Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial.

BACKGROUND: Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. The proof-of-concept study ORION-2 (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. METHODS: ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. RESULTS: The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. CONCLUSIONS: Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03851705.

A Choline-Based Antifreezing Complexing Agent with Selective Compatibility for Zn-Br2 Flow Batteries.

The high freezing point of polybromides, charging products, is a significant obstacle to the rapid development of zinc-bromine flow batteries (Zn-Br2 FBs). Here, a choline-based complexing agent (CCA) is constructed to liquefy the polybromides at low temperatures. Depending on quaternary ammonium group, choline can effectively complex with polybromide anions and form dense oil-phase that has excellent antifreezing property. Benefiting from indispensable strong ion-ion interaction, the highly selectively compatible CCA, consisting of choline and N-methyl-N-ethyl-morpholinium salts (CCA-M), can be achieved to further enhance bromine fixing ability. Interestingly, the formed polybromides with CCA-M are able to keep liquid even at -40 °C. The CCA-M endows Zn-Br2 FBs at 40 mA cm-2 with unprecedented long cycle life (over 150 cycles) and high Coulombic efficiency (CE, average ≈98.8%) at -20 °C, but also at room temperature (over 1200 cycles, average CE: ≈94.7%). The CCA shows a promising prospect of application and should be extended to other antifreezing bromine-based energy storage systems.

3D-Printed Biomimetic Structural Colors.

Resolution control and expansibility have always been challenges to the fabrication of structural color materials. Here, a facile strategy to print cholesteric liquid crystal elastomers (CLCEs) into complex structural color patterns with variable resolution and enhanced expansibility is reported. A volatile solvent is introduced into the synthesized CLC oligomers, modifying its rheological properties and allowing direct-ink-writing (DIW) under mild conditions. The combination of printing shear flow and anisotropic deswelling of ink drives the CLC molecules into an ordered cholesteric arrangement. The authors meticulously investigate the influence of printing parameters to achieve resolution control over a wide range, allowing for the printing of multi-sized 1D or 2D patterns with constant quality. Furthermore, such solvent-cast direct-ink-writing (DIW) strategy is highly expandable and can be integrated easily into the DIW of bionic robots. Multi-responsive bionic butterfly and flower are printed with biomimetic in both locomotion and coloration. Such designs dramatically reduced the processing difficulty of precise full-color printing and expanded the capability of structural color materials to collaborate with other systems.

Research on the phase error of a Sagnac interferometer induced by modulation of a multifunctional integrated optical modulator.

High-precision IFOG requires an optical sensitivity of up to 10-8 rads-1 for interferometers; noise and error are two of the main reasons limiting its accuracy improvement. Any potential source of the signal error is worth being studied. This article introduces work on the modulation signal error caused by the mechanical vibration energy loss of MIOC crystals. This article theoretically derives and simulates the frequency spectrum of an energy loss from the perspective of electromechanical coupling and verifies it through experiments. This article also verifies the influence of MIOC mechanical loss on the output of a Sagnac interferometer through experiments. This study is an indispensable part of the bottleneck for improving the accuracy of ultrahigh-precision closed-loop IFOG and has potential engineering application value.

Synergistic Electrocatalysis and Spatial Nanoconfinement to Accelerate Sulfur Conversion Kinetics in Aqueous Zn-S Battery.

Aqueous zinc batteries based on the conversion-type sulfur cathodes are promising in energy storage system due to the high theoretical energy density, low cost, and good safety. However, the multi-electron solid-state intermediate conversion reaction of sulfur cathodes generally possess sluggish kinetics, which leads to lower discharge voltage and inefficient sulfur utilization, thus suppressing the practical energy density. Herein, sulfur nanoparticles derived from metal-organic frameworks confined in situ within electrospun fibers derived sulfur and nitrogen co-doped carbon nanofibers (S@S,N-CNF) composite, which possesses yolk-shell S@C nanostructure, is fabricated through successive sulfidation, pyrolysis, and sulfide oxidation processes, and served as a high-performance cathode material for Zn-S battery. The S and N dopants on carbon can collectively catalyse sulfur reduction reaction (SRR) by lowering energy barrier and accelerating kinetics to increase discharge voltage and specific capacity. Meanwhile, the yolk-shell S@C structure with spatially confined S nanoparticle yolks is beneficial to improve charge transfer and lower activation energy, thus further expediting SRR kinetics. Furthermore, extensive density functional theory (DFT) calculations reveal that S and N dual-doping can thermodynamically and dynamically reduce the energy barrier of rate-determining step (i.e., the transformation of *ZnS4 into *ZnS2) for the overall SRR, thereby significantly accelerating SRR kinetics.

