Regulatory Considerations in the Approval of Rezafungin (REZZAYO) for the Treatment of Candidemia and Invasive Candidiasis in Adults.

On March 22, 2023, the FDA approved rezafungin (REZZAYO) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a Day 30 all-cause mortality primary endpoint and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in non-human primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other FDA-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options.

Resistive Memory Devices at the Thinnest Limit: Progress and Challenges.

The Si-based integrated circuits industry has been developing for more than half a century, by focusing on the scaling-down of transistor. However, the miniaturization of transistors will soon reach its physical limits, thereby requiring novel material and device technologies. Resistive memory is a promising candidate for in-memory computing and energy-efficient synaptic devices that can satisfy the computational demands of the future applications. However, poor cycle-to-cycle and device-to-device uniformities hinder its mass production. 2D materials, as a new type of semiconductor, is successfully employed in various micro/nanoelectronic devices and have the potential to drive future innovation in resistive memory technology. This review evaluates the potential of using the thinnest advanced materials, that is, monolayer 2D materials, for memristor or memtransistor applications, including resistive switching behavior and atomic mechanism, high-frequency device performances, and in-memory computing/neuromorphic computing applications. The scaling-down advantages of promising monolayer 2D materials including graphene, transition metal dichalcogenides, and hexagonal boron nitride are presented. Finally, the technical challenges of these atomic devices for practical applications are elaborately discussed. The study of monolayer-2D-material-based resistive memory is expected to play a positive role in the exploration of beyond-Si electronic technologies.

Fate characteristics and risk quantification of cyflumetofen from tomato cultivation to processing based on large-scale applications.

Elucidating the fate characteristics of cyflumetofen and its main metabolite 2-TFMBA in tomato from cultivation to processing is crucial for safeguarding the environment and humans from hazardous effects. Cyflumetofen and 2-TFMBA could exist stably in tomato matrices for at least 343 days under frozen and dark conditions according to UHPLC-MS/MS, with a limit of quantitation of 0.001 mg/kg and retention time within 2.12 min. The occurrence, dissipation, and concentration variation of cyflumetofen were reflected by original depositions of 0.02-0.44 mg/kg, half-lives of 1.7-7.2 days, and terminal magnitudes of 0.005-0.30 mg/kg, respectively, with various influencing factors, e.g., climate conditions and tomato cultivars. Additionally, 13.5-59.3% of cyflumetofen was metabolized to 2-TFMBA, showing significant toxicological effects ranging from cultivation to processing. When the concentration decreased by 0.06 mg/kg, cyflumetofen was effectively removed by peeling, while washing was the recommended method for removing 2-TFMBA with a processing factor of 0.70. The comparative dietary risks of sum cyflumetofen were assessed for all life cycle populations using deterministic and probabilistic models. The risk quotients decreased to 1.3-4.8 times during the preparation of home canning tomato paste. Despite the low exposure risk, the potential health hazards of sum cyflumetofen should be considered, given its ubiquity and cumulative effects.

Principle and design of clinical efficacy observation of extracorporeal cardiac shock wave therapy for patients with myocardial ischemia-reperfusion injury: A prospective randomized controlled trial protocol.

BACKGROUND: Acute ST-segment elevation myocardial infarction (STEMI) remains a serious life threatening event with a poor prognosis due to myocardial ischemia/reperfusion injury despite coronary revascularization. Extracorporeal cardiac shock wave (ECSW) is a safe, effective and non-invasive new method for the treatment of cardiovascular diseases. The current results show that extracorporeal cardiac shock wave provides a new treatment option for patients with severe and advanced coronary heart disease. However, there are relatively few clinical studies on the application of in vitro cardiac shock waves in patients with myocardial ischemia-reperfusion injury. We hypothesized that extracorporeal cardiac shock therapy would also be effective in reducing clinical endpoints in patients with STEMI reperfusion. OBJECTIVE: This study is order to provide a new therapeutic method for patients with myocardial ischemia-reperfusion injury and reveal the possible mechanism of ECSW for ischemia-reperfusion injury. METHODS AND MATERIALS: CEECSWIIRI is a single-center, prospective randomized controlled trial that plans to enroll 102 eligible patients with acute ST-segment elevation myocardial infarction reperfusion. Eligible patients with STEMI reperfusion will be randomly divided into external cardiac shock therapy (ECSW) trial group and blank control group. The blank control group will receive optimal drug therapy, and the experimental group will receive optimal drug therapy combined with ECSW. The shock wave treatment plan will be 3-month therapy, specifically 1 week of treatment per month, 3 weeks of rest, 3 times of ECSW in each treatment week, respectively on the first day, the third day and the fifth day of the treatment week, lasting for 3 months and follow-up for 2 years. The primary endpoint will be to assess the 2-year improvement in all-cause death, re-hospitalization due to cardiovascular disease, major unintentional cerebrovascular events, including cardiogenic death, myocardial infarction, heart failure, arrhythmia, emergency coronary revascularization, and stroke in patients with STEMI reperfusion. Secondary endpoints will include improvements in angina pectoris, quality of life, cardiac structure and function, coronary microcirculation, and endothelial progenitor cell-derived miR-140-3p in relation to survival outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov.org PRS:NCT05624203; Date of registration: November 12, 2022.

