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.

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.

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.

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.

The effects of childhood trauma on personality in unaffected first-degree relatives of patients with major depressive disorder.

ABSTRAC: OBJECTIVES: This study aimed to preliminarily and exploratorily examine the associations between childhood trauma (CT), its subtypes, and personality traits among unaffected first-degree relatives (FDR, children, or siblings) of patients with major depressive disorder (MDD). METHODS: The study sample included three subgroups: MDD patients (N = 85), Patients' FDRs (N = 35), and healthy control individuals (HC, N = 89). The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma and the Eysenck Personality Questionnaire was used to assess personality traits. RESULTS: Significant differences were found in a few personality traits (p < 0.05 for extraversion, neuroticism, and psychoticism) among MDD patients, FDR, and HC, and there were no significant differences between HC and FDR. In the FDR group, compared with those without CT, participants with CT scored significantly higher for neuroticism (N) (F = 3.246, p = 0.046). CT was significantly associated with N, psychoticism (P) and Lie (L), and the strongest association was between CT total score and N. Significantly positive correlations were found between N and sexual abuse (SA) (r = 0.344, p = 0.043), emotional neglect (EN) (r = 0.394, p = 0.019), physical neglect (PN) (r = 0.393, p = 0.019), and CTQ total score (r = 0.452, p = 0.006); between P and CTQ total score (r = 0.336, p = 0.049); and significant negative correlations were found between L and EN (r = -0.446, p = 0.007), CTQ total score (r = -0.375, p = 0.027). CONCLUSION: In unaffected FDRs, there were significant associations between childhood trauma and a few personality traits, including neuroticism, psychoticism, and lie, and emotional neglect was significantly associated with neuroticism.

Gas-particle partitioning of polycyclic aromatic hydrocarbons from oil combustion involving condensate, diesel and heavy oil.

This study focuses on the gas-particle (G-P) partitioning of 16 polycyclic aromatic hydrocarbons (PAHs) from oil combustion, which is one of the important contributors of anthropogenic PAHs but has been rarely studied. The combustions of different types of oils involving ultra-light to heavy oils were investigated, and the PAH partitioning mechanism was determined by the widely used Junge-Pankow adsorption model, Koa absorption model, and dual sorption model, respectively. The results show that the source-specific diagnostic ratios of Ant/(Ant+Phe) are between 0.09 and 0.24, the estimated regression slopes of G-P partition coefficients (KP) of the total PAHs on their sub-cooled liquid vapor pressures (PLO) are in the range of - 0.34 to - 0.25, and the predicted fractions of PAHs in the particle phase (φ) by Koa absorption model are close to the measured values, while the log KPvalues of the LMW PAHs from the combustions of diesel and heavy oil are better represented by the dual sorption model. Our findings indicate that PAHs are derived from mixed sources that include the unburned original oil and combustion products, and the PAH partitioning mechanism is governed by the process of absorption into organic matter because of the unburned oil, but both adsorption and absorption exist simultaneously in the lighter PAHs from the combustions of heavier oils (i.e., diesel and heavy oil). Based on these findings, the understanding of the fate and transport of PAH emissions and the optimization of the emergency responses to accidents such as marine oil spills would be potentially improved.

Modulation Doping: A Strategy for 2D Materials Electronics.

It remains a remarkable challenge to develop practical techniques for controllable and nondestructive doping in two-dimensional (2D) materials for their use in electronics and optoelectronics. Here, we propose a modulation doping strategy, wherein the perfect n-/p-type channel layer is achieved by accepting/donating electrons from/to the defects inside an adjacent encapsulation layer. We demonstrate this strategy in the heterostructures of BN/graphene, BN/MoS2, where the previously believed useless deep defects, such as the nitrogen vacancy in BN, can provide free carriers to the graphene and MoS2. The carrier density is further modulated by engineering the surroundings of the encapsulation layer. Moreover, the defects and carriers are naturally separated in space, eliminating the effects of Coulomb impurity scattering and thus allowing high mobility in the 2D limit. This doping strategy provides a highly viable route to tune 2D channel materials without inducing any structural damage, paving the way for high-performance 2D nanoelectronic devices.

Adjunctive Reboxetine for Schizophrenia: Meta-analysis of Randomized Double-blind, Placebo-controlled Trials.

