5%) experienced delays seeing a psychologist for sleep problems. 11/74 (14.9%) preferred to wait until they were able to attend the clinic in person. 21/74 (28.4%) had telehealth consultations with a sleep physician and/or psychologist. 19/21 (90.5%) described it easy to participate and 20/21 (95.2%) reported receiving satisfactory care through telehealth consultation. Only 5/21 (23.8%) preferred to attend in-person instead of participating in a telehealth consultation again. 11/74 (14.9%) had telephone consultations with a sleep physician and/or psychologist. 8/11 (72.7%) found it easy to participate and 8/11 (72.7%) reported receiving satisfactory care through telephone consultation. Only 3/11 (27.3%) preferred to attend in-person instead of participating in a telephone consultation again. Discussion During the COVID-19 pandemic, 35% of patients reported delays accessing healthcare for sleep problems. Most patients who participated in telehealth and telephone consultations described positive experiences.

Magnetic properties and microstructure of melt spun YCo5– x – y Fe x C y ( $x = 0$ –0.3 and $y = 0$ –0.3) ribbons are studied. Magnetic properties of YCo5 ribbons ( i H c = 144 kA/m and (BH) $_{\max } = 16.8$ kJ/m3 are slightly improved to i H c = 160–224 kA/m and (BH) $_{\max } = 21.6$ –27.2 kJ/m3 by Fe-doping, and are increased to i H c = 560–1128 kA/m and (BH) $_{\max }= 42.4$ –51.2 kJ/m3 by C-doping, respectively. Most interestingly, the optimal (BH) $_{\max }$ of 72.8 kJ/m3 with high i H c of 1200 kA/m achieved for Fe and C-co-doped YCo4.6Fe0.3C0.3 ribbons is the highest value in Y–Co alloy ribbons ever reported. The structural and thermo-magnetic analysis confirm that Fe and C enter the YCo5 (5:1) crystal structure and lead to the increase of Curie temperature. Besides, C-doping uniformly refines grain size and, therefore, improves the squareness of demagnetization curve and (BH) $_{\max }$ . The formation of YCo, Fe)5C x phase and the microstructure refinement are the main reasons to result in the enhancement of hard magnetic properties for the YCo4.4Fe0.3C0.3 ribbons. The presented results suggest that the YCo5 ribbons optimized by co-doping with Fe and C are promising candidate materials for making bonded magnets.

The reflection and transmission of polarized light for a cirrus cloud consisting of randomly oriented hexagonal columns were calculated by two very different vector radiative transfer models. The forward peak of the phase function for the ensemble-averaged ice crystals has a value of order 6 × 10 3 so a truncation procedure was used to help produce numerically efficient yet accurate results. One of these models, the Vectorized Line-by-Line Equivalent model (VLBLE), is based on the doubling–adding principle, while the other is based on a vector discrete ordinates method (VDISORT). A comparison shows that the two models provide very close although not entirely identical results, which can be explained by differences in treatment of single scattering and the representation of the scattering phase matrix. The relative differences in the reflected I and Q Stokes parameters are within 0.5% for I and within 1.5% for Q for all viewing angles. In 1971 Hansen [1] showed that for scattering by spherical particles the 3×3 approximation is sufficient to produce accurate results for the reflected radiance I and the degree of polarization (DOP), and he conjectured that these results would hold also for non-spherical particles. Simulations were conducted to test Hansen׳s conjecture for the cirrus cloud particles considered in this study. It was found that the 3×3 approximation also gives accurate results for the transmitted light, and for Q and U in addition to I and DOP. For these non-spherical ice particles the 3×3 approximation leads to an absolute error 2 × 10 − 6 for the reflected and transmitted I , Q and U Stokes parameters. Hence, it appears to be an excellent approximation, which significantly reduces the computational complexity and burden required for multiple scattering calculations.

The pharmacokinetics and safety of single-dose zanubrutinib (80 mg) were assessed in subjects with mild, moderate, and severe hepatic impairment (n = 6 each, Child–Pugh class A, B, and C) relative ...

Today, patients generate a massive amount of health records through electronic health records (EHRs). Extracting usable knowledge of patients&rsquo, pathological conditions or diagnoses is essential for the reasoning process in rule-based systems to support the process of clinical decision making. Association rule mining is capable of discovering hidden interesting knowledge and relations among attributes in datasets, including medical datasets, yet is more likely to produce many anomalous rules (i.e., subsumption and circular redundancy) depends on the predefined threshold, which lead to logical errors and affects the reasoning process of rule-based systems. Therefore, the challenge is to develop a method to extract concise rule bases and improve the coverage of non-anomalous rule bases, i.e., one that not only reduces anomalous rules but also finds the most comprehensive rules from the dataset. In this study, we generated non-anomalous association rules (NAARs) from a cerebrovascular examination dataset through several steps: obtaining a frequent closed itemset, generating association rule bases, subsumption checking, and circularity checking, to fit production rules (PRs) in rule-based systems. Toward the end, the rule inferencing part was performed by PROLOG to obtain possible conclusions toward a specific query given by a user. The experiment shows that compared with the traditional method, the proposed method eliminated a significant number of anomalous rules while improving computational time.

