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Inorganic heteroanionic materials are attracting increasing attention for exploring new nonlinear optical (NLO) materials because they could better satisfy the necessary but conflicting properties of NLO crystals, e.g. large SHG response and wide band-gap. Up to now, the reports on heteroanionic NLO materials have mainly focused on ultraviolet or visible oxide-based fluoroborates, fluorophosphates, borate-phosphates and borate-iodates. However, chalcogenides containing different kinds of anionic groups have barely been reported. Herein, we have synthesized the first oxychalcogenide-carbonate, Sr

Oxychalcogenides with the performance-advantages of both chalcogenides and oxides are emerging materials class for infrared (IR) nonlinear optical (NLO) crystals that can expand the wavelength of solid-state lasers to IR regions and are of importance in industrial and civil applications. But rationally designing a high-performance oxychalcogenide NLO crystal remains a great challenge. Herein, we chose the melilite-type Sr

Introduction: We have recently reported that ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, reduced BP and was generally well tolerated in a single ascending dose study of hypertensive patients. To further assess its safety profile, additional studies have been initiated to test the effects of peak ALN-AGT pharmacology during salt depletion or irbesartan add-on treatment. Methods: As part of a Phase 1 program, hypertensive patients (mean seated SBP of >130 and ≤165 mm Hg after washout of antihypertensive medication) were given a single dose of ALN-AGT 800 mg SC that has been shown to reduce serum AGT by ≥95%. At Day 43 (corresponding to expected peak serum AGT reduction), these ALN-AGT-treated patients were admitted to receive interventions of a 7-day sodium restricted diet (10 mmol sodium day) or a 14-day add-on treatment regimen with the angiotensin receptor blocker irbesartan 300 mg by oral administration daily. Results: In the salt depletion cohort, 12 patients (mean age 56 years, 75% male, 25% black, mean baseline 24-h SBP 141+/- 8 mm Hg) have been dosed 2:1 with ALN-AGT or placebo SC in advance of the sodium restricted diet. In the irbesartan add-on cohort, 10 patients (mean age 55 years, 30% male, 30% black, mean baseline 24-h SBP 147 +/- 8 mm Hg) have received ALN-AGT in advance of irbesartan add-on. The study has completed patient enrollment and interventions with no patient discontinuations due to AEs. The data analysis is ongoing at the time of abstract submission. Conclusions: This ongoing study will provide insight into ALN-AGT tolerability during potential augmented pharmacology, using salt restriction to test ALN-AGT’s effects during reduced extracellular fluid volume and irbesartan coadministration to assess the effects of ALN-AGT’s liver-specific AGT silencing during angiotensin II receptor blockade. Data on tolerability, laboratory safety monitoring, serum AGT reduction, RAAS-related biomarkers, and blood pressure will be presented.

Introduction: ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, is being evaluated as a novel treatment for hypertension in a multicenter, randomized, placebo-controlled single ascending dose study. Here we present new data on the long-term pharmacodynamic and antihypertensive effects of ALN-AGT six months after single-dose administration. Methods: As part of a Phase 1 program to assess the safety and tolerability of ALN-AGT, hypertensive patients (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after a washout of antihypertensive medications) were randomized 2:1 to ascending single doses of ALN-AGT (10-800 mg) or placebo. Change from baseline BP was measured by ambulatory BP monitoring (ABPM) at Week 8, Week 12, and Month 6. Interim results as of May 28, 2021 are reported. Results: 84 hypertensive patients (mean age 53 years, 61% male, 26% black, mean (SD) baseline 24-h SBP 140 (9) mm Hg) were enrolled in ascending single dose cohorts of ALN-AGT up to 800 mg SC. Dose-dependent and durable reductions in serum AGT levels were observed, with single doses ≥100 mg achieving serum AGT reductions >90% and 24-h SBP reductions >10 mm Hg (17 mm Hg in the 800 mg cohort) through Week 12. The 24-hour ABPM profile of ALN-AGT-treated patients showed sustained reductions of daytime BP with equally marked nighttime BP reduction. Notably, new data from follow-up visits show that all patients who received a single dose of 800 mg maintained serum AGT reductions >90% from Week 3 to Month 6, with a mean (SD) 24-h SBP reduction of 22 (15) mm Hg at Month 6 (5 of 8 patients without add-on antihypertensive treatment). There were no treatment-related serious adverse events or clinically significant elevations in blood creatinine or potassium. No patient required intervention for hypotension. Conclusions: Single dose administration of ALN-AGT to hypertensive patients was generally well tolerated and resulted in profound reductions in serum AGT and BP through Month 6. The durable reduction of serum AGT >90% with sustained 24-hour BP reduction over a period of 6 months after single dose SC administration of ALN-AGT 800 mg supports further evaluation of both quarterly and biannual dose administration.

