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Context: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia, hypercellular bone marrow, and dysplastic hematopoietic progenitors. Death is commonly caused by the effects of cytopenia, leading to infections or bleeding [1]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias. Objective: The objective was to develop a semi-mechanistic model of disease progression in MDS based on clinical data, involving relevant hematopoietic cells that can describe the effect of drug intervention with venetoclax azacitidine combination therapy. The model was subsequently used to simulate different treatment regimens (with respect to dose, dosing duration in a cycle, and number of cycles) and compare the outcomes. Study Design and Data: Data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax (400 mg or 800 mg for 28 days or 100 mg to 400 mg for 14 days in each 28-day cycle) with azacitidine (75 mg/m2 on days 1-7 of each cycle) in treatment-naive patients with higher-risk MDS were used for the analysis. The data contained venetoclax concentrations, neutrophil, red blood cell, and platelet count in the blood and blasts in the bone marrow. Methods: An integrated semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accounted for venetoclax PK and azacitidine treatment to describe time dynamics of neutrophils, red blood cells, and platelets. The model also included crowding in the bone marrow due to excess stem cells, MDS blasts, and progenitor cells, and its effect on hematopoiesis. Results: The model described the observed clinical data well and showed predictive ability across considered cell types. Complete remission (CR) and marrow complete remission (mCR) rates were predicted close to observed rates in the study. Simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are comparable to the expected outcomes from various dosing regimens. Conclusions: A model describing drug-disease interactions in MDS was developed that integrates multiple end points and differentiates disease driven from drug-induced cytopenia. Reference: [1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179. Disclosures: The analysis presented was funded by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. NT, JZ, RM, BE, JW, SM, and SG are employees of AbbVie and may hold stock. AHW receives honoraria from Novartis, Astellas, Pfizer, Macrogenics, Abbvie, Genentech, Servier, Celgene, Amgen, Astra Zeneca and Janssen. AHW also receives research funding from Novartis, Celgene, Abbvie, Servier, Astra Zeneca and Amgen. AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. G-GM is an investigator in AbbVie funded Clinical Trials. DM is a Genentech employee and may own stock. C.M. performed the analysis at AbbVie during an internship. C.M. also receives research funding from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grunenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and Sanofi) for the PharMetrX program

We report on the room-temperature single photon emission dynamics originating from defect states in hBN. Photo induced modification of the emission characteristics of thee defects under blue and green illumination is shown.

Aim To characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir, and dasabuvir) and adjunctive ribavirin and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. Methods Pharmacokinetic data from six phase 3 studies and one phase 2 study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 or 24 weeks were characterized using separate population pharmacokinetic models built using each component of the regimen from non-linear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Results The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, N = 2348) and ribavirin (N = 1841) adequately described their respective plasma-concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive performance. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, sex, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. Conclusion Population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase 3 and 2 HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen. This article is protected by copyright. All rights reserved.

The direct-acting antiviral regimen of 25 mg ombitasvir–150 mg paritaprevir–100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers ( n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration ( C max ) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean C max and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean C max and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

Item does not contain fulltext PURPOSE: Stable fixation of distal humerus fracture fragments is necessary for adequate healing and maintenance of reduction. The purpose of this study was to measure the reliability and accuracy of interpretation of postoperative radiographs to predict which implants will loosen or break after operative treatment of bicolumnar distal humerus fractures. We also addressed agreement among surgeons regarding which fracture fixation will loosen or break and the influence of years in independent practice, location of practice, and so forth. METHODS: A total of 232 orthopedic residents and surgeons from around the world evaluated 24 anteroposterior and lateral radiographs of distal humerus fractures on a Web-based platform to predict which implants would loosen or break. Agreement among observers was measured using the multi-rater kappa measure. RESULTS: The sensitivity of prediction of failure of fixation of distal humerus fracture on radiographs was 63%, specificity was 53%, positive predictive value was 36%, the negative predictive value was 78%, and accuracy was 56%. There was fair interobserver agreement (kappa = 0.27) regarding predictions of failure of fixation of distal humerus fracture on radiographs. Interobserver variability did not change when assessed for the various subgroups. CONCLUSIONS: When experienced and skilled surgeons perform fixation of type C distal humerus fracture, the immediate postoperative radiograph is not predictive of fixation failure. Reoperation based on the probability of failure might not be advisable. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III.