Introduction/Background To evaluate the prognostic significance of pretreatment serum CEA level in epithelial ovarian cancer. Methodology This retrospective cohort study was carried out in 326 epithelial ovarian cancer patients at Kaohsiung Chang Gung Memorial hospital between 2008–2016. All patients had histopathological confirmed diagnosis and pretreatment measurements of serum CA125 and CEA value. Data acquired from medical records including age, FIGO stage, Histology type, tumor size and debulking status. Statistical analysis The difference between proportions was evaluated by chi-square test. Univariate survival curves for progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. Multivariate Cox regression analysis was used to compare independent prognostic factors for PFS and OS. SPSS (version 20) was used for all statistical analyses. Results Our analysis showed the elevated pretreatment serum CEA value (cutoff 5 ng/ml) is an independent prognostic factor in epithelial ovarian cancer. These patients has lower PFS and OS compared with patients with normal CEA value. In multivariate analysis, FIGO stage, pretreatment CEA and CA125 value and debulking status are independent prognostic factors. The finding of CEA value as an independent prognostic factor was exception of tradition. CEA may carry prognostic information and this result may indicate that patients showing elevated value of pretreatment CEA could be included in high-risk group for recurrence. Currently, this study included extended and comprehensive database of relationship between epithelial ovarian cancer and serum CEA value. Conclusion Our study included all epithelial ovarian cancer patients with subgroup analysis and the detection of serum CEA value provided the convenience in clinical practice. Elevated pretreatment serum CEA value is an independent prognostic factor in epithelial ovarian cancer in both univariate and multivariate analysis. Disclosure Nothing to disclose.

Introduction/Background Expression of sex hormonal receptors (SHR) had been reported to influence survival outcomes in patients with epithelial ovarian cancer. In present study, we attempted to investigate the association and mechanism between SHR expression and chemosensitivity in epithelial ovarian cancer (EOC). Methodology We reviewed 71 patients with EOC who underwent surgery followed by adjuvant chemotherapy and analyzed sex hormone receptors (SHR) immunohistochemical (IHC) expression of tissue samples obtained from these patients. The disease-free survival (DFS), overall survival (OS), and percentage of chemosensitivity were compared between weak and strong SHR IHC expression. The effects of cisplatin administration on cell proliferation in ovarian cancer OC3-VGH cells with different SHR expression were investigated. Results Patients with strong androgen (AR) and progesterone receptors (PR) IHC expression had better 5-year DFS, OS, and chemosensitivity. In cell model data, overexpression of AR and PR OC3-VGH cells caused higher sensitivity to cisplatin treatment. OV3-VGH cisplatin resistant clone expressed lower level of AR and PR than wild-type. Overexpression of AR OC3-VGH cells showed higher DNA damage signals after cisplatin treatment. Conclusion Our data indicated that strong AR and PR expression were good prognostic factors via the mechanism of better cisplatin sensitivity. Novel therapeutics against AR and PR might be promising for treatment of EOC patients. Disclosure Nothing to disclose.

Hemoglobin functions as an oxygen transport protein, with each subunit containing a heme cofactor. We have developed a global disassembly model for human hemoglobin, linking hemin (ferric heme) disassociation and apo(heme-free)-protein unfolding pathways. The model was based on the evaluation of circular dichroism and visible absorbance measurements of guanidine hydrochloride-induced disassembly of holo (heme-bound)-hemoglobin and previous measurements of apohemoglobin unfolding. The populations of holo-intermediates and equilibrium disassembly parameters were determined quantitatively for adult and fetal hemoglobins. The key stages for disassembly into unfolded monomers are characterized by hemichrome intermediates with molten globule characteristics. Hemichromes, which occur when both hemin iron axial sites coordinate amino acids, are not energetically favored in native human hemoglobins. However, these hexacoordinate iron complexes are important for preventing hemin disassociation from partially unfolded species during early disassembly and late stage assembly events. Both our model evaluation and independent small angle X-ray scattering measurements demonstrate that heme disassociation during early disassembly leads to loss of tetrameric structural integrity. Dimeric and monomeric hemichrome intermediates occur along the disassembly pathway inside red cells where the hemoglobin concentration is very high. This prediction explains why in the red cells of patients with unstable hemoglobinopathies, misassembled hemoglobins often get trapped as hemichromes that accumulate into insoluble Heinz bodies. These Heinz bodies become deposited on the cell membranes and can lead to hemolysis. Alternatively, when acellular hemoglobin is diluted into blood plasma after red cell lysis, the disassembly pathway is dominated by early hemin disassociation events, which leads to the generation of higher fractions of apo-subunits and free hemin known to damage to the integrity of blood vessel walls. Thus, our model illuminates the pathophysiology of hemoglobinopathies and other disease states associated with unstable globins and red cell lysis, and provides insights into the factors governing hemoglobin assembly during erythropoiesis.SignificanceOur deconvolution and global analysis of spectral data led to both the characterization of “hidden” hemichrome intermediates and the development of a quantitative model for human hemoglobin disassembly/assembly. The importance of this mechanism is several-fold. First, the hemoglobin system serves as a general biological model for understanding the role of oligomerization and cofactor binding in facilitating protein folding and assembly. Second, the fitted parameters provide: (a) estimates of hemin affinity for apoprotein states; (b) quantitative interpretations of the pathophysiology of hemoglobinopathies and other diseases associated with unstable globins and red cell lysis; (c) insights into the factors governing hemoglobin assembly during erythropoiesis; and (d) a framework for designing targeted hemoglobinopathy therapeutics.