Background: Angiotensinogen (AGT) is the sole precursor of all angiotensin peptides and plays a key role in hypertension pathogenesis. We evaluated the effect of ALN-AGT01, a subcutaneous investigational RNAi therapeutic targeting hepatic AGT synthesis, on blood pressure in hypertensive patients. Methods: As part of a phase 1 program designed to assess the safety and tolerability of ALN-AGT01, we conducted a multicenter study randomizing patients aged 18-65 years with mild to moderate hypertension (mean seated systolic blood pressure [SBP] of >130 and ≤165 mmHg after washout of antihypertensive medication) 2:1 to ascending single doses of ALN-AGT01 or placebo. Change from baseline in BP at 8 weeks was measured by ambulatory BP monitoring (ABPM). We report interim results as of May 14, 2020. Results: Sixty patients (mean age 52 years, 45% female, mean baseline 24h SBP 139 +/- 7 mm Hg) were enrolled in ascending dose cohorts of 10 mg, 25 mg, 50 mg, 100 mg, or 200 mg. Dose-related reductions in serum AGT levels were observed (figure), with reductions >90% in the 100 and 200 mg dose cohorts. AGT remained durably reduced through 12 weeks after single dose administration. Concomitant reductions in BP from baseline were observed with AGT knockdown, with an over 10 mm Hg reduction of mean 24-hour SBP observed at Week 8 after single doses of 100 mg or 200 mg. No symptomatic hypotension, treatment-related serious adverse events, or clinically significant elevations in blood creatinine or potassium were seen. Conclusions: Single dose administration of ALN-AGT01 to hypertensive patients resulted in dose-related reductions in serum AGT and BP over 8 weeks without hypotension or other related serious adverse events. Durable AGT knockdown to 12 weeks supports further evaluation of once quarterly or potentially less frequent dose administration.

This paper studied the problem of signal coverage analysis of communication navigation and surveillance ground stations, analyzes the influence factors affecting radio signal transmission, including maximum range of the signal transmission, Line-of-Sight propagation model, terrain shelter, earth curvature, etc. A new methodology of general station coverage analysis is proposed, which reduces complex 3D spatial computation to 2D profile analysis. Key technologies are presented with the methodology, including elevation data extraction, spatial index construction, operating range model construction, terrain modification, coverage area extraction. Lastly, a station coverage impact evaluation system is developed authorship based WebGIS and the model. A field test is carried out by this system, and the results show that the proposed model has considerable practicability and generality and brings new thoughts to the development of signal coverage.

Background: ALKS 3831, a combination of olanzapine and samidorphan (OLZ/SAM), is in development for the treatment of schizophrenia and is intended to provide the antipsychotic efficacy of olanzapine while mitigating olanzapine-associated weight gain. We report the safety, tolerability, and efficacy of OLZ/SAM in patients with schizophrenia in a phase 3, 52-week, open-label extension study.Methods:Patients aged 18–70 years who completed a previous phase 3, 4-week, inpatient acute efficacy study were switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Study assessments included adverse events (AEs), weight, clinical laboratory testing, and Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S) scores.Results:281 patients were enrolled; 277 (mean age, 41.4 years) received ≥1 dose of study drug, and 183 (66.1%) completed the extension study. The most common reasons for discontinuation were withdrawal by patient (15.5%), loss to follow-up (6.9%), and AEs (5.8%). AEs were reported in 136 (49.1%) patients; most were mild in severity. The most common AEs were increased weight (13.4%), somnolence (8.3%), nasopharyngitis (4.0%), and headache (4.0%). Mean weight increase from baseline in patients completing 52 weeks of treatment was 1.86 kg, a 2.79% increase. No clinically significant changes in mean laboratory parameters were observed. Mean (SD) changes from baseline to week 52 in PANSS total score and CGI-S score were –16.2 (15.41) and –0.9 (0.92), respectively (both PDiscussion:OLZ/SAM was generally well tolerated with a safety profile that supports long-term treatment. During this 52-week extension study, there were improvements in schizophrenia symptoms.Funding Acknowledgements:This study was funded by Alkermes, Inc.