Spin-forbidden intravalley dark excitons in tungsten-based transition-metal dichalcogenides (TMDCs), because of their unique spin texture and long lifetime, have attracted intense research interest. Here, we show that we can control the dark exciton electrostatically by dressing it with one free electron or free hole, forming the dark trions. The existence of the dark trions is suggested by the unique magneto-photoluminescence spectroscopy pattern of the boron nitride (BN)-encapsulated monolayer WSe

Objective To evaluate distribution of hospital-level cancer diagnosis and treatment technologies along dimensions of racial residential segregation. Study design Cross-sectional analysis of residential segregation and availability of technologies associated with cancer diagnosis and treatment. Methods American Hospital Association data were merged with American Community Survey data, and hospital was the unit of analysis. Isolation index and Atkinson's index were calculated for racial residential segregation for the census tract in which the hospital is located based on the composite census block groups. Logistic regression was used to model presence of cancer technologies as a function of percent below poverty (scaled 1–10), number of neighboring hospitals, and rural status. Results Segregation measured by isolation index was associated with the availability of some technologies, independent of percentage below 125% poverty line, number of neighboring hospitals, and rural status. Diagnostic cancer technologies, such as CT scan (odds ratio [OR] = 0.928, 95% confidence interval [CI]: 0.894, 0.964), ultrasound (OR = 0.961, 95% CI: 0.927, 0.997), mammography (OR = 0.943, 95% CI: 0.914, 0.974), optical colonoscopy (OR = 0.932, 95% CI: 0.904, 0.961), and full-field digital mammography (OR = 0.948, 95% CI: 0.920, 0.977) and therapeutic cancer technology such as chemo therapy (OR = 0.963, 95% CI: 0.934, 0.992) appear to be less available in neighborhoods with higher isolation index. However, when segregation is measured by Atkinson's index, CT scan (OR = 1.064, 95% CI: 1.010, 1.121), ultrasound (OR = 1.087, 95% CI: 1.035, 1.141), mammography (OR = 1.094, 95% CI: 1.049, 1.141), and optical colonoscopy (OR = 1.053, 95% CI: 1.012, 1.095) are more available in neighborhoods with higher Atkinson's index. Conclusion These results suggest that cancer diagnostic capabilities in segregated areas are in the pathway between residential segregation and cancer treatment process, and future studies should evaluate individual-level associations.

Generation of an accurate humoral and a cell mediated adaptive immune responsesare dictated by binding of an antigen to a T- and a B-cell receptor, respectively (first signal) followed by ligation of costimulatory molecules (second signal). CD40, a costimulatory receptor molecule, expressed mainly on antigen presenting cells, some non-immune cells and tumors, binds to CD40 ligand molecule expressed transiently on T-cells and non-immune cells under inflammatory conditions. In the past decade, the CD40-CD40L interaction has emerged as an immune-potentiating system that governs and regulates host immune response against various diseases and pathogens, failing of which results in detrimental patho-physiologies including cancer and autoimmune disorders. CD40-CD40L transduces immune signals intracellularly via TRAF-dependent and independent mechanisms and further downstream by different MAPK pathways and transcription factors such as NF-κB, p38 etc. While CD40 signaling pathway through its cognate interaction between B and T cells promotes activation and proliferation of B-cells, Ig class switching, and generation of B cell memory; however, CD40-CD40L interaction involving other APCs and non-immune cells relay distinct cell signaling resulting in production of a variety of cytokines/chemokines and cell adhesion molecules ultimately conferring host defense against pathogen. In cancer and autoimmune disorders, CD40-CD40L interaction is also responsible for aberrant expression of many disease specific markers, class I/II MHC molecules and other co-stimulatory molecules such as B7 and CD28 in cell- and disease-specific manner. In the present review, the current state of understanding about the CD40-CD40L mediated regulation of immune and non-immune cells is presented. The current paradigm is to target CD40 using agonist anti-CD40 mAbs alone or in synergistic combination with chemotherapy in order to harness or confer anti-tumor and anti-inflammatory immunity.

Two-dimensional van der Waals (vdW) materials have emerged as a very attractive class of optoelectronic material due to the unprecedented strength in its interaction with light. Approaches to enhance this interaction even further using photonic structures such as microcavities and metamaterials is highly attractive for both fundamental investigations as well as for applications such as light emitting diodes and quantum technologies.