Microplastic size-dependent biochemical and molecular effects in alga Heterosigma akashiwo.

Micro- and nano-plastics (MNPs) are increasingly prevalent contaminants in marine ecosystems and have a variety of negative impacts on marine organisms. While their toxic impact on freshwater microalgae has been well-documented, limited research has been conducted on the influence of MNPs on marine red tide algae, despite their significant implications for human health and coastal ecological stability. This study investigated the physiological, biochemical and molecular reactions of the common harmful algal species, Heterosigma akashiwo, when exposed to polystyrene (PS) MNPs of 80 nm and 1 µm in size with the concentrations of 0, 1, 10, and 20 mg L-1 in 12 days. The results showed that 80 nm-sized MNPs (at concentrations of 10 mg L-1 and 20 mg L-1) inhibited algal growth. Despite the increased superoxide dismutase (SOD) activity and up-regulation of glutathione metabolism, exposure-induced oxidative stress remained the main cause of the inhibition. Up-regulation of aminoacyl-tRNA biosynthesis and amino acid biosynthesis pathways provide the necessary amino acid feedstock for the synthesis of antioxidant enzymes such as SOD. 1 µm sized PS MNPs increased chlorophyll a (Chl-a) content without significant effects on other parameters. In addition, H. akashiwo have an effective self-regulation ability to defend against two sized MNPs stress at concentrations of 1 mg L-1 by upregulating gene expression related to endocytosis, biotin metabolism, and oxidative phosphorylation. These results provided evidence that H. akashiwo was able to resist exposure to 1 µm MPs, whereas 80 nm NPs exerted a toxic effect on H. akashiwo. This study deepens our understanding of the interaction between MNPs and marine harmful algal at the transcriptional level, providing valuable insights for further evaluating the potential impact of PS MNPs on harmful algal blooms in marine ecosystems.

Antisymmetric Seebeck Effect in a Tilted Weyl Semimetal.

Tilting the Weyl cone breaks the Lorentz invariance and enriches the Weyl physics. Here, we report the observation of a magnetic-field-antisymmetric Seebeck effect in a tilted Weyl semimetal, Co_{3}Sn_{2}S_{2}. Moreover, it is found that the Seebeck effect and the Nernst effect are antisymmetric in both the in-plane magnetic field and the magnetization. We attribute these exotic effects to the one-dimensional chiral anomaly and phase space correction due to the Berry curvature. The observation is further reproduced by a theoretical calculation, taking into account the orbital magnetization.

Direct Observation of the Vapor-Liquid Phase Transition and Hysteresis in 2 nm Nanochannels.

The characterization of fluid phase transitions in nanoscale pores remains a challenging problem that can significantly affect various applications, such as drug delivery, carbon dioxide storage, and enhanced oil recovery. Previous theoretical and experimental studies have shown that the fluid phase transition changes drastically when the fluid is confined within nanocapillaries with dimensions of <10 nm, potentially due to the dominance of fluid-surface interactions compared to bulk effects. However, due to challenges in performing experiments at the nanoscale, there have been limited experimental observations of the phase transition at this scale. Recent advances in lab-on-a-chip (LOC) technology have enabled the observation of many nanoscale phenomena. In this study, for the first time, we present the direct observation and visualization of n-butane vapor-liquid phase transitions in a 2 nm slit pore using LOC technology. Our experiments, for the first time, measured and directly visualized the deviation of the vapor-liquid phase transition pressure in a 2 nm slit pore compared to the associated unconfined or bulk value. We also measured the liquid-vapor phase transition pressure and observed a significant difference from the vapor-liquid phase transition pressure. We complemented our experimental observations with grand canonical ensemble Monte Carlo molecular simulations to understand the underlying molecular-level mechanisms.

Community Intent to Activate Emergency Medical Services May Be Associated with Regional tPA Treatment.