Tungsten(VI) oxo complexes of the type WO(OR)

PurposeTo determine whether the efficacy and safety achieved with 2.0 mg intravitreal aflibercept injections (IAIs) for diabetic macular edema (DME) during the phase III VISTA DME trial were maintained with individualized, as-needed treatment.DesignPhase IV, multicenter, open-label extension study.MethodsSixty patients completing VISTA DME elected to enter the ENDURANCE extension study. All patients received IAIs in the presence of clinically relevant DME. Patients were observed at 4-, 8-, or 12-week intervals depending on the need for treatment. Main outcome measures were mean IAIs given through month 12 (M12), the proportion of patients receiving no IAIs, and the role of macular laser in decreasing treatment burden among patients requiring ongoing IAIs.ResultsA mean of 4.5 IAIs were administered through M12. Eighteen (30%) patients required no IAIs, and among those who met IAI retreatment criteria, a mean of 6.0 IAIs were administered through M12. Best-corrected visual acuity gains achieved during VISTA DME were maintained and stable with individualized dosing during ENDURANCE, fluctuating by

The study was designed to characterize the plasma pharmacokinetics and tissue depletion profiles (including eggs) of cyromazine (CYR) in chickens following oral administration alone or in combination with melamine (MEL). In order to assess the pharmacokinetic profile of CYR, chickens were administered 1 or 10 mg/kg (single oral doses), whereas residue studies were conducted in chickens fed CYR alone (5 or 10 mg/kg) or CYR (5 mg/kg) and MEL (5 mg/kg) for a period of 14 days. Estimates for the apparent volume of distribution (1.66 L/kg), clearance (7.17 mL/kg/min), and elimination half-life (2.82 h) were derived by noncompartmental analyses. The highest concentration of CYR occurred in liver but fell below detectable limits within 3 days following drug withdrawal from feed. Combined feeding of MEL with CYR did not significantly alter CYR tissue levels. CYR residues were detected only in egg white and were undetectable at the 2nd day postadministration. No MEL was found in eggs unless it had been added to the feed, and when present, it almost exclusively restricted to the egg white. Based upon the results of this initial study of CYR pharmacokinetics and residue depletion, it appears that use of CYR as a feed additive either alone (5 or 10 mg/kg) or in combination with MEL (both agents at 5 mg/kg) does not produce unsafe residue levels in edible products as long as appropriate withdrawal periods are followed for tissues (3 days) and eggs (2 days). However, our results indicate that adoption of a zero-day withdrawal period should be reconsidered in light of these results.

The hierarchical facility location problem (HFLP) is defined as determining the location of facilities in such a way that high-level facilities can serve the facilities in low-level efficiently. In this paper, a mixed integer programming model for the HFLP with the flow capacity constraint is proposed. An approach hybrided PSO and Tabu search (TS) (HPSO-TS) is proposed to solve the HFLP. The objective is to minimize overall demand-weighted distance travel, facility operating costs, and flow assignment costs. This method transforms PSO particles representing various dimensions of the attributes into a Tabu priority list and then constructs the assignment networks. The performance of the proposed algorithm is compared with branch-and-bound algorithm, a genetic algorithm, and classical PSO. Numerical results show that the performance of the proposed algorithm is better than those with exact methods when solving such problems. Finally, the proposed algorithm is applied to solve a case company in Jakarta.

Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure.

