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Purpose: Aflibercept is a soluble decoy VEGF receptor and angiogenesis inhibitor with potent preclinical antitumor activity in melanoma. We conducted a multicenter phase II study in patients with inoperable stage III or IV melanoma and no prior chemotherapy.Experimental Design: A two-stage design was adopted to evaluate 4-month progression-free survival rate (PFSR) and response rate. Aflibercept was given at 4 mg/kg intravenously every 2 weeks. Response was assessed every 8 weeks. First-stage accrual of 21 patients was specified and with an adequate 4-month PFSR accrual continued to a total of 41.Results: Forty-one patients of ages 23 to 84 (median = 57) were enrolled. Thirty-nine had American Joint Committee on Cancer stage IV (5 M1a, 7 M1b, and 27 M1c) and 2 had inoperable stage IIIC (N3). Eastern Cooperative Oncology Group (ECOG) performance status was 0 (27 patients) or 1 (14 patients). Ten patients had primary uveal melanoma, 28 cutaneous, and 3 had unknown primaries. A median of 7 cycles were initiated (range: 1–56). Grade 3 and 4 toxicities included hypertension in 9 patients (22%) and proteinuria in 6 (15%). Among 40 patients evaluable for efficacy (those who initiated aflibercept), 3 (7.5%) had a confirmed partial response and 20 had progression-free survival of 4 months or above. The predicted 1-year survival rate derived from the Korn meta-analysis model is 36% (N = 39), whereas we observed a corresponding 56.4% survival rate at 1 year (95% CI, 43–74, P < 0.005). Median overall survival in this trial is 16.3 months (95% CI, 9.2 to not reached). We observed a significant association between severity of hypertension following aflibercept and survival improvement.Conclusions: Aflibercept showed promising activity in patients with metastatic melanoma of cutaneous or uveal origin. Further evaluation of aflibercept as a single agent and in combination is warranted. Clin Cancer Res; 17(20); 6574–81. ©2011 AACR.

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The transition of control between partially automated vehicles and drivers is an important part of the operational design domain and poses unique and important design issues. One approach for enhancing the design of the transition of control mechanisms is to predict driver behavior during a takeover by analyzing his/her state before a takeover. Although there is a wealth of existing literature on modeling the prediction of driver behavior, little is known about the prediction of takeover performance (e.g., driver error) and its underlying data structure (e.g., window sizes or the inclusion of certain features). Thus, the goal of this study is to predict driver error during a takeover event using supervised machine learning algorithms for various window sizes. Three machine learning algorithms (i.e., decision tree, random forest, and support vector machine with a radial basis kernel) were applied to granular driving performance, physiological, and glance data from a driving simulator experiment examining automated vehicle driving. The results showed that a random forest algorithm with an area under the receiver operating characteristic curve of 0.72, trained on a 3 s window before the takeover time, had the best performance with regard to classifying driver error accurately. In addition, we identified the 10 most important predictors that resulted in the best error prediction performance. The results of this study could be useful in developing algorithms for driver state that could be integrated into highly automated systems and, potentially, improve the takeover process.

Background Panic disorder (PD) is highly comorbid with major depressive disorder (MDD) with potential impact on patient-reported outcomes of quality of life (QOL), functioning, and depressive symptom severity. Methods Using data from the sequenced treatment alternatives to relieve depression (STAR*D) trial, we compared entry and post-SSRI-treatment QOL, functioning, and depressive symptom severity scores in MDD patients with comorbid PD (MDD+PD) to MDD patients without PD (MDDnoPD). We also compared pre- and posttreatment proportions of patients with severe impairments in quality of life and functioning. Results MDD+PD patients experienced significantly lower QOL and functioning and more severe depressive symptoms than MDDnoPD patients at entry. Following treatment with citalopram, both groups showed significant improvements, however, nearly 30–60% of patients still suffered from severe quality of life and functioning impairments. MDD+PD patients exited with lower QOL and functioning than MDDnoPD patients, a difference that became statistically insignificant after adjusting for baseline measures of depressive symptom severity, functioning, and QOL, comorbid anxiety disorders (PTSD, GAD, social, and specific phobias), age, and college education. Conclusions Functional outcomes using QOL and functioning measures should be utilized in treating and researching MDD so that shortfalls in traditional treatment can be identified and additional interventions can be designed to address severe baseline QOL and functioning deficits in MDD comorbid with PD.

