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Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax-rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax-rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10-4 to be 57% (54-61%) and 63% (59-67%) at 12 and 24 months of treatment, respectively. Continued venetoclax treatment to 48 months only increased the predicted rate of negative BM MRD to 66% (63-70%). These results indicate that treatment with venetoclax-rituximab combination for a finite 2-year period would nearly maximize the rate of negative BM MRD (< 10-4 ). Preliminary clinical data agree with these predictions and more long-term follow-up data are awaited to confirm the same.

The field of plasmonics, which studies the resonant interactions of electromagnetic waves and free electrons in solid-state materials

We report enhanced second harmonic generation (SHG) from centrosymmetric bulk WSe2. This enhancement arises due to pumping in resonance with the Exciton-Polariton modes formed in self-hybridized bulk WSe2.

We demonstrate significant enhancement (> 40%) in valley coherence of localized excitons in monolayer WS2 via strain engineering. The observed enhancement is attributed to the suppression of inter valley scattering due to strain induced potential.

We demonstrate room-temperature ultralong-range transport >80 pm of exciton- polaritons in a disordered organic thin-film using a one-sided distributed Bragg reflector, which is orders of magnitude larger than expected for excitons in disordered systems.

The concept of modifying molecular dynamics in strongly coupled exciton-polariton systems is an emerging topic in photonics due to its potential to produce customized chemical systems with tailored photophysical properties. However, before such systems can be realized, it is essential to address the open questions concerning the nature and strength of electronic interactions between exciton-polaritons and localized excited states in chemical system as well as the proper way to measure such interactions. Here, we use transient optical spectroscopy to investigate dynamical interactions between exciton-polaritons, singlet excitons, and triplet excitons in a molecular singlet fission system that is strongly coupled to an optical microcavity. We identify some of the major limitations to modify molecular dynamics in the strong coupling regime. Simultaneous excitation of cavity polaritons and 'reservoir' states, defined as dark polaritons and dark excitons (e.g. triplets) from coupled molecules and excitons from uncoupled molecules, always occurs. In addition, slow conversion from reservoir states to cavity polaritons results in minimal changes to the overall population dynamics. Furthermore, we demonstrate how in addition to the usual population dynamics, transient optical measurements on microcavities reveal information pertaining to modification of the exciton-polariton transition energies due to changes in the population of molecular excited states and the exciton-photon coupling conditions. As a consequence of weak interactions between reservoir states and cavity polaritons, judicious design considerations are required to achieve modified chemical dynamics, necessitating the use of molecular systems with long excited-state lifetimes or strong coupling approaches that require a small number of molecules.

There is growing interest in using strongly coupled organic microcavities to tune molecular dynamics, including the electronic and vibrational properties of molecules. However, very little attention has been paid to the utility of cavity polaritons as sensors for out-of-equilibrium phenomena, including thermal excitations. Here, we demonstrate that non-resonant infrared excitation of an organic microcavity system induces a transient response in the visible spectral range near the cavity polariton resonances. We show how these optical responses can be understood in terms of ultrafast heating of electrons in the metal cavity mirror, which modifies the effective refractive index and subsequently the strong coupling conditions. The temporal dynamics of the microcavity are strictly determined by carriers in the metal, including the cooling of electrons via electron–phonon coupling and excitation of propagating coherent acoustic modes in the lattice. We rule out multiphoton excitation processes and verify that no real polariton population exists despite their strong transient features. These results suggest the cavity polaritons to be promising as sensitive probes of non-equilibrium phenomena.

We demonstrate valley dependent long-range propagation features in a polariton fluid formed via coupling WS2 excitons to Bloch surface waves at room temperatures.

Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. AbbVie in collaboration with Genentech/Roche.