Summary Objectives To evaluate the safety and efficacy of low-dose desmopressin in elderly men with and without nocturnal polyuria (NP) in real-life practice. Methods Patients with lower urinary tract symptoms (LUTS)/ benign prostate hyperplasia (BPH) who were≧ 65 years old with refractory nocturia were enrolled in this study. We retrospectively analysed elderly men treated with adding desmopressin to current medications for nocturia according to category of the baseline nocturnal urine volume. The 48-h frequency volume chart (FVC), International Prostate Symptom Score (IPSS) and quality of life (QoL) were initially assessed and re-evaluated 12 weeks later. Serum sodium level was checked 1 week, 4 weeks, and 12 weeks after initiation of desmopressin therapy or suspected hyponatremia event. The mean change in numbers of nocturnal voids was evaluated for efficacy of treatment. Results A total of 136 patients were included with 55 in non-NP group and 81 in NP group. Hypertension was more common in NP group in regard of comorbidities. During treatment period, there were significant reductions of nocturnal voids from 4.22 ± 1.38 to 2.31 ± 0.98 (p < 0.001) in non-NP group and from 4.52 ± 1.23 to 2.07 ± 0.89 (p < 0.001) in NP group. The reduction in nocturnal voids was more significant in NP group (2.44 ± 1.15 vs. 1.91 ± 1.48, p = 0.003). The mean decrease in serum sodium levels were 3.89 ± 1.22 mmol/l (p < 0.001) in non-NP group and 4.69 ± 3.5 mmol/l (p < 0.001) in NP group at the extreme value. Conclusions Long-term treatment with low-dose desmopressin is safe and effective for nocturia with or without NP in elderly patients with LUTS/BPH during real-life practice. Patients should be well informed about the disease and are closely followed.

This work investigates the gas heating process of a single microdischarge (MD) and the evolution of flow dynamics due to the induced pressure waves by using the transient 3D gas flow model of a single MD (GFM-MD) with the calculated heating sources validated. The heating sources of different heating mechanisms are calculated by the 1.5D plasma fluid model with the framework of air chemistry and provided as the source term of the energy equation solved in the steady-state 3D GFM-Reactor for obtaining the temperature distribution of the reactor to validate the overall heating source by comparing with experimental measurements. The validated heating sources in different temporal phases are provided as the volumetric heating sources in the sheath and bulk regions in the transient 3D GFM-MD to model the gas heating process and evolution of flow dynamics. The simulated power consumption of a single MD is around 0.068 W which is close to the average measured power consumption of a single MD as around 0.053 W. The average gas temperature in the central region of the reactive zone is around 440 K which agrees with the rotational temperature determined as 460 K. The maximum simulated surface temperature reaches 414 K which is in good agreement with that measured by the IR thermal imager as 435 K. The spatial average heating source increases dramatically to the level of 1011 W m−3 in a few ns during the breakdown (BD) phase from the low heating source of 107 W m−3 in the pre-BD. Detailed analysis shows that the kinetics and ionic Joule heating are dominant heating sources with comparable contributions. The heating source of the kinetics reaches the level of 1011 W m−3 across the gap with a moderate increase near the sheath region, while the heating source of the ionic Joule heating remains at a low level across the gap with a dramatic increase to the level of 1013 W m−3 in the sheath region in the BD phase, resulting in the rapid increase of gas temperature from 390 K to 550 K in the sheath region in a few ns. The dramatic increase of the ionic Joule heating in the sheath region in the BD phase results in the rapid increase of pressure to the level of around 1060 torr. An induced high-pressure wave is formed and moves from the sheath region to ambient air with the wave speed estimated as 410 m s−1 which is close to the speed of sound as observed experimentally. The high-pressure region results in a significant pressure gradient between the sheath region and ambient air in the gap, leading to an increase of the flow velocity. As air moves rapidly outward from the sheath region, the density in the sheath region decreases. The low-density zone in the sheath region results in the formation of a low-pressure wave after the induced high-pressure wave. The pressure waves move outward continuously, leading to the evolution of flow dynamics.

Chemical vapor deposition (CVD) is a deposition technique capable of depositing a thin layer of material through the gas-phase decomposition of precursor molecules. In addition to the deposition parameters, the choice of precursor is crucial in determining the stoichiometry, composition and properties of the films. The established library of CVD precursors for tungsten and molybdenum oxides has been extended well beyond the originally studied simple inorganic precursors to also include organometallic, metal–organic and metal salt precursors. Herein, we highlight the progress in precursor development for both metal oxides.