A series of copolymers containing covalently attached benzophenone (BP) photo-cross-linkers were synthesized, and their UV-induced gelation was monitored as a function of the extent of BP conversion. For poly(methyl methacrylate) copolymers, the recombination yield between BP- and aliphatic-centered radicals was estimated and compared to that for dimerization of each species, directly confirming that the high gelation efficiencies observed for these copolymers arise due to the additional cross-linking pathways provided by covalently incorporated BP, as compared to doping with a small-molecule cross-linker. The placement of the hydrogen species most susceptible to abstraction by triplet benzophenone is found to greatly influence gelation efficiency, since radical generation on the polymer backbone typically increases the probability of dislinking events, while hydrogen abstraction pendent to the copolymer backbone tends to enhance cross-linking. Finally, the presence of atmospheric oxygen during photo-cros...

We have developed a simple, compact, high power, diode-pumped, intracavity frequency-doubled, Nd:Y3Al5O12 laser capable of generating output powers of up to 70 W at 10 kHz, and 16.5 W at 1 kHz. The output beam quality is highly multimode, with an M2∼30. This, combined with the short output pulse duration of 36–60 ns, and the high average power, makes this laser ideal for pumping ultrafast Ti:sapphire laser amplifier systems.

In this communication, we show that liquid crystalline phases lower the activation energy barrier for proton transport. The liquid crystalline phases were obtained using a triphenylene core with alkyl chains bearing a triazole moiety at their termini.

© 2015 The Academy of Psychosomatic Medicine. Background: Recently, the application of meditative practices to the treatment of depressive disorders has met with increasing clinical and scientific interest, owing to a lower side-effect burden, potential reduction of polypharmacy, and theoretical considerations that such interventions may target some of the cognitive roots of depression. Objective: We aimed to determine the state of the evidence supporting this application. Methods: Randomized controlled trials of techniques meeting the Agency for Healthcare Research and Quality definition of meditation, for participants having clinically diagnosed depressive disorders, not currently in remission, were selected. Meditation therapies were separated into praxis (i.e., how they were applied) components, and trial outcomes were reviewed. Results: 18 studies meeting the inclusion criteria were identified, encompassing 7 distinct techniques and 1173 patients. Mindfulness-Based Cognitive Therapy comprised the largest proportion of studies. Studies including patients having acute major depressive episodes (. n = 10 studies), and those with residual subacute clinical symptoms despite initial treatment (. n = 8), demonstrated moderate to large reductions in depression symptoms within the group, and relative to control groups. There was significant heterogeneity of techniques and trial designs. Conclusions: A substantial body of evidence indicates that meditation therapies may have salutary effects on patients having clinical depressive disorders during the acute and subacute phases of treatment. Owing to methodologic deficiencies and trial heterogeneity, large-scale, randomized controlled trials with well-described comparator interventions and measures of expectation are needed to clarify the role of meditation in the depression treatment armamentarium.

We present results on the amplifier performance and characteristics of Yb-doped Single Mode fiber amplifiers spanning a broad range of wavelengths from 1028 nm to 1100 nm. Both PM and non-PM amplifiers are discussed, with emphasis on the use of polarization controllers in intrinsically non-PM amplifiers to obtain high Polarization Extinction Ratios (PER). In general, outside the 1064nm region, there has been relatively little discussion or work towards developing high power fiber amplifiers for operation at either 1030 nm or 1100 nm with narrow line-width and high brightness, primarily due to amplifier design and architecture issues related to strong re-absorption and amplified spontaneous emission. Here we address key fiber and amplifier design characteristics aimed at mitigating these issues while highlighting performance attributes and challenges for operation near either end of the above defined spectral range.