Strong optical nonlinearities play a central role in realizing quantum photonic technologies. Exciton-polaritons, which result from the hybridization of material excitations and cavity photons, are an attractive candidate to realize such nonlinearities. While the interaction between ground state excitons generates a notable optical nonlinearity, the strength of such interactions is generally not sufficient to reach the regime of quantum nonlinear optics. Excited states, however, feature enhanced interactions and therefore hold promise for accessing the quantum domain of single-photon nonlinearities. Here we demonstrate the formation of exciton-polaritons using excited excitonic states in monolayer tungsten diselenide (WSe2) embedded in a microcavity. The realized excited-state polaritons exhibit an enhanced nonlinear response ∼$${g}_{{pol}-{pol}}^{2s} \sim 46.4\pm 13.9\,\mu {eV}\mu {m}^{2}$$ g p o l − p o l 2 s ~ 46.4 ± 13.9 μ e V μ m 2 which is ∼4.6 times that for the ground-state exciton. The demonstration of enhanced nonlinear response from excited exciton-polaritons presents the potential of generating strong exciton-polariton interactions, a necessary building block for solid-state quantum photonic technologies.

Color centers in wide bandgap semiconductors are attracting broad attention as platforms for quantum technologies relying on room-temperature single-photon emission (SPE), and for nanoscale metrology applications building on the centers' response to electric and magnetic fields. Here, we demonstrate room-temperature SPE from defects in cubic boron nitride (cBN) nanocrystals, which we unambiguously assign to the cubic phase using spectrally resolved Raman imaging. These isolated spots show photoluminescence (PL) spectra with zero-phonon lines (ZPLs) within the visible region (496-700 nm) when subject to sub-bandgap laser excitation. Second-order autocorrelation of the emitted photons reveals antibunching with $g^{2}$ ~ 0.2 and a decay constant of 2.75 ns that is further confirmed through fluorescence lifetime measurements. The results presented herein prove the existence of optically addressable isolated quantum emitters originating from defects in cBN, making this material an interesting platform for opto-electronic devices and quantum applications., 7 pages, 3 figures

We examine the directional characteristics of emission from a dipole on hyperbolic metamaterial (HMM) and we show the possibility of chiral emission which is strongly dependent on the polarization of the dipole. Using rigorous solutions of the Maxwell equations, we present analytical results on chirality which depends on the excitation of different evanescent modes in the HMM, some of which are easily accessible in current experiments. The origin of chirality lies in the near field interference of emission arising from parallel and perpendicular components of the dipole polarization especially if the two polarizations are out of phase by $\ensuremath{\pi}/2$. The dependence of chirality on the distance of the dipole from the HMM is obtained. The truly unidirectional emission is possible for some specific complex elliptic polarization of the dipole. Our analysis is based on the Green's function for the multilayered HMM. We also present results on chiral emission from emitters on metal surfaces. These results provide opportunities for controlling the excitation of the surface waves and can have potential applications in sensing molecules on HMM surfaces.

Use of software solutions as a medium for data collection, monitoring and tracking of any intervention program is increasing rapidly in real-world scenarios. In this paper, we present a case study on the use of text mining on data collected through a software system in place for tracking and monitoring industry-relevant skill training programs for the youth of rural India. Insights derived through text analysis of training data from various centers is presented. The limitations and future research potentials inferred from the data analysis are also discussed.

With the ever-increasing demand for portable electronic devices to provide longer battery life, extremely low pow-er consumption becomes an SoC design imperative. Aggressive SoC and system-level power management methods (PMM) are key to this drive towards low power consumption and extended battery life. These methods pose many challenges to the validation of the low-power states, SoC and system-level debug, and overall product time to market (TTM). This paper discusses techniques developed to address these SoC validation and debug challenges efficiently.