This article develops methods of statistical monitoring of clinical trials with multiple co-primary endpoints, where success is defined as meeting both endpoints simultaneously. In practice, a group sequential design (GSD) method is used to stop trials early for promising efficacy, and conditional power (CP) is used for futility stopping rules. In this article, we show that stopping boundaries for the GSD with multiple co-primary endpoints should be the same as those for studies with single endpoints. Lan and Wittes proposed the B-value tool to calculate the CP of single endpoint trials and we extend this tool to calculate the CP for studies with multiple co-primary endpoints. We consider the cases of two-arm studies with co-primary normal and provide an example of implementation with simulated trial. A fixed-weight sample size reestimation approach based on CP is introduced.

BACKGROUND: ALKS 3831, currently under development for the treatment of schizophrenia, is composed of a flexible dose of olanzapine and a fixed dose of 10 mg of samidorphan. Samidorphan is intended to mitigate weight gain associated with olanzapine treatment alone. Here, we report the safety, tolerability and efficacy of ALKS 3831 in subjects with schizophrenia that were enrolled in a phase 3, 52 week open-label extension study. Subjects had completed a phase 3, 4-week, double-blind, inpatient acute efficacy study of ALKS 3831 compared to olanzapine or placebo. METHODS: Subjects were switched from either ALKS 3831, olanzapine or placebo from the previous study to receive treatment with ALKS 3831 10/10 (10 mg olanzapine/10 mg samidorphan) as investigators were blinded to previous treatment. Subsequently, treatment could be increased to 15/10 or 20/10 at any time during the study at the discretion of the Investigator. Study assessments included adverse event monitoring, clinical laboratory testing, evaluation of extrapyramidal symptoms, PANSS and CGI-S rating scales (last observed on treatment visit), and weight (observed case). Sites were located in the United States, Ukraine, Serbia and Bulgaria. RESULTS: In total, 281 patients were enrolled in this extension study and 277 subjects received at least 1 dose of study drug with the majority of subjects being male (58.1%), a mean (SD) age of 41.4 (11.31) years, and white (78.7%). The baseline weight of all 277 subjects was 79.1 kg (SD=17.8 kg). A total of 183 (66.1%) subjects completed the treatment period. Overall, the most common reasons for early termination were withdrawal by subject (15.5%), lost to follow-up (6.9%) and adverse event (5.8%). 1.8% of subjects discontinued due to lack of efficacy. Treatment emergent adverse events (TEAEs) were reported in 136 (49.1%) subjects. Serious adverse events were reported in 8 (2.9%) subjects and none were considered related to study drug. No deaths were reported. Most of the TEAEs were mild in severity. The common TEAEs (≥4%) were weight increase (13%), somnolence (8%), nasopharyngitis (4%), and headache (4%). The mean weight increase from baseline was 2.79%. There was a statistically significant improvement in PANSS and CGI-S scores with a 14.0 (SE=1.11; p

Modalclust is an R package which performs Hierarchical Mode Association Clustering (HMAC) along with its parallel implementation over several processors. Modal clustering techniques are especially designed to efficiently extract clusters in high dimensions with arbitrary density shapes. Further, clustering is performed over several resolutions and the results are summarized as a hierarchical tree, thus providing a model based multi resolution cluster analysis. Finally we implement a novel parallel implementation of HMAC which performs the clustering job over several processors thereby dramatically increasing the speed of clustering procedure especially for large data sets. This package also provides a number of functions for visualizing clusters in high dimensions, which can also be used with other clustering softwares.

The number of modes (also known as modality) of a kernel density estimator (KDE) draws lots of interests and is important in practice. In this paper, we develop an inference framework on the modality of a KDE under multivariate setting using Gaussian kernel. We applied the modal clustering method proposed by [1] for mode hunting. A test statistic and its asymptotic distribution are derived to assess the significance of each mode. The inference procedure is applied on both simulated and real data sets.