Panic disorder (PD) is highly comorbid with major depressive disorder (MDD) with potential impact on patient-reported outcomes of quality of life (QOL), functioning, and depressive symptom severity.Using data from the sequenced treatment alternatives to relieve depression (STAR*D) trial, we compared entry and post-SSRI-treatment QOL, functioning, and depressive symptom severity scores in MDD patients with comorbid PD (MDD+PD) to MDD patients without PD (MDDnoPD). We also compared pre- and posttreatment proportions of patients with severe impairments in quality of life and functioning.MDD+PD patients experienced significantly lower QOL and functioning and more severe depressive symptoms than MDDnoPD patients at entry. Following treatment with citalopram, both groups showed significant improvements, however, nearly 30-60% of patients still suffered from severe quality of life and functioning impairments. MDD+PD patients exited with lower QOL and functioning than MDDnoPD patients, a difference that became statistically insignificant after adjusting for baseline measures of depressive symptom severity, functioning, and QOL, comorbid anxiety disorders (PTSD, GAD, social, and specific phobias), age, and college education.Functional outcomes using QOL and functioning measures should be utilized in treating and researching MDD so that shortfalls in traditional treatment can be identified and additional interventions can be designed to address severe baseline QOL and functioning deficits in MDD comorbid with PD.

OBJECTIVE Major depressive disorder (MDD) patients often experience impaired sexual satisfaction (ISS) and poor quality of life (QOL). Selective serotonin reuptake inhibitors (SSRIs), the first-line treatment for MDD, can cause sexual dysfunction, potentially worsening ISS and QOL. This study examined the impact of MDD and the SSRI citalopram on sexual satisfaction and QOL in level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (July 2001-September 2006). METHOD A retrospective analysis was conducted of the change in sexual satisfaction, as measured by item 9 of the Quality of Life Enjoyment and Satisfaction Questionnaire, the primary outcome measure, in 2,280 patients with DSM-IV-TR-defined MDD who were treated with citalopram for 12 weeks. The Quick Inventory of Depressive Symptomatology-Self Report was used to evaluate the impact of depression ratings on impaired sexual satisfaction and on QOL. RESULTS Impaired sexual satisfaction was present in 64.3% of MDD patients at pretreatment, but that percentage declined to 47.1% at posttreatment with citalopram (P < .0001). Those who achieved remission had less ISS and better QOL. The prevalence of ISS in remitters was 21.2% versus 61.3% in nonremitters (P < 10(-8)). The mean ± standard deviation score for remitters increased from 2.32 ± 1.16 to 3.44 ± 1.23 (P < 10(-8); Cohen d = 0.81 [large effect size]), whereas in nonremitters it increased only from 1.99 ± 1.08 to 2.19 ± 1.19 (P < 10(-8); Cohen d = 0.16). The difference between remitters and nonremitters was highly significant (P < 10(-8)). Regression analyses at pretreatment and posttreatment demonstrated significant associations between depressive symptoms and ISS (P < .0001) and between ISS and lower QOL (P < .0001) as well as an association between citalopram and increased probability of ISS and a poorer QOL in patients who continue to have moderate-to-severe depression. CONCLUSIONS A majority of MDD patients have impaired sexual satisfaction, a symptom associated with poor QOL. Despite the sexual side effects of the SSR citalopram, treating depression to full remission was associated with improvements in sexual satisfaction and QOL. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00021528.