Strong light-matter coupling results in the formation of half-light half-matter quasiparticles that take on the desirable properties of both systems such as small mass and large interactions. Controlling this coupling strength in real-time is highly desirable due to the large change in optical properties such as reflectivity that can be induced in strongly coupled systems. Here we demonstrate modulation of strong exciton-photon coupling in a monolayer WS2 through electric field induced gating at room temperature. The device consists of a WS2 field effect transistor embedded inside a microcavity structure which transitions from strong to weak coupling when the monolayer WS2 becomes more n-type under gating. This transition occurs due to the reduction in oscillator strength of the excitons arising from decreased Coulomb interaction in the presence of electrostatically induced free carriers. The possibility to electrically modulate a solid state system at room temperature from strong to weak coupling is highly desirable for realizing low energy optoelectronic switches and modulators operating both in quantum and classical regimes.

Atomically thin transition metal dichalcogenides (TMDs) possess a number of properties that make them attractive for realizing room-temperature polariton devices. An ideal platform for manipulating polariton fluids within monolayer TMDs is that of Bloch surface waves, which confine the electric field to a small volume near the surface of a dielectric mirror. Here we demonstrate that monolayer tungsten disulfide ($\text{WS}_2$) can sustain Bloch surface wave polaritons (BSWPs) with a Rabi splitting of 43 meV and propagation constants reaching 33 $\mu$m. In addition, we evidence strong polariton-polariton nonlinearities within BSWPs, which manifest themselves as a reversible blueshift of the lower polariton resonance by up to 12.9$\pm$0.5 meV. Such nonlinearities are at the heart of polariton devices and have not yet been demonstrated in TMD polaritons. As a proof of concept, we use the nonlinearity to implement a nonlinear polariton source. Our results demonstrate that BSWPs using TMDs can support long-range propagation combined with strong nonlinearities, enabling potential applications in integrated optical processing and polaritonic circuits., Comment: 7 pages, 4 figures

Pain and anxiety are the two main reasons that contribute to the avoidance of dental care. Treating of such patients is stressful for the dentist which might ultimately results in the failure of the treatment, as regardless of practioner?s clinical skills, the dental treatment might become compromised without effective pain control system. The ability to provide excellent, high quality pain control in dentistry is required which is based on the practical knowledge of the clinically relevant aspects and updates about the recent advances in the field of topical and local anaesthesia. Knowledge of the local and topical anaesthetic agents and the ability of the clinicians to choose the best delivery methods has become a most important thing in today?s dentistry. Therefore, an attempt to compile the literature studies available on recent updates of local anaesthesia in general as well as pediatric dentistry is made for better understanding the procedure and its practical implications.

The control and enhancement of resonance energy transfer is highly desirable for a variety of applications ranging from solar cells to spectroscopic rulers. However, the process of direct resonance energy transfer is distance dependent and limited to ∼10 nm for typical donor–acceptor pairs. Here we demonstrate long-range (∼160 nm) direct energy transfer between donor quantum dots and acceptor dye molecules through the use of an optical topological transition (OTT) in a metamaterial. The OTT in a metamaterial, modifies the density of states between the donor and acceptor, resulting in the long-range energy transfer with transfer efficiency of ∼32%. Theoretical calculation based on master-equation formalism is used to model the system and is found to be in good agreement with the experimental observation. The use of OTTs in metamaterials to enhance and control energy transfer process can have wide array of potential applications ranging from organic solar cells to quantum entanglement.

The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations. Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations. The exposures [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (

The treatment of critical sized bone defect remains a significant challenge in orthopedics. The objective of the study is to evaluate the effect of the combination of bone morphogenetic protein 2 (BMP2) expressing genetically engineered mesenchymal stem cells (MSCs) [MSCs engineered using a multimam vector, pAceMam1, an emerging gene delivery vector] and an osteoconductive scaffold [silica coated nanohydroxyapatite-gelatin reinforced with fibers] in enhancing bone regeneration in critical sized segmental defects. The scaffold with transfected MSCs showed significantly higher viability, proliferation and osteogenic differentiation in vitro. Further, this group augmented union and new bone formation in critical sized rat femoral segmental defect at 12 weeks when compared to control groups (scaffold with MSCs and scaffold alone). These data demonstrated that the MSCs engineered for transient expression of BMP2 can improve the repair of segmental defects, which paves an avenue for using pAceMam1 as a vector for bone tissue regeneration.