A drug repurposing method based on inhibition effect on gene regulatory network.

Numerous computational drug repurposing methods have emerged as efficient alternatives to costly and time-consuming traditional drug discovery approaches. Some of these methods are based on the assumption that the candidate drug should have a reversal effect on disease-associated genes. However, such methods are not applicable in the case that there is limited overlap between disease-related genes and drug-perturbed genes. In this study, we proposed a novel Drug Repurposing method based on the Inhibition Effect on gene regulatory network (DRIE) to identify potential drugs for cancer treatment. DRIE integrated gene expression profile and gene regulatory network to calculate inhibition score by using the shortest path in the disease-specific network. The results on eleven datasets indicated the superior performance of DRIE when compared to other state-of-the-art methods. Case studies showed that our method effectively discovered novel drug-disease associations. Our findings demonstrated that the top-ranked drug candidates had been already validated by CTD database. Additionally, it clearly identified potential agents for three cancers (colorectal, breast, and lung cancer), which was beneficial when annotating drug-disease relationships in the CTD. This study proposed a novel framework for drug repurposing, which would be helpful for drug discovery and development.

Micrometer-precision absolute distance measurement with a repetition-rate-locked soliton microcomb.

The soliton microcomb has sparked interest in high-precision distance measurement, owing to its ultrahigh repetition rate and chip-integrated scale. We report absolute distance measurements based on synthetic wavelength interferometry with a soliton microcomb. We stabilized the repetition rate of 48.98 GHz through injection locking, with fluctuations below 0.25 Hz. Distance measurements up to 64 mm were demonstrated, presenting residuals below 2.7 µm compared with a referenced laser interferometer. Long-term distance measurements were made at two fixed positions of approximately 0.2 m and 1.4 m, resulting in a minimum Allan deviation as low as 56.2 nm at an average time of 0.05 s. The dynamic demonstration illustrated that the proposed system could track round-trip motion of 3 mm at speeds up to 100 mm/s. The proposed distance measurement system is, to our knowledge, the first microcomb-based synthetic wavelength interferometer and achieves a ranging precision of tens of nanometers, with potential applications in the fields of satellite formation flying, high-end manufacturing, and micro-nano processing.

Bioinformatics identification of ferroptosis-related genes and therapeutic drugs in rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is a chronic immune disease characterized by synovial inflammation and bone destruction, with a largely unclear etiology. Evidence has indicated that ferroptosis may play an increasingly important role in the onset and development of RA. However, ferroptosis-related genes are still largely unexplored in RA. Therefore, this work focused on identifying and validating the potential ferroptosis-related genes involved in RA through bioinformatics analysis. Methods: We screened differentially expressed ferroptosis-related genes (DEFGs) between RA patients and healthy individuals based on GSE55235 dataset. Subsequently, correlation analysis, protein-protein interaction (PPI) network analysis, GO, and KEGG enrichment analyses were performed using these DEFGs. Finally, our results were validated by GSE12021 dataset. Results: We discovered 34 potential DEFGs in RA based on bioinformatics analysis. According to functional enrichment analysis, these genes were mainly enriched in HIF-1 signaling pathway, FoxO signaling pathway, and Ferroptosis pathway. Four genes (GABARPL1, DUSP1, JUN, and MAPK8) were validated to be downregulated by GSE12021 dataset and were diagnostic biomarkers and therapeutic targets for RA via the regulation of ferroptosis. Discussion: Our results help shed more light on the pathogenesis of RA. Ferroptosis-related genes in RA are valuable diagnostic biomarkers and they will be exploited clinically as therapeutic targets in the future.

Suppressing Structural Relaxation in Nanoscale Antimony to Enable Ultralow-Drift Phase-Change Memory Applications.