We develop a mathematical and statistical framework to model the actions of underlying metabolites for carbon dioxide assimilation in photosynthesis. This study was motivated by a challenge posed by Syngenta Biotechnology to use modeling to better characterize photosynthesis in plants and subsequently better understand growth and crop yield. We use a dynamical system model proposed by Zhu., et al. [16], which describes the Calvin Cycle in spinach plants through changes in the concentrations of 38 metabolites (state variables) using non-linear enzyme kinetic ordinary differential equations and mass-balance laws that contain a total of 165 parameters. In our study of the CO2 assimilation rate, we pose our research questions with this dynamical system mathematical model and a statistical model to describe the observation process. In particular, we address the research question "Once a subset of parameters is fixed and the times at which data is collected are determined, can we identify which metabolites we should measure in order to optimize the confidence in our parameter estimates?" This problem of choosing the best subset of metabolites to measure is not well-explored in the existing literature. Here, we propose two methods. The first, the ad hoc Simple Linear Regression (SLR) method, models carbon assimilation as a linear function of the metabolites. Using simulated data, we implement a step-wise selection algorithm to determine the best subset of metabolites at each of 10 fixed time points. The second method, the Optimal Design Criterion method, fixes the number of metabolites to be observed and searches for the best combination by calculating a measure of the size of the Fisher Information Matrix (FIM) associated with measuring only the selected metabolites. Both methods suggest promise in determining appropriate sets of metabolites to observe for successful implementation of inverse problems. Our conclusions represent a paradigm for estimating parameters and designing experiments more efficiently in plant biological modeling. Ultimately, our results may be used to help engineer seeds that maximize carbon dioxide assimilation in photosynthesis and hence promote plant growth.

Alternative expressions for photoionization cross-sections and dielectric influence functions are suggested to study the photoionization cross-sections of atoms in solid system. The basic picture is that the photoionization cross-section of atoms in a real system can be described as the coupling between quantum quantity (QQ) and classical quantity (CQ) parts. The QQ part represents the photoionization cross-sections of an isolated particle, while the CQ part may represent most of the important influence of the macroscopic effects (e.g., the interactions of all surrounding polarized particles, and the dielectric property, etc.) on the photoionization cross-sections. The applications to the barium system show that the number-density-dependent new photoionization formula not only obtains the same cross-sections as those from the first order approximation for ideal gas, but also can generate the cross-sections for solid barium by transforming those of ideal gas of the same species using the dielectric influence function.

The differential cross sections and angular distribution parameter of the photoionization processes 2p 63s→ 2p 53skl of atomic Na have been calculated by using many-body perturbation theory. In the calculation, the resonant structure of the excitation process 2s→3p has been included. The electron correlation interaction was analyzed by using the effective diagram method. The summation of specific classes of these diagrams is to an infinite order. The results of calculations are compared with experimental data, which are in good agreement with the experiment.

With recent advances in technology, deep sequencing data will be widely used to further the understanding of genetic influence on traits of interest. Therefore not only common variants but also rare variants need to be better used to exploit the new information provided by deep sequencing data. Recently, statistical approaches for analyzing rare variants in genetic association studies have been proposed, but many of them were designed only for dichotomous outcomes. We compare the type I error and power of several statistical approaches applicable to quantitative traits for collapsing and analyzing rare variant data within a defined gene region. In addition to comparing methods that consider only rare variants, such as indicator, count, and data-adaptive collapsing methods, we also compare methods that incorporate the analysis of common variants along with rare variants, such as CMC and LASSO regression. We find that the three methods used to collapse rare variants perform similarly in this simulation setting where all risk variants were simulated to have effects in the same direction. Further, we find that incorporating common variants is beneficial and using a LASSO regression to choose which common variants to include is most useful when there is are few common risk variants compared to the total number of risk variants.

Based on the newly developed binary optics, a new kind of optics device used for laser beam mode transforming has been developed. This kind of binary optics device is worked with the principle of optical diffraction. It can be used to transform very efficiently the beam mode of high power laser of long wavelength. Using such a binary optics device of GaAs, a circle beam of high power CO 2 laser can be transformed into a line-shaped narrow beam with uniform power distribution. Using this device to do the treatments of laser hardening, alloying and cladding, the treating efficiency can be greatly increased. A very uniform strengthening layer in hardening depth, hardness and microstructure can be obtained. The tempenng effect, which will occur in the overlapped region when treating a large area with the common overlapping process, can be avoided.