The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations. The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis (‘non-cirrhotic’) and with compensated cirrhosis (‘cirrhotic’), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities. Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate–parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30–60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis.

Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug–drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) model was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co-administration with RTV. The magnitude and time course of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine’s plasma exposure by RTV diminishes by approximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV’s last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the reduced dose (2.5 mg QD) for 5 days after the last dose of RTV would increase daily average SBP by a maximum of 5.8 mmHg. Based on these results, either approach of resuming amlodipine’s full dose could be appropriate when combined with appropriate clinical monitoring. Electronic supplementary material The online version of this article (10.1007/s10928-018-9574-0) contains supplementary material, which is available to authorized users.

The study of single quantum objects embedded in confined electromagnetic environments is the main focus of the field of cavity quantum electrodynamics (CQED). According to a recent historical account by the 2012 Nobel laureate Sergei Haroche (1), the origins of this field can be traced back to the early days of quantum mechanics, with the famous debate between Albert Einstein and Niels Bohr concerning a gedankenexperiment about a photon in a box. While Einstein invoked the photon in a box as a theoretical construct, he might not have imagined that such a concept would reincarnate decades later into one of the favorite experimental playgrounds for scientists to test, explore, and control quantum mechanics. In fact, atoms in optical cavities have become one of the quintessential building blocks of contemporary quantum technologies, giving rise to high-fidelity sources of single photons, platforms to recreate effective photon–photon interactions, or even quantum simulators of many-particle systems. In recent years, an interdisciplinary outlook at the crossroads of CQED and chemistry termed “polariton chemistry” (2, 3) has emerged, which is centered around the question: Can materials change their chemical properties merely by being immersed in an optical cavity? Far-reaching consequences could follow if the answer to this question is positive, as one could potentially bypass time-consuming synthetic modifications of materials by harnessing CQED effects as an alternative. Indeed, much experimental (4⇓–6) and theoretical evidence (7⇓–9) points toward the fact that under certain circumstances, modifications to photochemical and ground-state kinetics, energy transfer, and charge transport are possible with the use of optical cavities. In PNAS, Schafer et al. (10) present compelling theoretical and computational evidence in support of these statements. Schafer et al. perform a study of a minimalistic quantum mechanical model which demonstrates that molecular excitation energy and charge-transfer … [↵][1]1To whom correspondence may be addressed. Email: jyuenzhou{at}ucsd.edu or vmenon{at}ccny.cuny.edu. [1]: #xref-corresp-1-1