Background There is a need to understand structural issues, such as differential access to or utilization of technologies or capabilities, to better understand racial disparities in cancer outcomes. The objective of this work was to evaluate time-to-treatment and survival in relation to cancer-related diagnostic and treatment technologies of the diagnosing hospital. Methods Colorectal tumor-level data from George Cancer Registry was merged with hospital-level cancer technology data from the American Hospital Association (2010–2015). Cox proportional hazard models were used to model time-to-treatment and time-to-death following cancer diagnosis with cancer-related technologies for colon and rectosigmoid/rectal tumors, stratified by race and controlling for personal and tumor characteristics. Results Black individuals experienced lower likelihood of treatment (HR: 0.92, 95 % CI: 0.89, 0.96) for colon tumors, but not significantly different survival (HR: 1.03, 95 % CI: 0.98, 1.09). Larger capacity or size indicators (total surgical operations, emergency room visits, and licensed beds) were associated with higher likelihood of treatment in whites, but not blacks. Higher counts of treatment related technologies were associated with better survival in whites (HR = 0.92, 95 % CI: 0.85, 0.99), but not blacks (HR: 1.07, 95 % CI: 0.95, 1.19). Virtual colonoscopy emerged as a technology related to survival favorably in whites (HR: 0.84, 95 % CI: 0.77, 0.92) and blacks (HR: 0.89, 95 % CI: 0.79, 1.00). Overall results were similar for rectosigmoid/rectal tumors as observed for colon tumors. Conclusion The role of cancer-related technologies presence or utilization for colorectal cancer outcomes and potential racial disparities warrants further research.

Two-dimensional (2D) Van der Waals materials have emerged as a very attractive class of optoelectronic material due to the unprecedented strength in its interaction with light. In this talk I will discuss approaches to enhance and control this interaction by integrating these 2D materials with microcavities, and metamaterials. I will first discuss the formation of strongly coupled half-light half-matter quasiparticles (microcavity excitonpolaritons) [1], their spin-optic [2], and electrical control/excitation (Fig. 1) [3], in the 2D transition metal dichalcogenide (TMD) systems. Prospects for enhanced nonlinear optical interaction using Rydberg states in TMDs will be discussed. Use of photonic hypercrystals and hyperbolic media to enhance the spontaneous emission from the TMDs will also be presented. Following this, I will discuss the routing of valley excitons in 2D TMDs using chiral metasurfaces (Fig. 2) [4]. Finally, time permitting, I will briefly talk about developing deterministic quantum emitters at room temperature using defects in hexagonal boron nitride [5] and prospects of coupling these emitters to high Q resonators.

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Exciton polaritons that arise through the strong coupling of excitons and cavity photons are used to demonstrate a wide array of fundamental phenomena and potential applications that range from Bose-Einstein-like condensation

Optical waveguides are vital components of data communication system technologies, but their scaling down to the nanoscale has remained challenging despite advances in nano-optics and nanomaterials. Recently, we theoretically predicted that the ultimate limit of visible photon guiding can be achieved in monolayer-thick transition metal dichalcogenides. Here, we present an experimental demonstration of light guiding in an atomically thick tungsten disulfide membrane patterned as a photonic crystal structure. In this scheme, two-dimensional tungsten disulfide excitonic photoluminescence couples into quasi-guided photonic crystal modes known as resonant-type Wood’s anomalies. These modes propagate via total internal reflection with only a small portion of the light diffracted to the far field. Such light guiding at the ultimate limit provides more possibilities to miniaturize optoelectronic devices and to test fundamental physical concepts. A monolayer WS2 membrane patterned as a photonic crystal sustains guided optical modes that propagate via total internal reflection.

In this talk we will discuss our recent work on electrical and optical control of strongly-coupled exciton-polaritons in two-dimensional Van der Waals materials. The possibility to optically address the valley degree of freedom of polariton states via optical excitation will be discussed [1]. Following this we will discuss the modulation of coupling strength between excitons and photons in a microcavity via electric field [2]. The possibility to enhance the nonlinear optical response of the polariton states by exploiting the higher order Rydberg states will also be presented. Finally, we will discuss the realization of room temperature quantum emitter array using strain engineered hexagonal boron nitride and coupling them to high quality factor resonators [3]. [1] Optical control of room temperature valley polaritons, Z. Sun, et al., Nature Photonics 11, 491 (2017). [2] Control of strong light-matter interaction in monolayer WS2 through electric field gating, B. Chakraborty et al., Nano. Lett. (2018) DOI: 10.1021/acs.nanolett.8b02932 [3] Near-deterministic activation of room temperature quantum emitters in hexagonal boron nitride, N. Proscia et al. Optica (In Press) [ArXiv: 1712.01352 ]