PURPOSE To determine the efficacy of a novel application of a surgical internal limiting membrane flap technique that requires no additional surgical adjuvants in closure of large full-thickness macular holes (FTMHs). METHODS The electronic medical records of patients (n = 8) with large (>400 µm) FTMHs repaired with the "Texas Taco" technique were retrospectively reviewed. RESULTS Operated patients had a mean age of 63.8 ± 19.2 (range, 19-80) years. There were five (62.5%) phakic and three (37.5%) pseudophakic eyes preoperatively. Mean follow-up time was 9.1 ± 4.7 (1.5-14.5) months. Across all patients, mean FTMH diameter at the shortest and greatest widths were 529 ± 101 (404-661) and 1,189 ± 290 (829-1,656) µm, respectively. Mean best-corrected logarithm of the minimum angle of resolution visual acuity was 1.3 ± 0.23 preoperatively (approximately Snellen acuity 20/400) and 0.66 ± 0.40 postoperatively (approximately Snellen acuity 20/100) (P < 0.001). All FTMHs remained closed at all postoperative visits. CONCLUSION The Texas Taco technique provided anatomical and functional improvement in challenging cases of large FTMHs without the need of additional surgical adjuvants.

Purpose To determine the relationship between central drusen volume and low-luminance deficit (LLD) in visual acuity (VA) in patients with intermediate age-related macular degeneration (AMD). Methods In this cross-sectional study, 42 patients with intermediate AMD underwent testing for VA and low-luminance VA (LLVA), as well as spectral-domain optical coherence tomography. LLD was calculated as the difference between VA and LLVA. Central drusen volume was measured in the central 3 mm of the macula, defined as the volume between the inner border of the retinal pigment epithelium and Bruch's membrane. Results Mean ± standard deviation (SD) LLD was 0.32 ± 0.12 logMAR and mean ± SD drusen volume was 0.18 ± 0.09 mm3. No linear relationship was identified between central 3 mm drusen volume and LLD (P = 0.215). R2 for the bivariate linear model was 0.038 (95% confidence interval 0–0.222). Limitation of the analysis to drusen volumes measured in the central 1 mm of the macula did not impact results (R2 = 0.075), nor did incorporation of lens status into the model (R2 = 0.067) or censoring of patients with nonfoveal subretinal drusenoid deposits (R2 = 0.071). Conclusions The amount of drusen within the central 3 mm of the macula does not appear to be related to LLD in intermediate AMD. These measures may be manifestations of different underlying pathophysiological mechanisms. Translational Relevance Understanding relationships between markers for AMD progression may help guide development of improved clinical grading scales for AMD.

Objective This study interviewed youth with unilateral hearing, utilizing their responses to generate candidate items for a condition-specific patient-reported instrument. Study Design Mixed methods, cross-sectional. Setting Tertiary care children's hospital. Participants and Methods Youth with unilateral hearing loss and normal hearing in the contralateral ear were identified and recruited for participation through query of an audiometric database and through hearing loss clinics. Interviews with the youth were qualitatively analyzed to identify common themes and generate items related to functional impact. A multi-institutional expert panel reviewed items with prespecified item selection criteria. Participants rated items for impact on daily life. For preliminary criterion validity assessment, statistical analyses explored correlations between functional scores and type and severity of hearing loss. Results Thirty-nine youth aged 9 to 18 years with unilateral hearing loss participated; 31% used a hearing device. Fifteen youth participated in interviews; thematic analysis, item crafting, and expert panel item review resulted in 41 items. Twenty-six youth responded to the items, reporting low functional scores in the domains of sound localization, ear positioning, and noise environment. They reported better levels of function in carrying out group conversations, focusing on schoolwork, and feeling safe during activities. Multivariate linear regression found that youth scored 0.4 points (or approximately 8%) lower on the functional impact scale with every 20-dB HL increase in pure tone average in the abnormal ear. Conclusion Youth with unilateral hearing loss report functional impact, particularly related to sound localization, ear positioning, and noise environment; therefore, they may benefit from a condition-specific functional assessment instrument.

AIMS To identify the optimal transarterial chemoembolisation (TACE) approach in patients with large hepatocellular carcinoma (HCC; >5 cm) by comparing conventional TACE (cTACE) and drug-eluting-bead (DEB)-TACE. MATERIALS AND METHODS This retrospective study included 63 consecutive HCC patients who received TACE at a single medical centre from September 2009 to October 2015. Primary endpoints were 3-year overall survival (OS) rate and time-to-progression (TTP). Hazard ratios (HRs) from Kaplan–Meier curves were calculated to compare survival estimates. RESULTS The median OS was shorter in the cTACE group, but was not significantly different from the DEB-TACE group (33.9 versus 35.6 months, respectively; p=0.52). The mean TTP was shorter in the cTACE group than in the DEB-TACE group (13.9 versus 17.5 months, respectively; p=0.01). There was no difference in 3-year survival (HR=0.95, 95% confidence interval [CI]: 0.51–1.78; p=0.880) and TTP (HR=0.70, 95% CI: 0.42–1.16; p=0.147) between the groups; however, patients treated with DEB-TACE were more likely to have longer TTP in the first 2 years following treatment (HR=0.51, 95% CI: 0.29–0.88; p=0.009). CONCLUSION Although DEB-TACE is not superior in terms of TTP or OS in patients with large HCC, it may have greater efficacy in the first 24 months following therapy.