INTRODUCTION: Acute stroke treatments are underutilized in the USA. Enhancing stroke preparedness, the recognition of stroke symptoms, and intent to call emergency medical services (EMS) could reduce delay in hospital arrival thereby increasing eligibility for time-sensitive stroke treatments. Whether higher stroke preparedness is associated with higher tissue plasminogen activator (tPA) treatment rates is however uncertain. We therefore set out to determine the contribution of stroke preparedness to regional variation in tPA treatment. METHODS: The region was defined by hospital service area (HSA). Stroke preparedness was determined by using Behavioral Risk Factor Surveillance System survey questions assessing stroke symptom recognition and intent to call 911 in response to a stroke. We used Medicare data to determine the percentage of tPA-treated hospitalized stroke patients in 2007, 2009, and 2011, adjusting for number of stroke hospitalizations in each HSA (primary outcome). We performed multivariate linear regression to estimate the association of regional stroke preparedness on log-transformed tPA treatment rates controlling for demographic, EMS, and hospital characteristics. RESULTS: The adjusted percentage of stroke patients receiving tPA ranged from 1.4% (MIN) to 11.3% (MAX) of stroke/TIA hospitalizations. Across HSAs, a median (IQR) of 86% (81-90%) of responses to a witnessed stroke indicated intent to call 911, and a median (IQR) of 4.4 (4.2-4.6) out of 6 stroke symptoms was recognized. Every 1% increase in an HSA's intent to call 911 was associated with a 0.44% increase in adjusted tPA treatment rate (p = 0.05). Lower accuracy of recognition of stroke symptoms was associated with higher adjusted tPA treatment rates (p = 0.05). CONCLUSIONS: There was little regional variation in intent to call EMS and stroke symptom recognition. Intent to call EMS and stroke symptom recognition are modest contributors to regional variation in tPA treatment.

Detection and Analysis of Microplastics in Human Sputum.

Microplastic pollution is an emerging environmental problem, and little research has focused on its impact on the human body. Based on retrospective case series, the study required participants to fill out a questionnaire and provide sputum samples in order to investigate the presence of microplastics in human sputum and determine whether humans involuntarily inhale them. A total of 22 patients suffering from different respiratory diseases were recruited. We used an Agilent 8700 laser infrared imaging spectrometer and Fourier-transform infrared microscope to analyze sputum samples and evaluate microplastics in the respiratory tract. Remarkably, the size range of the method for detecting microplastics in our study is 20-500 µm. The results showed that 21 types of microplastics were identified, and polyurethane was dominant, followed by polyester, chlorinated polyethylene, and alkyd varnish, accounting for 78.36% of the total microplastics. Most of the aspirated microplastics detected are smaller than 500 µm in size (median: 75.43 µm; interquartile range: 44.67-210.64 µm). Microplastics are ubiquitous in all sputum, indicating that inhalation is a potential way for plastics to enter the human body. Additionally, the quantities of microplastic types in the respiratory tract are related to smoking, invasive examination, etc. (P < 0.05). This study sheds new light on microplastic exposure, which provides basic data for the risk assessment of microplastics to human health.

Complementary Photo-Synapses Based on Light-Stimulated Porphyrin-Coated Silicon Nanowires Field-Effect Transistors (LPSNFET).

Neuromorphic computing has emerged as the high-energy-efficiency and intelligent solution for processing sensory data. As a potential alternative to neuromorphic computing, photo-excited synaptic systems can integrate the functions of optoelectronic sensing and synaptic computing to realize the low-power and high-performance visual perception. However, one major challenge in high-efficient photo-excited synaptic system is to realize the complementarily enhanced and inhibited synaptic behaviors with small hardware cost as possible. Another challenge is to fabricate the photo-synapse devices with complementary metal oxide semiconductor (CMOS)-compatible process to achieve high enough integration density for practical application. Here, a CMOS-compatible Light-stimulated Porphyrin-coated Silicon Nanowire Field Effect Transistor (LPSNFET) technology is proposed and developed to form the complementary photo-synapses with only two CMOS-like transistors. LPSNFET exhibits fivefold improvement in photo-sensitivity compared to the bare silicon nanowire (SiNW) devices, and can still show obvious responses when incident illumination power is as low as 0.1 mW cm-2 . Moreover, it enables tunable dynamic synaptic plasticity and versatile synaptic functions. Especially, the complementarily enhanced and inhibited behaviors can be realized by modulating SiNW/porphyrin interface via simply changing the MOS type of LPSNFET, which acts like the photonic counterpart of CMOS technology to provide the basic brick for building complex neuromorphic circuits efficiently and economically. Finally, the CMOS process compatibility of LPSNFET provides potential application in future large scale in-sensor computing.