Introduction: Heavy menstrual bleeding (HMB) is a type of abnormal uterine bleeding (AUB) that affects 30% of women of reproductive age and up to 40% of adolescents. Furthermore, 10-40% of adolescents with HMB have an underlying inherited bleeding disorder like von Willebrand disease or platelet dysfunction, requiring management by pediatric hematologists. HMB has been described as more than 80 ml of blood loss during one cycle and clinically, it is defined by several parameters such as the length of each cycle, severity of soaking through pads or tampons, size of clots passed and pictorial blood loss assessment chart (PBAC) score. Studies in adult women show a significant impact of HMB on their psychosocial and financial health. However, little is known about the psychological effects of HMB in adolescent females. In the adolescent population, depression is twice as common in females as it is in males, likely due to a combination of biological and social differences. In this study, we examine the association between heavy menstrual bleeding and depressive symptoms in adolescent girls. Methods: We conducted a retrospective records review of adolescent females aged 10-21 years that were seen as new patients at the Adolescent Medicine and Young Women's Bleeding Disorders clinics at our institution between January 1, 2018 and March 31, 2020. Patients were included in the study if they had started menses, and had a doumented menstrual history as well as a completed Patient Health Questionnaire (PHQ-9), a validated screening tool for depression.Patients with a severe underlying chronic medical disorder (Including but not limited to end stage renal disease, Juvenile Rheumatoid Arthritis, Systemic Lupus Erythematosis, severe eating disorder, previously diagnosed bipolar disorder or psychotic disorders) were excluded. HMB was determined by either a PBAC score of >100 or the presence of two or more of the following criteria: Menses lasting >7days Soaking through pad or tampon Soaking through bed clothes or changing pads at night Passing large clots Low ferritin < 15ng/ml (indicative of low iron stores) Anemia with Hemoglobin < 12g/dl not due to any other cause (e.g. dietary, immunosuppression, medication induced) Depression was determined by a PHQ-9 score of 9 or greater. The two variables were dichotomized, and a chi-square test of independence was performed to test the association with a significance level of p < 0.05. Results: A total of 203 records were reviewed after meeting inclusion and exclusion criteria. The mean age was 15.94 years (median 16, mode 16) with a range of 12-20years. 42 girls (20.7%) had a PHQ-9 score of >9 and 52 (25.6%) had HMB. Eighteen of the 42 patients (42.8%) with elevated PHQ-9 score had HMB and 34/52 patients (65.3%) with HMB had an elevated PHQ-9 score. Pearson's chi-square test of independence showed a significant relation between HMB and PHQ-9 score of 9 or more with χ 2 (1, n=203) = 8.2618, p = 0.004. After the application of Yates correction, the result was still significant with χ 2 = 7.1603 and p = 0.007. Discussion and Conclusions: This study shows a significant association in the adolescent population between heavy menstrual bleeding and moderate or severe depression as defined by the presence of a PHQ-9 score of 9 or more. This retrospective analysis does not establish causation, but demonstrates a clinically noteworthy finding that has not been described before. The PHQ-9 is used widely across this population to screen for depression, but it is also important to screen young women aged 10-21years for HMB as a contributing factor to depression followed by timely and appropriate management of both problems. Additionally, it may be worthwhile to evaluate all young women with HMB through additional methods to diagnose depression as this patient population appears to be at higher risk. Future prospective studies are needed to better characterize this association. Disclosures No relevant conflicts of interest to declare.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100 mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Efficient Forster resonant energy transfer is observed between excitons in a two-dimensional (2D) monolayer of the transition metal dichalcogenide, MoSe2, and an 2 nm thick layer of the organic material, 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA). The exciton transition dipoles are horizontally aligned, enabling efficient energy transfer between these dissimilar materials. Energy transfer is observed using time-resolved and steady state photoluminescence and photoluminescence excitation spectroscopy. Time-resolved measurements show a reduction in the donor (PTCDA) lifetime, and steady state emission experiments show a decrease in donor and an increase in acceptor (MoSe2) emission. Photoluminescence excitation spectra show a spectral dependence of the energy transfer process, with a maximum efficiency at the absorption maximum of the donor. The planar dipole orientation is determined using Fourier space imaging. The efficient energy transfer from low mobility organic materials to higher mobility...

Color centers in hexagonal boron nitride (hBN) are presently attracting broad interest as a novel platform for nanoscale sensing and quantum information processing. Unfortunately, their atomic structures remain largely elusive and only a small percentage of the emitters studied thus far have the properties required to serve as optically addressable spin qubits. Here, we use confocal fluorescence microscopy at variable temperatures to study a new class of point defects produced via cerium ion implantation in thin hBN flakes. We find that, to a significant fraction, emitters show bright room-temperature emission, and good optical stability suggesting the formation of Ce-based point defects. Using density functional theory (DFT) we calculate the emission properties of candidate emitters, and single out the CeVB center—formed by an interlayer Ce atom adjacent to a boron vacancy—as one possible microscopic model. Our results suggest an intriguing route to defect engineering that simultaneously exploits the singular properties of rare-earth ions and the versatility of two-dimensional material hosts.