Phase-change random-access memory (PCRAM) devices suffer from pronounced resistance drift originating from considerable structural relaxation of phase-change materials (PCMs), which hinders current developments of high-capacity memory and high-parallelism computing that both need reliable multibit programming. This work realizes that compositional simplification and geometrical miniaturization of traditional GeSbTe-like PCMs are feasible routes to suppress relaxation. While to date, the aging mechanisms of the simplest PCM, Sb, at nanoscale, have not yet been unveiled. Here, this work demonstrates that in an optimal thickness of only 4 nm, the thin Sb film can enable a precise multilevel programming with ultralow resistance drift coefficients, in a regime of ≈10-4 -10-3 . This advancement is mainly owed to the slightly changed Peierls distortion in Sb and the less-distorted octahedral-like atomic configurations across the Sb/SiO2 interfaces. This work highlights a new indispensable approach, interfacial regulation of nanoscale PCMs, for pursuing ultimately reliable resistance control in aggressively-miniaturized PCRAM devices, to boost the storage and computing efficiencies substantially.

EMDR versus waiting list in individuals at clinical high risk for psychosis with post-traumatic stress symptoms: A randomized controlled trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) is highly prevalent in the individuals at clinical-high risk for psychosis (CHR). The aim of this study was to examine the efficacy and safety of Eye Movement Desensitization and Reprocessing (EMDR) in individuals at CHR with comorbid PTSD or subthreshold PTSD in a randomized controlled trial. METHODS: Fifty-seven individuals at CHR with PTSD or subthreshold PTSD formed the study sample. The eligible participants were randomly assigned to a 12 weeks EMDR treatment (N = 28) or a waiting list condition (WL, N = 29). The structured interview for psychosis risk syndrome (SIPS), the clinician administered post-traumatic stress disorder scale (CAPS) and a battery of self-rating inventories covering depressive, anxiety and suicidal symptoms were administered. RESULTS: Twenty-six participants in the EMDR group and all the participants in the WL group completed the study. The analyses of covariance revealed greater reduction of the mean scores on CAPS (F = 23.2, Partial η2 = 0.3, P < 0.001), SIPS positive scales (F = 17.8, Partial η2 = 0.25, P < 0.001) and all the self-rating inventories in the EMDR group than in the WL group. Participants in the EMDR group were more likely to achieve remission of CHR compared to those in the WL group at endpoint (60.7 % vs. 31 %, P = 0.025). CONCLUSIONS: EMDR treatment not only effectively improved traumatic symptoms, but also significantly reduced the attenuated psychotic symptoms and resulted in a higher remission rate of CHR. This study highlighted the necessity of adding a trauma-focused component to the present approach of early intervention in psychosis.

Detecting early-warning signals for influenza by dysregulated dynamic network biomarkers.

As a dynamical system, complex disease always has a sudden state transition at the tipping point, which is the result of the long-term accumulation of abnormal regulations. This paper proposes a novel approach to detect the early-warning signals of influenza A (H3N2 and H1N1) outbreaks by dysregulated dynamic network biomarkers (dysregulated DNBs) for individuals. The results of cross-validation show that our approach can detect early-warning signals before the symptom appears successfully. Unlike the traditional DNBs, our dysregulated DNBs are anchored and very few, which is essential for disease early diagnosis in clinical practice. Moreover, the genes of dysregulated DNBs are significantly enriched in the influenza-related pathways. The source code of this paper can be freely downloaded from https://github.com/YanhaoHuo/dysregulated-DNBs.git.

Recent advances of bioactive proteins/polypeptides in the treatment of breast cancer.

Proteins do not only serve as nutrients to fulfill the demand for food, but also are used as a source of bioactive proteins/polypeptides for regulating physical functions and promoting physical health. Female breast cancer has the highest incidence in the world and is a serious threat to women's health. Bioactive proteins/polypeptides exert strong anti-tumor effects and exhibit inhibition of multiple breast cancer cells. This review discussed the suppressing effects of bioactive proteins/polypeptides on breast cancer in vitro and in vivo, and their mechanisms of migration and invasion inhibition, apoptosis induction, and cell cycle arrest. This may contribute to providing a basis for the development of bioactive proteins/polypeptides for the treatment of breast cancer.

Resistive switching mechanism of MoS2based atomristor.

The non-volatile resistive switching process of a MoS2based atomristor with a vertical structure is investigated by first-principles calculations. It is found that the monolayer MoS2with a S vacancy defect (VS) could maintain an insulation characteristic and a high resistance state (HRS) is remained. As an electrode metal atom is adsorbed on the MoS2monolayer, the semi-conductive filament is formed with the assistance ofVS. Under this condition, the atomristor presents a low resistance state (LRS). The ON state current of this semi-filament is increased close to two orders of magnitude larger than that without the filament. The energy barrier for an Au-atom to penetrate the monolayer MoS2viaVSis as high as 6.991 eV. When it comes to a double S vacancy (VS2), the energy barrier is still amounted to 3.554 eV, which manifests the bridge-like full conductive filament cannot form in monolayer MoS2based atomristor. The investigation here promotes the atomic level understanding of the resistive switching properties about the monolayer MoS2based memristor. The physics behind should also work in atomristors based on other monolayer transition-metal dichalcogenides, like WSe2and MoTe2. The investigation will be a reference for atomristor-device design or optimization.