Hand written documents are one of the most important sources of writing media in ancient Kerala. Due to improper storage of manuscripts, about 80% of them got degraded. Noises are one of the most common degrading factor which affects the visibility of the images and makes them unclear. The main noises found in manuscripts are pepper salt noise, speckle noise and holes on billings etc. There are many denoising methods available. In this paper we have made a literature analysis, both basic and advanced algorithms. Finally compared the output of each methods, Gibbs Sampling technique gives more accurate output in handwritten manuscripts. But holes in documents were not removed. For this we have given an enhancement using Circle Hough Transform(CHT) Which detects the circles and can identify exact hole by comparing the boundary pixels of circle and background of the script. In future we can recognize the characters using Support Vector Machine(SVM) and H2istogram of orientation Gradients(HOG).

We demonstrate coupling of hBN defect emission to Si3N4 microdisk cavities and high-Q plasmonic surface lattice resonances by exploiting the topography of the photonic elements to engineer strain-activated color centers within the element’s field-mode.

Half-light half-matter quasiparticles termed exciton-polaritons arise through the strong coupling of excitons and cavity photons. They have been used to demonstrate a wide array of fundamental phenomena and potential applications ranging from Bose-Einstein like condensation to analog Hamiltonian simulators and chip-scale interferometers. Recently the two dimensional transition metal dichalcogenides (TMDs) owing to their large exciton binding energies, oscillator strength and valley degree of freedom have emerged as a very attractive platform to realize exciton-polaritons at elevated temperatures. Achieving electrical injection of polaritons is attractive both as a precursor to realizing electrically driven polariton lasers as well as for high speed light-emitting diodes (LED) for communication systems. Here we demonstrate an electrically driven polariton LED operating at room temperature using monolayer tungsten disulphide (WS2) as the emissive material. To realize this device, the monolayer WS2 is sandwiched between thin hexagonal boron nitride (hBN) tunnel barriers with graphene layers acting as the electrodes. The entire tunnel LED structure is embedded inside a one-dimensional distributed Bragg reflector (DBR) based microcavity structure. The extracted external quantum efficiency is ~0.1% and is comparable to recent demonstrations of bulk organic and carbon nanotube based polariton electroluminescence (EL) devices. The possibility to realize electrically driven polariton LEDs in atomically thin semiconductors at room temperature presents a promising step towards achieving an inversionless electrically driven laser in these systems as well as for ultrafast microcavity LEDs using van der Waals materials.

Cooperative phenomena stemming from radiation-field-mediated coupling between individual quantum emitters are presently attracting broad interest for on-chip photonic quantum memories and long-range entanglement. Common to these applications is the generation of electromagnetic modes over macroscopic distances. Much research, however, is still needed before such systems can be deployed in the form of practical devices, starting with the investigation of alternate physical platforms. Quantum emitters in two-dimensional (2D) systems provide an intriguing route because these materials can be adapted to arbitrarily shaped substrates to form hybrid systems where emitters are near-field-coupled to suitable optical modes. Here, we report a scalable coupling method allowing color center ensembles in a van der Waals material - hexagonal boron nitride - to couple to a delocalized high quality plasmonic surface lattice resonance. This type of architecture is promising for photonic applications, especially given the ability of the hexagonal boron nitride emitters to operate as single-photon sources at room temperature., Comment: 8 pages, 4 Figures

India has a long history of monuments built in stone—from prehistoric megaliths to later religious monuments like stupas, temples etc. covering a period of nearly four millennia. In this paper we discuss the influence of astronomy on the design and layout of some of these monuments, as well as depiction and incorporation of astronomical objects and phenomena in several of these or their components. In several instances, prehistoric rock art features Sun and Moon motifs, which are also seen in later sculptural art in temples, hero stones, etc.

With so much emphasis on reducing attrition and becoming more efficient in the delivery of healthcare, there are many opportunities to leverage existing clinical data in drug development and to foster the practice of reverse translation. The application of quantitative approaches to convert clinical trial and real‐world data to knowledge will continue to drive innovation. Herein we discuss recent examples of reverse translation and consider future opportunities to capture critical clinical knowledge to inform decision‐making in drug development.