BACKGROUND: Results of previous studies on the safety and efficacy of adjunctive reboxetine for schizophrenia have been inconsistent. AIM: The aim of this study was to examine the efficacy and tolerability of reboxetine as an adjunct medication to antipsychotic treatment in a meta-analysis of randomized controlled trials (RCTs). METHODS: Two independent investigators extracted data for a random effects meta-analysis and assessed the quality of studies using risk of bias and the Jadad scale. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio (RR)±95% confidence intervals (CIs) were calculated. RESULTS: Nine RCTs (n=630) with double-blind design were identified. Reboxetine outperformed placebo in improving negative (9 RCTs, n=602, SMD: -0.47 [95% CI: -0.87, -0.07], p=0.02; I2=82%), but not the overall, positive, and general psychopathology scores. The significant therapeutic effect on negative symptoms disappeared in the sensitivity analysis after removing an outlying study and in 50% (6/12) of the subgroup analyses. Reboxetine outperformed placebo in reducing weight (3 RCTs, n=186, WMD: -3.83 kg, p=0.04; I2=92%) and body mass index (WMD: -2.23 kg/m2, p=0.04; I2=95%). Reboxetine caused dry mouth but was associated with less weight gain overall and weight gain of ≥7% of the initial weight. All-cause discontinuation and other adverse events were similar between reboxetine and placebo. CONCLUSION: Adjunctive reboxetine could be useful for attenuating antipsychotic-induced weight gain, but it was not effective in treating psychopathology including negative symptoms in schizophrenia.

Comparison of cognitive performance in bipolar disorder, major depressive disorder, unaffected first-degree relatives, and healthy controls.

AIM: The extent and specifics regarding cognitive dysfunction in patients with bipolar disorder (BD) or major depressive disorder (MDD) and their unaffected first-degree relatives (FDR) have not been addressed in any single study. The present study compared the cognitive function of patients with BD or MDD, their FDR, and healthy control (HC) individuals. METHODS: The study population comprised adults (aged 18-55 years) with BD, adults with MDD, FDR (children or siblings of patients with BD or MDD), and HC (n = 105, 109, 85, and 95, respectively). The Repeatable Battery for the Assessment of Neuropsychological Status was used to assess neurocognitive functions, with five domains and 12 tests. A Wechsler Adult Intelligence Scale brief form was applied to evaluate IQ. Status of mood was assessed using the Young Mania Rating Scale and the Hamilton Depression Scale. RESULTS: The mixed model indicated significant variation among the four groups in cognitive function. Cognitive impairments, compared to HC, progressively greater from least to most were found in: FDR, MDD, and BD (F = 32.74, P < 0.001). Years of education correlated with cognitive performance (F = 17.04, P < 0.001), as did IQ (F = 240.63, P < 0.001). The total score for the Hamilton Rating Scale for Depression negatively correlated with cognitive function (F = 5.78, P = 0.017). CONCLUSION: Among the study groups, patients with BD had the most severe deficits, followed by MDD patients and FDR. Cognitive deficits could not be associated with a specific psychiatric disorder, but differences in degree were noted.

Risk assessment and prediction for toxic heavy metals in chestnut and growth soil from China.

BACKGROUND: Toxic heavy metals (THMs) cause severe environmental hazards and threaten human health through various consumption of food stuff. However, little is known of THMs in chestnuts. In this study, the risk assessment and prediction of THMs [lead (Pb), arsenic (As), chromium (Cr), cadmium (Cd) and mercury (Hg)] in chestnuts and growth soils from China were investigated. RESULTS: The main detected THMs in chestnuts and growth soils were As and Cd. The total pollution levels of the five THMs (Nemerow pollution indexes, NPIs) were 0.062 and 1.06, respectively. The dietary risks for children were higher than those of adults, especially short-term non-carcinogenic risk. The main combined risks from the relationships between THMs were Pb-Cr (r = 0.85, P < 0.01) in chestnuts and Pb-As (r = 0.59, P < 0.01) in growth soils. The risk source was found to be the uptake effect of THMs from soil to chestnut, with the highest bioaccumulation factors (BCFs) of Cd (0.254). Several comprehensive risk models were established with the highest coefficient of determination (R2 ) of 0.79. In addition, the main contribution rates of different soil parameters to comprehensive risk of THMs uptake were 49.8% (Cd), 23.4% (pH), 13.8% (Cr) and 13.0% (organic carbon). CONCLUSION: The total pollution levels of THMs fell outside of the safety domain in growth soils. Furthermore, more attention needs to be paid to Cd pollution owing to its low environment background value and high accumulation ability. Three main soil parameters (Cr content, pH, organic carbon) played important roles in the formations and accumulations of THMs in chestnuts. © 2019 Society of Chemical Industry.

Directional Forces by Momentumless Excitation and Order-to-Order Transition in Peierls-Distorted Solids: The Case of GeTe.

Time-dependent density-functional theory molecular dynamics reveals an unexpected effect of optical excitation in the experimentally observed rhombohedral-to-cubic transition of GeTe. The excitation induces coherent forces along [001], which may be attributed to the unique energy landscape of Peierls-distorted solids. The forces drive the A_{1g} optical phonon mode in which Ge and Te move out of phase. Upon damping of the A_{1g} mode, phase transition takes place, which involves no atomic diffusion, defect formation, or the nucleation and growth of the cubic phase.