Response to Persistent ER Stress in Plants: A Multiphasic Process That Transitions Cells from Prosurvival Activities to Cell Death.

The unfolded protein response (UPR) is a highly conserved response that protects plants from adverse environmental conditions. The UPR is elicited by endoplasmic reticulum (ER) stress, in which unfolded and misfolded proteins accumulate within the ER. Here, we induced the UPR in maize (Zea mays) seedlings to characterize the molecular events that occur over time during persistent ER stress. We found that a multiphasic program of gene expression was interwoven among other cellular events, including the induction of autophagy. One of the earliest phases involved the degradation by regulated IRE1-dependent RNA degradation (RIDD) of RNA transcripts derived from a family of peroxidase genes. RIDD resulted from the activation of the promiscuous ribonuclease activity of ZmIRE1 that attacks the mRNAs of secreted proteins. This was followed by an upsurge in expression of the canonical UPR genes indirectly driven by ZmIRE1 due to its splicing of Zmbzip60 mRNA to make an active transcription factor that directly upregulates many of the UPR genes. At the peak of UPR gene expression, a global wave of RNA processing led to the production of many aberrant UPR gene transcripts, likely tempering the ER stress response. During later stages of ER stress, ZmIRE1's activity declined, as did the expression of survival modulating genes, Bax inhibitor1 and Bcl-2-associated athanogene7, amid a rising tide of cell death. Thus, in response to persistent ER stress, maize seedlings embark on a course of gene expression and cellular events progressing from adaptive responses to cell death.

Chirality-Dependent Hall Effect and Antisymmetric Magnetoresistance in a Magnetic Weyl Semimetal.

Weyl semimetals host a variety of exotic effects that have no counterpart in conventional materials, such as the chiral anomaly and magnetic monopole in momentum space. These effects give rise to unusual transport properties, including a negative magnetoresistance and a planar Hall effect, etc. Here, we report a new type of Hall and magnetoresistance effect in a magnetic Weyl semimetal. Unlike antisymmetric (with respect to either magnetic field or magnetization) Hall and symmetric magnetoresistance in conventional materials, the discovered magnetoresistance and Hall effect are antisymmetric in both magnetic field and magnetization. We show that the Berry curvature, the tilt of the Weyl node, and the chiral anomaly synergically produce these phenomena. Our results reveal a unique property of Weyl semimetals with broken time reversal symmetry.

An Approach for the Synthesis of Pyrazolo[1,5-a]pyrimidines via Cu(II)-Catalyzed [3+3] Annulation of Saturated Ketones with Aminopyrazoles.

A one-step synthesis of diversely substituted pyrazolo[1,5-a]pyrimidines from saturated ketones and 3-aminopyrazoles is presented. This transformation involves the in situ formation of α,ß-unsaturated ketones via a radical process, followed by [3+3] annulation with 3-aminopyrazoles in one pot. Mechanistic studies have shown that the dual C(sp3)-H bond functionalization of inactive ketones is required for the formation of the title compounds. Notably, this dehydrogenative coupling process provides access to a host of functionalized pyrazolo[1,5-a]pyrimidines with antitumor potential from commercially available substrates.

Vanishing quantum oscillations in Dirac semimetal ZrTe5.

One of the characteristics of topological materials is their nontrivial Berry phase. Experimental determination of this phase largely relies on a phase analysis of quantum oscillations. We study the angular dependence of the oscillations in a Dirac material [Formula: see text] and observe a striking spin-zero effect (i.e., vanishing oscillations accompanied with a phase inversion). This indicates that the Berry phase in [Formula: see text] remains nontrivial for arbitrary field direction, in contrast with previous reports. The Zeeman splitting is found to be proportional to the magnetic field based on the condition for the spin-zero effect in a Dirac band. Moreover, it is suggested that the Dirac band in [Formula: see text] is likely transformed into a line node other than Weyl points for the field directions at which the spin zero occurs. The results underline a largely overlooked spin factor when determining the Berry phase from quantum oscillations.

A Hollow-Core Photonic-Crystal Fiber-Optic Gyroscope Based on a Parallel Double-Ring Resonator.