Pediatric drug development is a challenging process due to the rarity of the population, the need to meet regulatory requirements across the globe, the associated uncertainty in extrapolating data from adults, the paucity of validated biomarkers, and the lack of systematic testing of drugs in pediatric patients. In oncology, pediatric drug development has additional challenges that have historically delayed availability of safe and effective medicines for children. In particular, the traditional approach to pediatric oncology drug development involves conducting phase 1 studies in children once the drug has been characterized and in some cases approved for use in adults. The objective of this article is to describe clinical pharmacology factors that influence pediatric oncology trial design and execution and to highlight efficient approaches for designing and expediting oncology drug development in children. The topics highlighted in this article include (1) study design considerations, (2) updated dosing approaches, (3) ways to overcome the significant biopharmaceutical challenges unique to the oncology pediatric population, and (4) use of data analysis strategies for extrapolating data from adults, with case studies. Finally, suggestions for ways to use clinical pharmacology approaches to accelerate pediatric oncology drug development are provided.

The key objective of utilizing sustainable energy in a developing country like India is to enhance economic growth and development, energy security, access to clean energy and to alleviate environmental problems. Sustainable growth of a nation is possible only through the adoption of renewable energy technologies and by providing access to these technologies to all the citizens. This paper discusses how the product attributes described by Rogers’ theory of innovation of diffusion such as the relative advantage of technology, compatibility, complexity, observability, and trialability influence consumer’s intention to diffuse solar panels. A questionnaire survey consisting of 23 questions has been designed and it was administered to 63 adopters of solar panels in the Thrissur district of Kerala. After the collection of data, reliability test and factor analysis were conducted for determining the reliability and validity of the questionnaire. Multiple regression analysis was conducted to determine the relationship between the purchase intention of customers with five sub-factors under product attributes as specified by Rogers’ theory of innovation diffusion. The results obtained from the analysis showed that compatibility and trialability of a product significantly influence the intention to purchase the solar panels.

The robust spin and momentum valley locking of electrons in two-dimensional semiconductors makes the valley degree of freedom of great utility for functional optoelectronic devices. Owing to the difference in optical selection rules for the different valleys, these valley electrons can be addressed optically. The electrons and excitons in these materials exhibit the valley Hall effect, where the carriers from specific valleys are directed to different directions under electrical or thermal bias. Here we report the optical analog of valley Hall effect, where the light emission from the valley-polarized excitons in a monolayer W S 2 propagates in different directions owing to the preferential coupling of excitonic emission to the high momentum states of the hyperbolic metamaterial. The experimentally observed effects are corroborated with theoretical modeling of excitonic emission in the near field of hyperbolic media. The demonstration of the optical valley Hall effect using a bulk artificial photonic media without the need for nanostructuring opens the possibility of realizing valley-based excitonic circuits operating at room temperature.

Sub-wavelength nanostructured systems with tunable electromagnetic properties, such as hyperbolic metamaterials (HMMs), provide a useful platform to tailor spontaneous emission processes. Here, we investigate a system comprising $Eu^{ 3+}(NO_{3})_{3}6H_{2}O$ nanocrystals on an HMM structure featuring a hexagonal array of Ag-nanowires in a porous $Al_{2}O_{3}$ matrix. The HMM-coupled $Eu^{ 3+}$ ions exhibit up to a 2.4-fold increase of their decay rate, accompanied by an enhancement of the emission rate of the $^{ 5}D_{0}\rightarrow$ $^{ 7}F_{2}$ transition. Using finite-difference time-domain modeling, we corroborate these observations with the increase in the photonic density of states seen by the $Eu^{ 3+}$ ions in the proximity of the HMM. Our results indicate HMMs can serve as a valuable tool to control the emission from weak transitions, and hence hint at a route towards more practical applications of rare-earth ions in nanoscale optoelectronics and quantum devices.