Neuregulin-1 (NRG1) ligand and its epidermal growth factor receptor (EGFR)/ERBB family regulate normal cellular proliferation and differentiation in many tissues including the cochlea. Aberrant NRG1 and ERBB signaling cause significant hearing impairment in mice. Dysregulation of the same signaling pathway in humans is involved in certain types of cancers such as breast cancer or non-small cell lung cancer (NSCLC). A new irreversible pan-ERBB inhibitor, canertinib, has been tested in clinical trials for the treatment of refractory NSCLC. Its possible ototoxicity was unknown. In this study, a significant dose-dependent canertinib ototoxicity was observed in a zebrafish model. Canertinib ototoxicity was further confirmed in two mouse models with different genetic backgrounds. The data strongly suggested an evolutionally preserved ERBB molecular mechanism underlying canertinib ototoxicity. Thus, these results imply that clinical monitoring of hearing loss should be considered for clinical testing of canertinib or other pan-ERBB inhibitors.

Process mining (PM) aims at extracting a process model from an event log to represent the process behavior recorded in that event log. An extracted process model with high fitness and precision means it can reflect most of the process behavior recorded in the event log (fitness) and will not generate extra behavior not recorded in the event log (precision). Most of the existing PM methods, such as the genetic process mining (GPM), focused only on the achievement of high fitness, but ignore the pursuit of high precision. This research presents a hybrid PM approach that integrates the GPM, particle swarm optimization, and differential evolution to extract process models with high fitness and precision (FP values) from event logs. The results show that the proposed approach achieves improvement in extracting process models from event logs with higher FP values.

The zebrafish lateral line can be used to identify small molecules that protect against cisplatin-induced hair cell death.Cisplatin is a commonly used chemotherapeutic agent, which causes hearing loss by damaging hair cells of the inner ear. There are currently no FDA-approved pharmacologic strategies for preventing this side effect. The zebrafish lateral line has been used successfully in the past to study hair cell death and protection.In this study, we used the zebrafish lateral line to screen a library of 10,000 small molecules for protection against cisplatin-induced hair cell death. Dose-response relationships for identified protectants were determined by quantifying hair cell protection. The effect of each protectant on uptake of a fluorescent cisplatin analog was also quantified.From this screen, we identified 2 compounds exhibiting dose-dependent protection: cisplatin hair cell protectant 1 and 2 (CHCP1 and 2). CHCP1 reduced the uptake of a fluorescent cisplatin analog, suggesting its protective effects may be due to decreased cisplatin uptake. CHCP2 did not affect uptake, which suggests an intracellular mechanism of action. Evaluation of analogs of CHCP2 revealed 3 additional compounds that significantly reduced cisplatin-induced hair cell death, although none exceed the effectiveness or potency of the parent compound.The zebrafish lateral line was used to identify 2 small molecules that protected against cisplatin-induced hair cell death.

A well-defined, light-responsive copolymer poly(spiropyrane)-block-poly(ethylene glycol) (PSP-b-PEG) was synthesized by RAFT polymerization. The final copolymer can self-assembled into spherical mi...

Developing next-generation cellular technology (5G) in the mm-wave bands will require low-cost phased-array transceivers [1]. Even with the benefit of beamforming, due to space constraints in the mobile form-factor, increasing TX output power while maintaining acceptable PA PAE, LNA NF, and overall transceiver power consumption is important to maximizing link budget allowable path loss and minimizing handset case temperature. Further, the phased-array transceiver will need to be able to support dual-polarization communication. An IF interface to the analog baseband is desired for low power consumption in the handset or user equipment (UE) active antenna and to enable use of arrays of transceivers for customer premises equipment (CPE) or basestation (BS) antenna arrays with a low-loss IF power-combining/splitting network implemented on an antenna backplane carrying multiple tiled antenna modules.