Electronic state evolution of oxygen-doped monolayer WSe2 assisted by femtosecond laser irradiation.

Electronic states are significantly correlated with chemical compositions, and the information related to these factors is especially crucial for the manipulation of the properties of matter. However, this key information is usually verified by after-validation methods, which could not be obtained during material processing, for example, in the field of femtosecond laser direct writing inside materials. Here, critical evolution stages of electronic states for monolayer tungsten diselenide (WSe2) around the modification threshold (at a Mott density of ∼1013 cm-2) are observed by broadband femtosecond transient absorption spectroscopy, which is associated with the intense femtosecond-laser-assisted oxygen-doping mechanism. First-principles calculations and control experiments on graphene-covered monolayer WSe2 further confirm this modification mechanism. Our findings reveal a photochemical reaction for monolayer WSe2 under the Mott density condition and provide an electronic state criterion to in situ monitor the degrees of modification in monolayer transition metal dichalcogenides during the femtosecond laser modification.

Level and risk assessment of selected polychlorinated biphenyls, polycyclic aromatic hydrocarbons, and organochlorine pesticides in walnut and soil.

It is unknown how hydrophobic organic contaminants (HOCs) are distributed and how they affect the environment in high-fat nuts and their planted soil. The profile of HOCs in walnut/soil system was investigated in this study. Polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and organochlorine pesticides (OCPs) were found in walnuts at concentrations of 0.67, 127, and 116 µg/kg, respectively. The target hazard quotients (THQ) of 17 PCBs, 16 PAHs, and 21 OCPs from walnut consumption by human were 0.06, 0.01, and 0.11, respectively. The highest concentrations of HOC in the soil were found in Nap and toxaphene, with concentrations of 2580 and 902 µg/kg, respectively. Bioaccumulation factors (BAF) and biota-sediment accumulation factors (BSAF) in walnuts were ranged from <0.01 to 7.04 and <0.01 to 3.83, respectively. Concentrations of most individual HOCs in soil samples were significantly correlated with soil organic matter (SOM) (p < 0.01) and minerals (p < 0.01), with maximum correlation coefficients of 0.70 (OM-PCB81) and -0.84 (P-BaP). According to this study, high-fat walnuts do not have a high bioaccumulation of HOCs from soil, and the risk of consumption is within the safe range.

Gut microbiome-based noninvasive diagnostic model to predict acute coronary syndromes.

Background: Previous studies have shown that alterations in the gut microbiota are closely associated with Acute Coronary Syndrome (ACS) development. However, the value of gut microbiota for early diagnosis of ACS remains understudied. Methods: We recruited 66 volunteers, including 29 patients with a first diagnosis of ACS and 37 healthy volunteers during the same period, collected their fecal samples, and sequenced the V4 region of the 16S rRNA gene. Functional prediction of the microbiota was performed using PICRUSt2. Subsequently, we constructed a nomogram and corresponding webpage based on microbial markers to assist in the diagnosis of ACS. The diagnostic performance and usefulness of the model were analyzed using boostrap internal validation, calibration curves, and decision curve analysis (DCA). Results: Compared to that of healthy controls, the diversity and composition of microbial community of patients with ACS was markedly abnormal. Potentially pathogenic genera such as Streptococcus and Acinetobacter were significantly increased in the ACS group, whereas certain SCFA-producing genera such as Blautia and Agathobacter were depleted. In addition, in the correlation analysis with clinical indicators, the microbiota was observed to be associated with the level of inflammation and severity of coronary atherosclerosis. Finally, a diagnostic model for ACS based on gut microbiota and clinical variables was developed with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.963 (95% CI: 0.925-1) and an AUC value of 0.948 (95% CI: 0.549-0.641) for bootstrap internal validation. The calibration curves of the model show good consistency between the actual and predicted probabilities. The DCA showed that the model had a high net clinical benefit for clinical applications. Conclusion: Our study is the first to characterize the composition and function of the gut microbiota in patients with ACS and healthy populations in Southwest China and demonstrates the potential effect of the microbiota as a non-invasive marker for the early diagnosis of ACS.

Recent Progress in Double-Layer Honeycomb Structure: A New Type of Two-Dimensional Material.