Venetoclax is a first in class BCL-2 inhibitor that is approved for treatment of CLL and AML. It is currently under evaluation in other indications in adult and pediatric populations. Venetoclax is available as 10 mg, 50 mg, and 100 mg film-coated tablets. While the 100 mg tablet is most commonly used, the smaller size of the lower strength tablets is preferred by patients experiencing difficulty swallowing large tablets. Moreover, two powder formulations for suspension (0.72% and 7.2%) to be mixed with delivery vehicles were developed. In this abstract we present data from clinical studies that evaluated the bioavailability of the different venetoclax formulations relative to the commercially available 100 mg tablet. Three open-label, single-dose, crossover bioavailability studies in healthy female subjects were conducted. The first study evaluated the bioavailability of the commercially available 10 and 50 mg tablets relative to the 100 mg tablet. Forty subjects received a 100 mg dose of venetoclax (1x100 mg tablet, 2x50 mg tablets or 10x10 mg tablets) at the start of each period after a low-fat breakfast. The second study evaluated the bioavailability of the two powder formulations relative to the 100 mg tablet. Sixteen subjects received a 100 mg dose of venetoclax (1x100 mg film-coated tablet; 100 mg 0.72% powder formulation; 100 mg 7.2% powder formulation; and 4x25 mg dispersible tablets for oral suspension used in the Phase 1 study) in each of the 4 periods after a high fat breakfast. The third study evaluated the bioavailability of the two powder formulations when administered with different dosing vehicles relative to water. Twenty-four subjects (12 per cohort) received 100 mg of venetoclax (0.72% powder formulation or the 7.2% powder formulation) with either water, apple juice, apple sauce or yogurt in each of the 4 periods after a moderate fat breakfast. Bioavailability assessment of the commercial tablets demonstrated that ten 10 mg tablets were bioequivalent to one 100 mg tablet, two 50 mg tablets were bioequivalent to one 100 mg tablet, and two 50 mg tablets were bioequivalent to ten 10 mg tablets. The two powder formulations for oral suspension (0.72% and 7.2%) met the bioequivalence criteria (0.80-1.25) to the commercial 100 mg tablet with respect to AUCt and AUC∞, but the lower bound of the 90% CI of the Cmax extended slightly below 0.80. The delivery vehicles (water, apple juice, apple sauce and yogurt) did not affect the bioavailability of venetoclax 0.72% or 7.2% oral suspensions Citation Format: Mohamed Badawi, Bo Tong, Xin Chen, Tammy Palenski, Su Young Kim, Divya Samineni, David Hoffman, Rajeev Menon, Ahmed Hamed Salem. Clinical assessment of the bioavailability of venetoclax tablet and powder formulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 641.

Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF. Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2. References: Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222-e223. doi:10.3324/haematol.2018.213157 Beziat G, Gauthier M, Protin C, et al. Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep. 2020;8(2):269-273. Published 2020 Jan 10. doi:10.1002/ccr3.2580 Disclosures Salem: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Arrendale:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Nonreciprocal optical devices based on magneto-optical ferrites in their low-loss regimes have been widely investigated as a promising platform for integrated photonics. Nonreciprocity in such devices originates from circular birefringence, leading to frequency splitting of forward and backward modes and, as a result, nonreciprocal transmission. In this paper, we propose an alternative approach to realize nonreciprocal devices based on magneto-optical circular dichroism and relying on the very presence of optical absorption. Our approach relies on the phenomenon of spin-Hall effect of light, which gives rise to chiral near field interactions of light carrying transverse angular momentum with matter, which, in lossy regimes, yields a disparate absorption for forward and backward optical modes. As an example of practical application, we design an optical isolator based on ring resonator integrating Ce:YIG ferrite, and we demonstrate isolation near 880 nm absorption line due to the ionic electric dipole transition. A Ce:YIG film asymmetrically placed on the inner side of the ring yields different critical coupling conditions due to the chiral nature of evanescent light for forward and backward waves, leading to nonreciprocal absorption and transmission. The proposed approach to nonreciprocity may significantly broaden the possible choice of magneto-optical materials for nonreciprocal devices, enabling operation even in lossy regimes.