Pilot plant test campaigns can be expensive and time-consuming. Therefore, it is of interest to maximize the amount of learning and the efficiency of the test campaign given the limited number of experiments that can be conducted. This work investigates the use of sequential design of experiments (SDOE) to overcome these challenges by demonstrating its usefulness for a recent solvent-based CO2 capture plant test campaign. Unlike traditional design of experiments methods, SDOE regularly uses information from ongoing experiments to determine the optimum locations in the design space for subsequent runs within the same experiment. However, there are challenges that need to be addressed, including reducing the high computational burden to efficiently update the model, and the need to incorporate the methodology into a computational tool. We address these challenges by applying SDOE in combination with a software tool, the Framework for Optimization, Quantification of Uncertainty and Surrogates (FOQUS) (Miller et al., 2014a, 2016, 2017). The results of applying SDOE on a pilot plant test campaign for CO2 capture suggests that relative to traditional design of experiments methods, SDOE can more effectively reduce the uncertainty of the model, thus decreasing technical risk. Future work includes integrating SDOE into FOQUS and using SDOE to support additional large-scale pilot plant test campaigns.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses. The traditional antidepressants often take several weeks, even months, to obtain clinical effects. However, recent clinical studies have shown that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects within 2h and are long-lasting. The aim of the present study was to investigate whether dopaminergic system was involved in the rapid antidepressant effects of ketamine. The acute administration of ketamine (20 mg/kg) significantly reduced the immobility time in the forced swim test. MK-801 (0.1 mg/kg), the more selective NMDA antagonist, also exerted rapid antidepressant-like effects. In contrast, fluoxetine (10 mg/kg) did not significantly reduced the immobility time in the forced swim test after 30 min administration. Notably, pretreatment with haloperidol (0.15 mg/kg, a nonselective dopamine D2/D3 antagonist), but not SCH23390 (0.04 and 0.1 mg/kg, a selective dopamine D1 receptor antagonist), significantly prevented the effects of ketamine or MK-801. Moreover, the administration of sub-effective dose of ketamine (10 mg/kg) in combination with pramipexole (0.3 mg/kg, a dopamine D2/D3 receptor agonist) exerted antidepressant-like effects compared with each drug alone. In conclusion, our results indicated that the dopamine D2/D3 receptors, but not D1 receptors, are involved in the rapid antidepressant-like effects of ketamine.

Objective To report and compare medical, radiological, and audiological outcomes in pediatric cochlear implant recipients who underwent 1.5 and 3 Tesla strength MRI with and without retained magnet. Methods Retrospective chart review at a tertiary care pediatric hospital and review of literature. Patients were identified via electronic medical records database search and were included if they had MRI after cochlear implant. Results Of twelve instances of MRI in pediatric cochlear implant recipients at our institution, two minor complications and one major complication were recorded. The rate of complication was equal between patients who underwent MRI with and without retained magnet. All minor complications resulted from MRI with retained magnet whereas the only major complication resulted from magnet removal. Two novel complications are reported, including: magnet removal resulting in silastic tear necessitating reimplantation and magnet dislocation with spontaneous reduction. Magnet removal significantly decreased the size of artifact, but did not alter the diagnostic utility of the MRI. While audiological measures varied chronologically from MRI scans, they did not appear to be appreciably altered by MRI. Conclusion MRI with and without magnet retention appear to carry risks of both major and minor complications. For the regions of interest for each scan, MRI quality was not appreciably altered by magnet status. Audiological measures appear unaffected by magnet status during MRI however, this may reflect natural variation.

Background/aimsTo evaluate the efficacy and safety of individualised 2.0 mg intravitreal aflibercept retreatment for diabetic macular oedema (DME) through the fifth year of management.MethodsThis is a phase IV, 2-year, open-label extension study. Sixty patients completing the 3-year VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial enrolled in the ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study. All patients received aflibercept in the presence of clinically relevant DME. Intervals between visits were prescribed according to disease activity. The main outcome measure was mean aflibercept injections given through 2 years.ResultsA mean of 7.7 aflibercept injections were administered through 2 years. Fifteen (25%) patients required no retreatment and 48% (n=29) of patients received five or fewer injections through 2 years. Among patients who received at least one aflibercept retreatment during ENDURANCE, the mean number of injections through 2 years was 9.5. The mean visual acuity and central retinal thickness gains achieved during VISTA DME were maintained and stable during ENDURANCE. The most notable safety signal was progression of diabetic retinopathy. Six (10%) patients converted from non-proliferative to proliferative diabetic retinopathy (PDR), and a total of eight patients experienced PDR events occurring at a mean of 387 days following the previous aflibercept treatment.ConclusionThe need for aflibercept retreatment was substantially reduced in the fourth and fifth years of aflibercept dosing for DME following initiation of therapy in the VISTA DME trial. While vision gains achieved during the 3-year VISTA DME trial were maintained through ENDURANCE with a reduced treatment burden, clinically relevant worsening of diabetic retinopathy was observed with progression to PDR in 10% of the eyes.Trial registration numberNCT02299336