Major depressive disorder (MDD) negatively impacts different aspects of an individual’s life leading to grave impairments in quality of life (QOL). We performed a detailed analysis of the interaction between depressive symptom severity, functioning, and QOL in outpatients with MDD in order to better understand QOL impairments in MDD. This cross-sectional study was conducted with 319 consecutive outpatients seeking treatment for DSM-IV-diagnosed MDD at an urban hospital-based outpatient clinic from 2005 to 2008 as part of the Cedars-Sinai Psychiatric Treatment Outcome Registry, a prospective cohort study of clinical, functioning, and patient-reported QOL outcomes in psychiatric disorders using a measurement-based care model. This model utilizes the following measures: (a) Depressive symptom severity: Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR); (b) Functioning measures: Global Assessment of Functioning (GAF), Sheehan Disability Scale (SDS), Work and Social Adjustment Scale, and the Endicott Work Productivity Scale; and (c) Quality of Life measure: Quality of Life, Enjoyment, and Satisfaction Questionnaire—Short Form (Q-LES-Q). QOL is significantly impaired in MDD, with a mean Q-LES-Q score for this study population of 39.8 % (SD = 16.9), whereas the community norm average is 78.3 %. Regression modeling suggested that depressive symptom severity, functioning/disability, and age all significantly contributed to QOL. QIDS-SR (measuring depressive symptom severity), GAF, and SDS (measuring functioning/disability) scores accounted for 48.1, 17.4, and 13.3 % (semi-partial correlation values) of the variance in Q-LES-Q, respectively. Our results show that impairment of QOL increases in a monotonic fashion with depressive symptom severity; however, depression symptom severity only accounted for 48.1 % of the QOL variance in our patient population. Furthermore, QOL is uniquely associated with measures of Functioning. We believe these results demonstrate the need to utilize not only Symptom Severity scales, but also Functioning and Quality of Life measures in MDD assessment, treatment, and research.

In this presentation we review the progress on amplification of narrow line-width signals to high power levels in fiber amplifiers using Large Mode Area (LMA) fibers.

Panic Disorder (PD) is a classic example of a disease where symptom remission may be achieved, yet patient quality of life (QOL) remains low, providing further support for the need to measure QOL as an additional outcome in patient care. The objectives of this review are to examine the substantial QOL impairments in PD and to determine whether modern treatments for PD, which have been proven to achieve symptom remission, have been shown to restore QOL.We identified studies on QOL in PD from 1980 to 2010 by searching MEDLINE, PsycINFO, and PubMed databases.The literature reveals substantial QOL impairments in PD, often resulting in poor sense of health, frequent utilization of medical services, occupational deficiency, financial dependency, and marital strife. Modern therapies have been demonstrated to achieve symptom remission and improve QOL in PD; however, post-treatment QOL is still significantly lower than community averages.QOL needs to be added as an essential outcome measure in patient care. Further research should be conducted to better understand the nature of comorbidities in PD as well as to determine whether additional interventions that have been studied in other psychiatric disorders, such as exercise, meditation, yoga, humor, massage, and nutritional supplements, can be utilized to improve QOL in PD to normal community levels.

We cover the advantages of resonantly pumped Ho-doped silica fibers operating at wavelengths >2.1μm, as compared with Tm-fibers and cover the recent progress in power scaling these results to high CW power levels.

Beam combining of fiber lasers has attracted much interest as a practical means to power scale fiber laser/amplifiers beyond the limitations of a single mode output from an individual fiber [1]. Almost all of the high power demonstrations to date that deliver good beam quality after the combing process (coherent and spectral) require some linewidth control for efficient combining, typically less than 10GHz [2,3,4]. Previously we demonstrated single mode, Yb-doped LMA fiber amplifiers operated with around 7GHz linewidth at 1kW output power [5]. In this paper, the latest generations of these amplifiers, based on the latest developments in LMA Yb-doped fiber technology demonstrate the capability to operate with linewidths around 3GHz at the 1kW power level. We present the latest data on optical properties of these new Yb-doped amplifiers and the SBS threshold as a function of input seed laser linewidth and discuss the technologies being developed to operate at higher power levels and narrower linewidths.

Transporting protons is essential in several biological processes as well as in renewable energy devices, such as fuel cells. Although biological systems exhibit precise supramolecular organization of chemical functionalities on the nanoscale to effect highly efficient proton conduction, to achieve similar organization in artificial systems remains a daunting challenge. Here, we are concerned with transporting protons on a micron scale under anhydrous conditions, that is proton transfer unassisted by any solvent, especially water. We report that proton-conducting systems derived from facially amphiphilic polymers that exhibit organized supramolecular assemblies show a dramatic enhancement in anhydrous conductivity relative to analogous materials that lack the capacity for self-organization. We describe the design, synthesis and characterization of these macromolecules, and suggest that nanoscale organization of proton-conducting functionalities is a key consideration in obtaining efficient anhydrous proton transport. Efficient conduction of protons on a micrometre scale is critical for the development of fuel cell membranes — a key component of clean energy sources. Now, self-assembling amphiphilic polymers have been shown to provide a nanoscale organization of proton-conducting functionalities that dramatically increases anhydrous proton conductivity.