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.

Valley-polarized light–matter quasiparticles in two-dimensional semiconductor microcavities are demonstrated. Access to spin–valley physics may be useful for photonic quantum technologies. The formation of half-light half-matter quasiparticles under strong coupling results in properties unique from those of the constituent components. Fingerprints of both light and matter are imprinted on the new quasiparticles, called polaritons. In the context of two-dimensional (2D) materials, this opens up the possibility of exploiting the intriguing spin–valley physics of a bare semiconductor combined with the light mass of the photonic component for possible quantum technologies. Specifically, the valley degree of freedom1,2, which remained largely unexplored until the advent of these materials, is highly attractive in this context as it provides an optically accessible route for the control and manipulation of electron spin. Here, we report the observation of room-temperature strongly coupled light–matter quasiparticles that are valley polarized because of the coupling of photons with specific helicity to excitons that occupy quantum mechanically distinct valleys in momentum space. The realization of valley polaritons in 2D semiconductor microcavities presents the first step towards engineering valley-polaritonic devices.

Demonstration of clinical effectiveness of a non-Hodgkin's lymphoma (NHL) treatment generally involves determination of progression-free survival (PFS). However, the long evaluation time of PFS limits its utility to make timely decisions in drug development. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in NHL. A database was systematically developed from 513 identified NHL trials reported from 1996 to 2015. Potential predictors of the relationship between response rates and PFS were evaluated, including age, sex, treatment, percentage of treatment-naive patients, and subtype of NHL. Seventy-three trials involving 86 cohorts were included in the meta-analysis. Linear regression analysis using logit of response rates and logarithm of median PFS indicated that the correlation between overall response rate (ORR) and median PFS was higher (R2 = 0.70) when compared to that of complete response (CR) rate and median PFS (R2 = 0.57). Furthermore, the correlation was improved with the addition of percentage of treatment-naive patients and percentage of patients with follicular lymphoma (FL) (P

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C trough, paritaprevir C max, and ritonavir C max. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product’s labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C trough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.

We study the optoelectronic properties of a type-II heterojunction (HJ) comprising a monolayer of the transition metal dichalcogenide (TMDC), WS2, and a thin film of the organic semiconductor, 3,4,9,10-perylene tetracarboxylic dianhydride (PTCDA). Both theoretical and experimental investigations of the HJ indicate that Frenkel states in the organic layer and two-dimensional Wannier–Mott states in the TMDC dissociate to form hybrid charge transfer excitons at the interface that subsequently dissociate into free charges that are collected at opposing electrodes. A photodiode employing the HJ achieves a peak external quantum efficiency of 1.8 ± 0.2% at a wavelength of 430 ± 10 nm, corresponding to an internal quantum efficiency (IQE) as high as 11 ± 1% in these ultrathin devices. The photoluminescence spectra of PTCDA and PTCDA/WS2 thin films show that excitons in the WS2 have a quenching rate that is approximately seven times higher than in PTCDA. This difference leads to strong wavelength dependence in IQE.