Two-dimensional (2D) materials are no doubt the most widely studied nanomaterials in the past decade. Most recently, a new type of 2D material named the double-layer honeycomb (DLHC) structure opened a door to achieving a series of 2D materials from traditional semiconductors. However, as a newly developed material, there still lacks a timely understanding of its structure, property, applications, and underlying mechanisms. In this review, we discuss the structural stability and experimental validation of this 2D material, and systematically summarize the properties and applications including the electronic structures, topological properties, optical properties, defect engineering, and heterojunctions. It was concluded that the DLHC can be a universal configuration applying to III-V, II-VI, and I-VII semiconductors. Moreover, these DLHC materials indeed have exotic properties such as being excitonic/topological insulators. The successful fabrication of DLHC materials further demonstrates it is a promising topic. Finally, we summarize several issues to be addressed in the future, including further experimental validation, defect engineering, heterojunction engineering, and strain engineering. We hope this review can help the community to better understand the DLHC materials timely and inspire their applications in the future.

Photoinduced Ultrafast Transition of the Local Correlated Structure in Chalcogenide Phase-Change Materials.

Revealing the bonding and time-evolving atomic dynamics in functional materials with complex lattice structures can update the fundamental knowledge on rich physics therein, and also help to manipulate the material properties as desired. As the most prototypical chalcogenide phase change material, Ge_{2}Sb_{2}Te_{5} has been widely used in optical data storage and nonvolatile electric memory due to the fast switching speed and the low energy consumption. However, the basic understanding of the structural dynamics on the atomic scale is still not clear. Using femtosecond electron diffraction, structure factor calculation, and time-dependent density-functional theory molecular dynamic simulation, we reveal the photoinduced ultrafast transition of the local correlated structure in the averaged rocksalt phase of Ge_{2}Sb_{2}Te_{5}. The randomly oriented Peierls distortion among unit cells in the averaged rocksalt phase of Ge_{2}Sb_{2}Te_{5} is termed as local correlated structures. The ultrafast suppression of the local Peierls distortions in the individual unit cell gives rise to a local structure change from the rhombohedral to the cubic geometry within ∼0.3 ps. In addition, the impact of the carrier relaxation and the large number of vacancies to the ultrafast structural response is quantified and discussed. Our Letter provides new microscopic insights into contributions of the local correlated structure to the transient structural and optical responses in phase change materials. Moreover, we stress the significance of femtosecond electron diffraction in revealing the local correlated structure in the subunit cell and the link between the local correlated structure and physical properties in functional materials with complex microstructures.

A simple pre-disease state prediction method based on variations of gene vector features.

BACKGROUND: The progression of disease can be divided into three states: normal, pre-disease, and disease. Since a pre-disease state is the tipping point of disease deterioration, accurately predicting pre-disease state may help to prevent the progression of disease and develop feasible treatment in time. METHODS: In the perspective of gene regulatory network, the expression of a gene is regulated by its upstream genes, and then it also regulates that of its downstream genes. In this study, we define the expression value of these genes as a gene vector to depict its state in a specific sample. Then, we propose a novel pre-disease prediction method by such vector features. RESULTS: The results of an influenza virus infection dataset show that our method can successfully predict the pre-disease state. Furthermore, the pre-disease state related genes predicted by our methods are highly associated with each other and enriched in influenza virus infection related pathways. In addition, our method is more time efficient in calculation than previous works. The code of our method is accessed at https://github.com/ZhenshenBao/sPGVF.git.

Lignin-based non-crosslinked nanocarriers: A promising delivery system of pesticide for development of sustainable agriculture.

Lignin sulfonate (LS), a waste material from the paper pulping, was modified with benzoic anhydride to obtain benzoylated lignin sulfonates of adjustable hydrophilicity (BLS). When BLS was combined with difenoconazole (Di), a broad-spectrum fungicide, lignin-based, non-crosslinked nanoparticles were obtained either by solvent exchange or solvent evaporation. When a mass ratio of 1:5 LS: benzoic anhydride was used, the Di release from Di@BLS5 after 1248 h was ca. 74 %, while a commercial difenoconazole microemulsion (Di ME) reached 100 % already after 96 h, proving the sustained release from the lignin nanocarriers. The formulation of Di in lignin-based nanocarriers also improved the UV stability and the foliar retention of Di compared to the commercial formulation of the fungicide. Bioactivity assay showed that Di@BLS5 exhibited high activities and duration against strawberry anthracnose (Colletotrichum gloeosporioides). Overall, the construction of fungicide delivery nano-platform using BLS via a simple non-crosslinked approach is a novel and promising way to develop new formulations for nanopesticide and the development of sustainable agriculture.