Progress is being made developing monolithic, all-fiber 2μm wavelength devices that operate robustly at higher power levels. This development includes the critical Tm-doped LMA fiber technology, compatible components such as pump combiners and couplers, along with the optimization of high brightness, high efficiency 790nm pump diodes. In this paper we present recent CW power scaling results and demonstrate a monolithic MOPA system operating at 400W output power with around 20% E-O efficiency.

Scott Christensen is a research associate at the Thailand Development Research Institute (TDRI) in Bangkok. A doctoral candidate in political science at the University of Wisconsin at Madison, he is completing his doctoral dissertation on "State and Society in Thailand: Policymaking and the Politics of Economic Transformation, 1973-1991." Portions of this article are based on a larger study of Thai democracy supported by TDRI. Few expected that tensions between the armed forces and the civilian cabinet of Prime Minister Chatichai Choonhaven would lead to a military coup on 23 February 1991 and the fall of Thailand's first elected prime minister since 1976. The event suggests that despite the increasing presence of many "preconditions" for democracy--a dynamic economy, widespread political pluralism, literacy, and a more open society--Thailand has not been able to put a permanent end to authoritarian rule. The struggle for power between men in uniform and civilian politicians continues to play a major role in Thai politics. Although elites accept the principle of popular sovereignty, they differ among themselves on how best to distribute power equitably. The February coup reflects two distinguishing features that have shaped Thai democracy. The first is the relatively recent formation and consolidation of the Thai state. After the revolt against the hereditary monarchy in 1932, generals and the civil service ruled over and above any formal state institutions. Recently, however, state structures have been institutionalized, while the old elite has been challenged by professional politicians and public interest groups. Political competition has created an intense power struggle among these elites, new and old, for control of the infrastructure of the Thai state. ~ The second feature involves the ways in which agents of political change build coalitions among themselves and bargain with the old ruling elite. 2 Thai political parties have concentrated mostly on undermining and

The performance of a kilowatt-level, Yb-doped, fiber amplifier is reported. Monolithic design, excellent beam quality, polarization-maintaining capability, and high speed safety interlocks make this amplifier an ideal building block for high power beam combining experiments.

We demonstrate a simple and practical, single-stage, ultrafast laser amplifier system that operates at a repetition frequency from 1 to 10kHz, with millijoule pulse energy, and up to 13W average power.

What is the impact of mixing two proton-conducting heterocycles on proton conductivity? Herein we answer this question through our investigations on two linear rod-like compounds 2-(4-(dodecyloxy)phenyl)-1H-imidazole (4) and 5-(4-(dodecyloxy)phenyl)-1H-1,2,3-triazole (10). We have found that mixtures of molecules 4 and 10 at certain compositions show enhanced proton conductivity compared to their pure components. We attribute the increased conductivity in these materials to the increased charge density due to facile co-ionization and increased mobility due to the incorporation of long alkyl chains, which prevent crystallization of protogenic groups while maintaining the required hydrogen bonded network. Our results suggest a new strategy for enhancing intrinsic proton conductivity in heterocyclic systems.

In this communication, we introduce squaric acid derivatives as anhydrous proton conductors. We report the synthesis, characterization and proton conductivities of four squaric acid derivatives. The anhydrous proton conductivity of one of the derivatives was 2.3 × 10(-3) S cm(-1) at 110 °C, comparable to the conductivity of molten 1H-1,2,3-triazole or 1H-imidazole.

We demonstrate a high efficiency PM fiber amplifier delivering 20W output power and operating in conjunction with an external single frequency, seed source at 2037nm (linewidth ~100kHz). The system is not limited by SBS.