Electric field analyses on monolayer semiconductors: the example of InSe.

External electric fields can be used to manipulate the electronic properties of two-dimensional (2D) materials. 2D InSe semiconductors possess high electron mobility and wide band gap tunability. Therefore, they have been proposed for use in ultrathin electronic devices. Here, using first-principles calculations, we study the charge polarization, structure, electronic structure, and gas adsorption of an InSe monolayer under vertical electric fields. We find that both the structural evolution and charge polarization rely on the directions of the electric fields. The hole effective mass at the valance band maximum can be decreased by fields that offer a possible route to increase mobility. In contrast, the fields have little impact on the effective mass of electrons at the conduction band minimum. Therefore, high electron mobility in InSe is retained under the fields. Besides, electric fields could alter the absorption intensity for gas molecules. Therefore, gas sensors could be an expected application. More importantly, this work systematically points out some key steps for setting up electric-field calculations in the popular VASP code, such as the cancellation of the symmetrisation of the charge density, avoiding electrons spilling out into the vacuum under high fields.

Non-phase-separated 2D B-C-N alloys via molecule-like carbon doping in 2D BN: atomic structures and optoelectronic properties.

Two-dimensional (2D) B-C-N alloys have recently attracted much attention but unfortunately, Chemical Vapor Deposition (CVD) B-C-N alloys typically phase separate. In spite of that, our analysis of the B-C-N alloy fabricated by electron-beam irradiation suggests that non-phase-separated B-C-N may in fact exist with a carbon concentration up to 14 at%. While this analysis points to a new way to overcome the phase-separation in 2D B-C-N, by first-principles calculations, we show that these B-C-N alloys are made of motifs with even numbers of carbon atoms, in particular, dimers or six-fold rings (in a molecule-like form), embedded in a 2D BN network. Moreover, by tuning the carbon concentration, the band gap of the B-C-N alloys can be reduced by 35% from that of BN. Due to a strong overlap of the wavefunctions at the conduction band and valance band edges, the non-phase-separated B-C-N alloys maintain the strong optical absorption of BN.

Impact of childhood trauma on sensory gating in patients with first-episode schizophrenia.

BACKGROUND: Childhood trauma (CT) has been found to contribute to the onset of schizophrenia and auditory sensory gating deficit is a leading endophenotype for schizophrenia. However, the association between the CT and sensory gating in first-episode schizophrenia remains elusive. METHODS: Fifty-six patients and 49 age and sex-matched healthy controls were assessed using the Childhood Trauma Questionnaire-Short Form (CTQ-SF) for CT and Positive and Negative Syndrome Scale (PANSS) for symptoms severity. Sensory gating was tested using the modified paradigm, perceived spatial separation-induced prepulse inhibition (PSS-PPI), and the perceived spatial co-location PPI (PSC-PPI or classical PPI). RESULTS: Comparing with healthy controls, the patients had significantly higher score on sexual abuse (t = 2.729, p < 0.05), lower PSS- PPI, % (ISI = 120 ms and ISI = 60 ms) (t = - 3.089, - 4.196, p < 0.05). Univariate analysis revealed the absence of a significant correlation among CT, PPI paradigms and symptoms. However, multiple linear regression analyses demonstrated the CTQ-SF total was negatively associated with PSS PPI (ISI = 120 ms) (p = 0.018). CONCLUSION: The current study illustrates that the impact of CT on sensory gating in patients with first-episode schizophrenia, and thus we conclude that CT may be a risk factor to the occurrence of schizophrenia through its impact on sensory gating.

Erythropoietin for Cognitive Deficits Associated with Schizophrenia, Bipolar Disorder, and Major Depression: A Systematic Review.

INTRODUCTION: The purpose of this study is to systematically review the efficacy and safety of adjunctive erythropoietin (EPO) in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression based on randomized controlled trials (RCTs). METHODS: Two evaluators independently and systematically searched and selected studies, extracted data, and conducted quality assessment. RESULTS: Four RCTs with 144 patients (71 in the EPO group and 73 in the placebo group) met the study entry criteria. Adjunctive EPO could improve schizophrenia-related cognitive performance. In patients with bipolar disorder, EPO could also enhance sustained attention, recognition of happy faces, and speed of complex information processing across learning, attention, and executive function when compared with placebo. In addition, EPO could enhance verbal recall, recognition, and memory in patients with major depression. DISCUSSION: This preliminary study found that adjunctive EPO appears to be effective in treating cognitive deficits associated with schizophrenia, bipolar disorder, and major depression without major adverse effects observed. Further higher quality RCTs with larger samples are needed to confirm the findings. REVIEW REGISTRATION: CRD42017058094.

Electronic excitation induced hydrogen-bond adjustment and lattice control in organic-inorganic hybrid cubic perovskites: a fixed occupation molecular dynamics study.