BACKGROUND AND OBJECTIVE: Longitudinal quantification of retinal nonperfusion (RNP) in eyes with retinal vein occlusion (RVO) undergoing anti-vascular endothelial growth factor therapy. PATIENTS AND METHODS: Thirty eyes with ischemic RVO were randomized to ranibizumab (Lucentis; Genentech, South San Francisco, CA) (monotherapy) or ranibizumab plus peripheral laser (combination therapy) in a 12-month, prospective trial. RNP on fluorescein angiography was quantified within the macula through 12 months of follow-up. RESULTS: Baseline mean macular RNP areas were 5.04 mm 2 and 8.30 mm 2 in the monotherapy (n = 5) and combination therapy (n = 15) cohorts, respectively. Through month 12, mean macular RNP area increased 0.36 mm 2 and 0.53 mm 2 in the monotherapy and combination therapy cohorts, respectively ( P = .77). Marked, progressive RNP was observed in three eyes (12%). No areas of reperfusion were detected in any eye. CONCLUSION: Among ischemic RVO eyes in WAVE, macular RNP was common at baseline and remained stable over time in most eyes, though marked RNP progression occurred in a minority of eyes. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:258–264.]

Background/AimsProspectively evaluate outcomes in the third year of neovascular age-related macular degeneration (AMD) management using ranibizumab with continued treat and extend (TREX) dosing compared with monthly visits with retreatment upon evidence of exudative disease activity (PRN, pro re nata).MethodsSubjects with treatment-naïve neovascular AMD were randomised 1:2 to Monthly or TREX and managed through 2 years. In the third year, subjects randomised to Monthly were managed PRN while subjects randomised to TREX were continued on TREX dosing or transitioned to PRN after achieving an interval of 12 weeks between visits.ResultsSixty subjects enrolled and 46 (77%) completed month 36 (M36). Transition from Monthly to PRN was associated with a decline in best corrected visual acuity (BCVA) (+10.5 letters (month 24) to +5.4 (M36, p=0.09)); three (15%) subjects required no dosing during year 3, and 47% (114/243) of possible PRN injections were delivered, yielding a mean of 6.1 injections during year 3. Among the 9 (23%) TREX subjects transitioned to PRN, the need for ongoing anti-vascular endothelial growth factor retreatments was small, with 4 (4%) intravitreal injections being delivered among 106 PRN visits; this subgroup displayed an inferior BCVA trajectory compared with the remainder of subjects. Outcomes among subjects continued on TREX were more favourable, with a mean gain of +5.0 letters at M36.ConclusionsUpon transition to PRN, subjects randomised to monthly dosing experienced a decline in BCVA. Among subjects initially randomised to TREX who transitioned to PRN after achieving a 12-week interval between visits, the overall need for additional treatment was low.Trial registration numberNCT01748292, Results.

To evaluate the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes and treatment burden in eyes with diabetic macular edema (DME).Phase I/II prospective, randomized, controlled clinical trial.Forty eyes of 29 patients with center-involved macular edema secondary to diabetes mellitus.Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3 mg ranibizumab (Lucentis, Genentech, South San Francisco, CA) or combination therapy with 0.3 mg ranibizumab and TRP guided by widefield fluorescein angiography. All eyes received 4 monthly ranibizumab injections followed by monthly examinations and pro re nata (PRN) re-treatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a 1-disc area margin in the combination therapy arm at week 1, with re-treatment at months 6, 18, and 25, if indicated.Mean change in ETDRS BCVA from baseline and number of intravitreal injections administered.At baseline, mean age was 55 years, mean BCVA was 20/63 (Snellen equivalent), and mean central retinal subfield thickness (CRT) was 530 μm. Thirty-four eyes (85%) completed month 36, at which point mean BCVA improved 13.9 and 8.2 letters (P = 0.20) and mean CRT improved 302 and 152 μm (P = 0.03) in the monotherapy and combination therapy arms, respectively. The mean number of injections administered through month 36 was 24.4 (range, 10-34) and 27.1 (range, 12-36), with 73% (362/496) and 80% (433/538) of PRN injections administered (P = 0.004) in the monotherapy and combination therapy arms, respectively. Goldmann visual field isopter III-4e area decreased by 2% and 18% in the monotherapy and combination therapy arms, respectively (P = 0.30).In this 3-year randomized trial of 40 eyes with DME, there was no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced treatment burden compared with ranibizumab alone.

Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion. This element also activates an internal exon when placed in a corresponding intronic position in a heterologous reporter. The impact of these two factors is further enhanced by high levels of RBM39, whose expression rises during erythroid differentiation as exon 16 inclusion increases. TIA1 and Pcbp1 associate in a complex containing RBM39, which interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point. Our results provide a mechanism for exon 16 3' splice site activation in which a coordinated effort among TIA1, Pcbp1, and RBM39 stabilizes or increases U2 snRNP recruitment, enhances spliceosome A complex formation, and facilitates exon definition through RBM39-mediated splicing regulation.