All-oral direct-acting antiviral regimens that include combinations of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin were evaluated in hepatitis C virus-infected patients in phase II/III clinical studies. The objective of these analyses was to quantify the relationship between exposures of the components of the regimen and laboratory values and to determine covariates that could influence the relationship. Exposure–safety response relationships between individual components of the direct-acting antiviral regimens and clinically important laboratory values were explored using data from 2998 patients from 11 phase II/III clinical studies. Multivariate logistic regression analyses were used to identify significant relationships between predictor variables and response variables. No statistically significant associations were observed between ombitasvir, dasabuvir, or ritonavir exposures and maximum post-baseline alanine aminotransferase (ALT) or total bilirubin grade or minimum hemoglobin grade. A two-fold increase in paritaprevir exposure from therapeutic exposure was predicted to increase the probability of experiencing a grade 3 or higher increase in ALT by 0.5% and bilirubin by 1.1%. In the phase II/III clinical studies, ALT and bilirubin increases were reversible with continued dosing or after treatment cessation. Other correlates with adverse events of clinical importance included concomitant ribavirin treatment, sex, race, and presence of cirrhosis, consistent with previous observations. Exposure–response analyses from phase II/III studies with the combination direct-acting antiviral regimen indicated no statistically significant relationships with ombitasvir, dasabuvir, or ritonavir exposure, but a statistically significant association was observed between paritaprevir exposure and the probability of experiencing a grade 3 or higher increase in ALT or bilirubin.

ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727). Data from patients who received ABT-414 monotherapy at a dose of 1–4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia’s formula (QTcF). Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses ≥2 mg/kg, the estimated mean ∆QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure–response analysis showed no statistically significant relationship between ΔQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ∆QTcF value >30 ms. ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors.

We evaluated the performance of an early prototype core molecular mirroring nuclear magnetic resonance detection platform (Mentor-100) to detect toxigenic Clostridium difficile from stool. This technology uses customized nanoparticles bound to target specific oligonucleotide probes that form binaries in the presence of nucleic acid from the target microorganism. Liquid patient stool specimens were seeded with C. difficile or other Clostridium species to determine the analytical sensitivity and specificity. Samples underwent nucleic acid extraction and target amplification with probes conjugated with iron nanoparticles. Signal from nuclear magnetic resonance spin–spin relaxation time was measured to detect the presence or absence of toxigenic C. difficile. The limit of detection was

AbbVie's 3 direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with and without ribavirin is approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Safe and efficacious antiviral regimens resulting in minimal to no drug-drug interactions (DDIs) with antiretrovirals are needed to ensure that patients coinfected with HCV and the human immunodeficiency virus (HIV) achieve 12-week sustained virologic response rates similar to HCV-monoinfected patients. Also, the prevalence of injection drug use history is high in both monoinfected and HIV/HCV-coinfected patients. This review summarizes results from phase 1 DDI studies of the 3D regimen and antiretrovirals or drugs to treat substance abuse. Data suggest the 3D regimen is a viable option for HIV/HCV-coinfected patients on antiretroviral therapy containing tenofovir/emtricitabine, abacavir/lamivudine, dolutegravir, raltegravir, or atazanavir. HCV-infected patients receiving medications for substance abuse, particularly methadone or buprenorphine/naloxone, can also be treated with the 3D regimen.

Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that ombitasvir has a low potential for drug interactions.

Organizational- and departmental-level budgeting suffer from various shortcomings, such as asymmetric ratcheting. In this regard, we theorize, and propose, budgeting at the transaction-cycle level for effective budget designs. The transaction-cycle level budget requires management justification for resource assignment to business processes, often spanning multiple departments. The transaction-cycle typology consists of five cycles: production, expenditure, financial, revenue, and human-resources. In order to distinguish among transaction cycles, we use their relative positions within the value chain and technology content in their business processes. As a proof-of-concept, we develop theoretical arguments for asymmetric ratcheting in operating budgets at the transaction-cycle level in hospitals, and empirically examine this phenomenon using longitudinal archival data. Our hypotheses examine budgetary responses to overspending and underspending variances in operating budgets for fixed and variable costs. Our findings suggest that a transaction cycle's position in the value chain and its technology content play a role in determining asymmetric ratcheting during budgeting. We discuss our contributions from the perspectives of theory and practice of accounting, budgeting, and accounting information systems.