The organic-inorganic hybrid perovskite has become a new type of semiconductor for low cost and highly efficient solar cells. However, the mechanism of interactions between the organic cation and the inorganic framework is still not completely clear under optical electronic excitation. In this work, we employ first-principles molecular dynamics with electronic excitation effects to prove that the hydrogen-bond interaction between the molecular cation and the inorganic lattice can be readily adjusted by several-percentage-valence-electron excitations in cubic CH3NH3PbI3. While the hydrogen-bond interaction causes serious lattice distortions, the electronic excitation can recover the lattice symmetry largely by weakening hydrogen bonding. The study offers atomic dynamics to understand the excitation process in the organic-inorganic hybrid perovskite semiconductor.

Giant lattice expansion by quantum stress and universal atomic forces in semiconductors under instant ultrafast laser excitation.

Femtosecond lasers (fs) can cause a disparity between electronic and lattice temperatures in the very short period after irradiation. In this relatively cool lattice regime, the material properties can differ drastically from those under thermal equilibrium. In particular, first-principles calculations reveal two general mechanical effects on semiconductors. Firstly, the excitation can induce a negative pressure on the lattice, causing a >10% expansion, even for superhard diamond. Secondly, it induces inhomogeneous local forces on the atoms, for both perfect and distorted lattices. In the case of phase-change-memory for Ge2Sb2Te5 and GeTe alloys, such random forces cause a simultaneous phase transition from crystalline to amorphous, which enables faster data writing. These excitation effects are further supported by the time-dependent density functional theory. This work could be an important step in advancing fs laser techniques for the atomic-level control of structures, rather than relying on traditional melting or ablation approaches which often apply to much larger and non-atomic scales.

Effect of childhood trauma on cognitive functions in a sample of Chinese patients with schizophrenia.

In this study, we aimed to determine the influence of various types of childhood trauma (CT) on cognitive functions in Chinese patients presented with schizophrenia. One hundred sixty-two patients were assessed with the Childhood Trauma Questionnaire-Short Form (CTQ-SF) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). We investigated the correlations between various types of CT, demographic characteristics, and cognitive functions. Significant negative correlations were observed in physical abuse (PA) and sexual abuse (SA) with the language score (r=-0.190, -0.216, respectively, p<0.05). Similarly, physical neglect (PN) and the total score of CTQ were negatively correlated with the attention score (r=-0.17, -0.206, p<0.05, respectively) as well as the total RBANS score (r=-0.199, -0.223, respectively P<0.05). PN was also negatively correlated with delayed memory (r=-0.167, p<0.05). Regressions analysis indicated significant negative correlations between PN and attention, as well as the cognitive total score (p<0.001). Furthermore, demographic variables (years of education, family income) and clinical characteristics (type of anti-psychotics, duration of illness and times of recurrence) were correlated with cognitive functions. The current study showed that different types of CT could impact specific cognitive functions in Chinese schizophrenia patients. Therefore, we recommend that trauma-focused mental interventions for schizophrenia patients should be developed and routinely offered to patients.

Extrapyramidal Symptoms During Risperidone Maintenance Treatment in Schizophrenia: A Prospective, Multicenter Study.

The risperidone maintenance treatment in schizophrenia study was designed to identify the duration of maintenance treatment required with an initial therapeutic dose in contrast to reducing the dose over time. This study investigated extrapyramidal symptoms (EPSs) in different risperidone maintenance treatment paradigms over 1 year. Clinically stabilized patients with schizophrenia (n = 374) were randomized to a no-dose-reduction group and 4-week and 26-week reduction groups, in which the dose was gradually reduced by 50% over 8 weeks and maintained. Extrapyramidal symptoms were assessed at baseline and monthly for 6 months, followed by every 2 months. The Simpson-Angus Scale of Extrapyramidal Symptoms-Chinese version assessed EPS severity. Data were analyzed by a generalized linear mixed model (GLMM). The frequency of EPS at baseline was 23.2%, 20.0%, and 21.3% in the 4-week, 26-week, and no-dose-reduction groups, respectively. Risperidone dosage, positive symptoms, and disorganized thoughts at baseline predicted development of EPS. The GLMM indicated that a significant decrease in EPS was maintained, and different trajectories occurred over time across groups. In the 235 patients who continued treatment after 1 year, the incidence of EPS decreased to 4.1%, 2.8%, and 10.0% in the 4-week, 26-week, and no-dose-reduction groups, respectively, whereas the numbers of dropouts because of intolerable EPS were not significantly different (4.8%, 6.7%, and 6.2%, respectively). These novel findings indicate EPSs were tolerable and differentially decreased depending on the dose paradigm during the 1-year treatment period. Future studies should implement a GLMM to investigate antipsychotic adverse effects during long-term treatment.