A novel system structure of resonant fiber optical gyroscope using a parallel double hollow-core photonic crystal fiber ring resonator is proposed, which employs the double closed loop and reciprocal modulation-demodulation technique to solve the problem of the length mismatch between rings. This structure can suppress the residual amplitude modulation noise and laser frequency noise, essentially eliminating the influence of the Rayleigh backscattering noise and dramatically reduce the Kerr-effect-induced drift by three orders of magnitude. Thanks to its excellent noise suppression effect, the sensitivity of this novel system can approach the shot-noise-limited theoretical value of 8.94 × 10-7 rad/s assuming the length of the fiber ring resonator is 10 m.

Subcutaneous Face and Neck lift: A Traditional Method With Definite Effects Among Asians.

BACKGROUND: The mainstream facelifts in Western countries always involve the superficial fascia/superficial musculoaponeurotic system treatment. Meanwhile, subcutaneous face and neck lifts are widely applied among Asians. OBJECTIVES: The authors sought to evaluate outcomes of subcutaneous face and neck lift, including patient-reported and 3-dimensional (3D) measurement outcomes, and report on details of surgical procedures. METHODS: Patients who received a subcutaneous face and neck lift from January 2017 to June 2019 were asked to complete FACE-Q scales, and facial information was collected by the Vectra 3D imaging system preoperatively and postoperatively. Volume changes in midface and possible displacement of facial landmarks were measured. The range of dissection and the amount of skin removed were recorded intraoperatively. RESULTS: In total, 119 patients (median age, 46 years, interquartile range, 40-53 years) received a subcutaneous face and neck lift. Among them, 88 patients completed pre- and postoperative FACE-Q scales. Patients' satisfaction with facial subunits improved and wrinkles were significantly relieved (P < 0.001). Nineteen patients (38 midface sides) completed 3D image data collection. Postoperatively, zygomatic volume increased, and nasolabial and lateral cheek volumes decreased (volume change of 2.2 ±â€…1.3 mL). Mouth, nose, and eye displacements were negligible postoperatively. The widths of skin removed at the middle temporal, front of the sideburns, upper helix, earlobe, and retro-auricular were 13.8 ±â€…1.9 mm, 19.6 ±â€…3.1 mm, 27.6 ±â€…3.9 mm, 16.4 ±â€…3.9 mm, and 32.2 ±â€…4.0 mm, respectively. CONCLUSIONS: The authors' subcutaneous face and neck lift was effective in relieving nasolabial sagging, improving wrinkles, and achieving facial rejuvenation.

Experimental investigation of far-field human cough airflows from healthy and influenza-infected subjects.

Seasonal influenza epidemics have been responsible for causing increased economic expenditures and many deaths worldwide. Evidence exists to support the claim that the virus can be spread through the air, but the relative significance of airborne transmission has not been well defined. Particle image velocimetry (PIV) and hot-wire anemometry (HWA) measurements were conducted at 1 m away from the mouth of human subjects to develop a model for cough flow behavior at greater distances from the mouth than were studied previously. Biological aerosol sampling was conducted to assess the risk of exposure to airborne viruses. Throughout the investigation, 77 experiments were conducted from 58 different subjects. From these subjects, 21 presented with influenza-like illness. Of these, 12 subjects had laboratory-confirmed respiratory infections. A model was developed for the cough centerline velocity magnitude time history. The experimental results were also used to validate computational fluid dynamics (CFD) models. The peak velocity observed at the cough jet center, averaged across all trials, was 1.2 m/s, and an average jet spread angle of θ = 24° was measured, similar to that of a steady free jet. No differences were observed in the velocity or turbulence characteristics between coughs from sick, convalescent, or healthy participants.

Light depolarization based on dispersion degree of polarization.

The dispersion degree of polarization, a new definition of the depolarization degree of partially polarized beams, is first proposed, to the best of our knowledge, to measure the performance of fiber depolarizers. First, the description of the polarization based on the Poincaré sphere is introduced. Then, the modified Delaunay triangulation algorithm is introduced, and the calculation formula of the dispersion degree of polarization is given based on this algorithm. The experimental device was set up, and the dispersion degree of polarization of the depolarized light after the fiber depolarizer was measured to be 47.3%. The components and proportions of polarization in the depolarized light were also obtained. Compared with the degree of polarization, the dispersion degree of polarization can quantitatively analyze the light polarization evaluation in the time dimension and provide a numerical reference for improving the depolarizer, thus increasing the fiber sensor's accuracy.