Introduction: Venetoclax (VEN), an orally bioavailable selective BCL-2 inhibitor, was granted accelerated approval by the FDA for the treatment of acute myeloid leukemia (AML) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships using data from the nonrandomized Phase 1/2 studies and the confirmatory Phase 3 studies in subjects with treatment-naïve AML who are ineligible for intensive chemotherapy. Methods: A population pharmacokinetic (PK) model for VEN was characterized using data from 771 AML subjects across 5 Phase 1 - 3 studies including subjects with relapsed/refractory AML and subjects with treatment-naïve AML who were ineligible for intensive chemotherapy. PK parameters from this model were used to calculate the exposure metric, the area under the plasma concentration-time curve at steady-state (AUCss), for exposure-efficacy and exposure-safety analyses. Logistic regression and Cox proportional-hazards models were used to characterize the exposure-response relationships for overall survival, event-free survival, and conversion to post-baseline transfusion independence for red blood cells or platelets as well as key safety endpoints of treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, and infections. Additionally, best overall response of complete remission (CR), CR + CR with incomplete blood count recovery (CRi), and CR + CR with partial hematological recovery (CRh) were also characterized in the exposure-response analyses. Separate analyses were performed for VEN + HMA and VEN + LDAC, including subjects taking placebo (PBO) + HMA or PBO + LDAC, respectively, to inform the intercepts. A total of 575 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + HMA and 279 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + LDAC. Results: VEN + HMA: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + HMA as compared to PBO in combination with azacitidine (AZA). When PBO patients were included, significant exposure-response relationships between VEN exposure and overall survival and event-free survival were identified, and a maximal effect (Emax) model best described the statistically significant positive relationships between VEN exposure and best overall response of CR + CRi and CR + CRh. However, there were no apparent relationships between VEN exposure and any efficacy endpoint without the inclusion of PBO subjects, suggesting that the beneficial effect of VEN is already maximized in the dose range studied (400 to 1200 mg daily [QD]). No exposure-response relationship was identified between VEN exposure and treatment-emergent Grade ≥ 3 thrombocytopenia or infections. An Emax model best described the statistically significant relationship between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, consistent with the clinical finding that subjects in the VEN + HMA treatment arms had higher rates of reported neutropenia than those in the PBO + AZA arm. VEN + LDAC: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + LDAC as compared to PBO + LDAC. With PBO subjects included, an Emax model best described the statistically significant relationships between VEN exposure and best overall response of CR, CR + CRi, and CR + CRh, with probability of response plateauing at exposures corresponding to 600 mg QD of VEN. There were no apparent relationships between VEN exposure and any efficacy endpoint when the PBO subjects were excluded from analysis, indicating that the beneficial effect of VEN is already maximized at 600 mg QD. Although reported rates of treatment-emergent Grade ≥ 3 neutropenia were higher in the VEN + LDAC treatment arms as compared to PBO + LDAC, no significant exposure-response relationships were found between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, or infections. Conclusion: The VEN exposure-efficacy and exposure-safety analyses confirm the benefit of adding VEN to either HMA or LDAC and support the dose regimens of VEN 400 mg QD in combination with an HMA and VEN 600 mg QD in combination with LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy. Disclosures Eckert: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Smith:Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy. Wei:AbbVie Inc.: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding. Hayslip:Abbvie Inc: Current Employment, Other: may hold stock or other options. Miles:Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Mensing:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Zha:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

The low quantum yield observed in two-dimensional semiconductors of transition metal dichalcogenides (TMDs) has motivated the quest for approaches that can enhance the light emission from these systems. Here, we demonstrate broadband enhancement of spontaneous emission and increase in Raman signature from archetype two-dimensional semiconductors: molybdenum disulfide (MoS2) and tungsten disulfide (WS2) by placing the monolayers in the near field of a photonic hypercrystal having hyperbolic dispersion. Hypercrystals are characterized by a large broadband photonic density of states due to hyperbolic dispersion while having enhanced light in/out coupling by a subwavelength photonic crystal lattice. This dual advantage is exploited here to enhance the light emission from the 2D TMDs and can be utilized for developing light emitters and solar cells using two-dimensional semiconductors.

The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles. The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens. Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure. DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study. The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.

The Communist Party of India (CPI) adopted a revolutionary line in 1948, but agrarian insurrection was efficiently suppressed by the newly independent Indian state. The CPI moved towards an engagement with parliamentary communism, and in 1957, Kerala became the first state in the world to elect a communist government to power. However, the idea of transformative, revolutionary violence stayed alive and became the premise for brutal internecine warfare between the Left and its opponents in the northern part of Kerala. This paper argues, pace Benjamin, that this violence must be seen as instituting another law than that of the state, positing the ideal of justice over the mere rhythms of parliamentary representation.

Surface-enhanced Raman scattering (SERS) is commonly associated with noble metal substrates. However, over the years modest Raman enhancements ( 3 × 105 enhancement in SERS signal from an organic molecule (4-mercaptopyridine) placed in the near field of a two-dimensional semiconductor molybdenum disulfide (MoS2) monolayer. This large enhancement in the SERS signal is attributed to the charge transfer (CT) state formed at the interface of the 2D semiconductor and organic molecule and is found to occur when the excitation source is chosen to be in resonance with the CT state. This approach provides a new strategy for carrying out SERS experiments on molecules with very weak Raman sig...

Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [(14)C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [(14)C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steady-state concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug.