Venetoclax plus cytarabine and azacitidine in relapsed/refractory AML: An open-label, single-arm, phase 2 study.

BACKGROUND: The outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. OBJECTIVE: This phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. METHODS: Thirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1-7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. RESULTS: The CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3-4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. CONCLUSION: The VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

Characterization of heavy metal, antibiotic pollution, and their resistance genes in paddy with secondary municipal-treated wastewater irrigation.

Secondary municipal-treated wastewater irrigation may introduce residual antibiotics into the agricultural systems contaminated with certain heavy metals, ultimately leading to the coexistence of antibiotics and heavy metals. The coexistence may induce synergistic resistance to both in the microbial community. Here, we investigated the effects of long-term municipal-treated irrigation for rice on the microbiome and resistome. The results showed that the target antibiotics were undetectable in edible grains, and the heavy metal concentrations did not exceed the standard in edible rice grains. Heavy metal resistance genes (MRGs) ruvB and acn antibiotic resistance genes (ARGs) sul1 and sul2 were the dominating resistant genes. The coexistence of antibiotics and heavy metals affected the microbial community and promoted metal and antibiotic resistance. Network analysis revealed that Proteobacteria were the most influential hosts for MRGs, ARGs, and integrons, and co-selection may serve as a potential mechanism for resistance maintenance. MRG czcA and ARG sul1 can be recommended as model genes to study the co-selection of ARGs and MRGs in environments. The obtained results highlight the importance of considering the co-occurrence of heavy metals and antibiotics while developing effective methods to prevent the transmission of ARGs. These findings are critical for assessing the possible human health concerns associated with secondary municipal-treated wastewater irrigation for agriculture and improving the understanding of the coexistence of heavy metals and antibiotics.

Practical Finite-Time Command-Filtered Adaptive Backstepping With Its Applications to Quadrotor Hovers.

In this article, a practical finite-time command-filtered adaptive backstepping (PFTCFAB) control method is presented for a class of uncertain nonlinear systems with nonparametric unknown nonlinearities and external disturbances. Unlike PFTCFAB control techniques that use neural networks (NNs) or fuzzy-logic systems (FLSs) to deal with system uncertainties, the proposed method is capable of handling such uncertainties without the need for NNs or FLSs, thus reducing complexity and increasing reliability. In the proposed approach, novel function adaptive laws are designed to directly estimate unknown nonparametric nonlinearities and external disturbances by means of command filter techniques, and a type of practical finite-time command filters is proposed to obtain such laws. Moreover, the PFTCFAB controllers and finite-time command filters are designed with practical finite-time Lyapunov stability, which ensures finite-time stability of system tracking and filter estimation errors. Experimental results with a quadrotor hover system are presented and discussed to demonstrate the advantages and effectiveness of the proposed control strategy.

Spatial and variety distributions, risk assessment, and prediction model for heavy metals in rice grains in China.

In this study, 6229 brown rice grains from three major rice-producing regions were collected to investigate the spatial and variety distributions of heavy metals in rice grains in China. The potential sources of heavy metals in rice grains were identified using the Pearson correlation matrix and principal component analysis, and the health risks of dietary exposure to heavy metals via rice consumption were assessed using the hazard index (HI) and total carcinogenic risk (TCR) method, respectively. Moreover, 48 paired soil and rice samples from 11 cities were collected to construct a predicting model for Cd accumulation in rice grains using the multiple linear stepwise regression analysis. The results indicated that Cd and Ni were the main heavy metal pollutants in rice grains in China, with approximately 10% of samples exceeding their corresponding maximum allowable limits. The Yangtze River basin had heavier pollution of heavy metals than the Southeast Coastal Region and Northeast Plain, and the indica rice varieties had higher heavy metal accumulation abilities compared with the japonica rice. The Cu, Pb, and Cd mainly originated from anthropogenic sources, while As, Hg, Cr, and Ni originated from both natural and anthropogenic sources. The mean HI and TCR values of dietary exposure to heavy metals via rice consumption ranged from 2.92 to 4.31 and 9.74 × 10-3 to 1.44 × 10-2, respectively, much higher than the acceptable range, and As and Ni were the main contributor to the HI and TCR for Chinese adults and children, respectively. The available Si (ASi), total Cd (TCd), available Mo (AMo), and available S (AS) were the main soil factors determining grain Cd accumulation. A multiple linear stepwise regression model was constructed based on ASi, TCd, AMo, and AS in soils with good accuracy and precision, which could be applied to predict Cd accumulation in rice grains and guide safe rice production in contaminated paddy fields.

Preclinical long-term safety of intraspinal transplantation of human dorsal spinal GABA neural progenitor cells.

Human pluripotent stem cell (hPSC)-derived neurons have shown promise in treating spinal cord injury (SCI). We previously showed that hPSC-derived dorsal spinal γ-aminobutyric acid (GABA) neurons can alleviate spasticity and promote locomotion in rats with SCI, but their long-term safety remains elusive. Here, we characterized the long-term fate and safety of human dorsal spinal GABA neural progenitor cells (NPCs) in naive rats over one year. All grafted NPCs had undergone differentiation, yielding mainly neurons and astrocytes. Fully mature human neurons grew many axons and formed numerous synapses with rat neural circuits, together with mature human astrocytes that structurally integrated into the rat spinal cord. The sensorimotor function of rats was not impaired by intraspinal transplantation, even when human neurons were activated or inhibited by designer receptors exclusively activated by designer drugs (DREADDs). These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

Response of heavy-metal and antibiotic resistance genes and their related microbe in rice paddy irrigated with treated municipal wastewaters.

Paddy irrigation with secondary effluents from municipal wastewater treatment plants (MWTPs) is a well-established practice to alleviate water scarcity. However, the reuse might lead to more complicated contamination caused by interactions between residual antibiotics in effluents and heavy metals in paddy soil. To date, no information is available for the potential effects of dual stress of heavy metals and antibiotics on heavy-metal resistance genes (MRGs) and antibiotic resistance genes (ARGs). Here, this study investigated the response of heavy metal and antibiotic resistance genes, and related microorganisms to the dual threat of antibiotics and heavy metals under the long-term MWTP effluent irrigation for rice paddy using metagenome. The results showed that there was not a negative effect on rice consumption if MWTP effluent was used to irrigate rice for a long time. The concentration of antibiotics could reshape the ARGs and MRG profiles in rice paddy soil. The findings revealed the co-occurrence of ARGs and MRGs in rice paddy soils, thus highlighting the need for simultaneous elimination of antibiotics and heavy metals to effectively reduce ARGs and MRGs. Acn and sul1 genes encoding Iron and sulfonamides resistance mechanisms are the most abundant MRG and ARG, respectively. Network analysis revealed the possibility that IntI1 plays a role in the co-transmission of MRG and ARG to host microbes, and that Proteobacteria are the most dominant hosts for MRG, ARG, and integrons. The presence of antibiotics in irrigated MWTP effluents has been found to stimulate the proliferation of heavy metal and antibiotic resistances by altering soil microbial communities. This study will enhance our comprehension of the co-selection between ARGs and MRGs, as well as reveal the concealed environmental impacts of combined pollution. The obtained results have important implications for food safety and human health in rice.

Successful Hemostasis With Prolonged Balloon Inflation at the Proximal Site of the Coronary Perforation.

Coronary perforation (CP) is a rare complication of percutaneous coronary intervention (PCI) and can lead to pericardial tamponade. Prolonged balloon inflation is a reasonable treatment for CP, but there is no standard recommendation on the preferable choice between the balloon site for prolonged balloon inflation (ie, proximal and in situ of the perforation). We present a rare case of successful prolonged balloon inflation at the proximal site of the CP after the failure of balloon inflation at the site of perforation. The patient developed CP during balloon inflation post-stent, rapidly progressing to cardiac tamponade. In situ prolonged balloon inflation (3 times) failed to close the CP, but proximal inflation could manage the CP. The take-home message from this case is that balloon expansion at the proximal site could be better than in situ of perforation in patients with CP after PCI.

Research Advances in the Treatment of Bone Marrow Edema Syndrome.

Bone marrow edema syndrome (BMES) is a relatively uncommon clinical condition. It has been poorly reported in the literature. Hence, doctors are not sufficiently aware of the disease and are prone to misdiagnosis and mistreatment, which can undoubtedly prolong the course of the disease, reduce the quality of life of patients and even affect their function. This paper reviews the literature and summarizes the treatment options for bone marrow edema syndrome, such as symptomatic treatment, extracorporeal shock waves therapy (ESWT), pulsed electromagnetic fields (PEFs), hyperbaric oxygen (HBO), vitamin D, iloprost, bisphosphonates, denosumab, and surgery, etc. This informs clinicians in treating bone marrow edema syndrome, hopefully improving patients' quality of life and shortening the duration of their disease.

Static and Dynamic Plantar Pressure Distribution in 94 Patients with Different Stages of Unilateral Knee Osteoarthritis Using the Footscan® Platform System: An Observational Study.

BACKGROUND Plantar pressure analysis is widely used in the study of knee osteoarthritis (KOA). The present study aimed to investigate the static and dynamic plantar pressure distribution in patients with different stages of unilateral KOA using the Footscan® platform system. MATERIAL AND METHODS We recruited 94 patients aged 61.75±7.23 years old with different stages of unilateral KOA for static and dynamic analysis using the Footscan® platform system. The static pressure (%) of the left, right, anterior, posterior, and the pelvic rotation (°) was assessed. The peak pressure (PP, kPa) was investigated in 10 areas of the foot: medial heel (MH), lateral heel (LH), midfoot (MF), first to fifth metatarsals (M1-M5), hallux (T1), and toes 2-5 (T2-5). The correlation between KOA stages and plantar pressure distributions was investigated. RESULTS The results revealed that static pressure on the unaffected side and pelvic rotation were positively correlated with KOA stages. In addition, there was a positive correlation between KOA stages and PP of M5, MF, and LH zones on the affected side and PP of M2, M3, and M4 zones on the unaffected side, and a negative correlation between KOA stages and PP of T1 and T2-5 zones on the affected side. CONCLUSIONS With the progression of KOA, static plantar pressure tends to distributed on the unaffected side, and the dynamic plantar pressure tends to be distributed laterally on both feet. The plantar pressure distributions in unilateral KOA patients are abnormal and are closely related to the severity of KOA.

Human spinal GABA neurons survive and mature in the injured nonhuman primate spinal cord.

Spinal cord injury (SCI) leads to permanent neural dysfunction without effective therapies. We previously showed that human pluripotent stem cell (hPSC)-derived spinal GABA neurons can alleviate spasticity and promote locomotion in rats after SCI, but whether this strategy can be translated into the clinic remains elusive. Here, a nonhuman primate (NHP) model of SCI was established in rhesus macaques (Macaca mulatta) in which the T10 spinal cord was hemisected, resulting in neural conduction failure and neural dysfunction, including locomotion deficits, pain, and spasms. Grafted human spinal GABA neurons survived for up to 7.5 months in the injured monkey spinal cord and retained their intrinsic properties, becoming mature and growing axons and forming synapses. Importantly, they are functionally alive, as evidenced by designer receptors exclusively activated by designer drug (DREADD) activation. These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

COVID-19 and risk spillovers of China's major financial markets: Evidence from time-varying variance decomposition and wavelet coherence analysis.

COVID-19 has influenced financial markets drastically; however, this influence has received little attention, particularly in China. This study investigates risk spillovers across China's financial and shipping markets through dynamic spillover measures based on time-varying parameter vector autoregression and generalized forecast error variance decompositions. Stock, fund, and futures markets are identified as major risk senders, whereas other markets are identified as major risk receivers. Surprisingly, bonds, gold, and shipping are safe havens that facilitate portfolio optimization. Furthermore, using wavelet coherence analysis, we find that the coherence between dynamic total spillover and COVID-19 varies across time and frequency domains.

Real-time route planning of unmanned aerial vehicles based on improved soft actor-critic algorithm.

With the application and development of UAV technology and navigation and positioning technology, higher requirements are put forward for UAV maneuvering obstacle avoidance ability and real-time route planning. In this paper, for the problem of real-time UAV route planning in the unknown environment, we combine the ideas of artificial potential field method to modify the state observation and reward function, which solves the problem of sparse rewards of reinforcement learning algorithm, improves the convergence speed of the algorithm, and improves the generalization of the algorithm by step-by-step training based on the ideas of curriculum learning and transfer learning according to the difficulty of the task. The simulation results show that the improved SAC algorithm has fast convergence speed, good timeliness and strong generalization, and can better complete the UAV route planning task.

Non-equilibrium spin-transport properties of Co/phosphorene/Co MTJ with non-collinear electrodes under mechanical bending.

Monolayer phosphorene has outstanding mechanical flexibility, making it rather attractive in flexible spintronics that are based on 2D materials. Here, we report a first-principles study on non-equilibrium electronic-transport properties of the Co/phosphorene/Co magnetic tunnel junction (MTJ) with two α-Co electrodes. The magnetic moments of the two electrodes are considered in the parallel configuration (PC) and the anti-parallel configuration (APC). The tunneling current through the MTJ is investigated at a small bias from 0 to 40 mV when mechanical bending is applied on the MTJ with different central angle (θ) values. For both the PC and APC, the tunneling current increases evidently and monotonously with increasing mechanical bending for 25° < θ < 40°, as compared to that without bending, which is mainly due to the reduced tunnel barrier. In the PC, the spin-injection efficiency (SIE) of the current is largely increased at a small bias from 0 to 40 mV for 25° ≤ θ ≤ 30° with a maximum of 90%, while the SIE is overall increased under all mechanical bending angles for the APC. The tunnel magnetoresistance is decreased with an increasing bias voltage, which can be largely enhanced for θ ≥ 25°, especially at small bias. Our results indicate that the Co/phosphorene/Co MTJ has promising applications in flexible low-power spintronic devices.

Astrocyte transplantation for repairing the injured spinal cord.

Spinal cord injury (SCI) leads to permanent deficits in neural function without effective therapies, which places a substantial burden on families and society. Astrocytes, the major glia supporting the normal function of neurons in the spinal cord, become active and form glial scars after SCI, which has long been regarded as a barrier for axon regeneration. However, recent progress has indicated the beneficial role of astrocytes in spinal repair. During the past three decades, astrocyte transplantation for SCI treatment has gained increasing attention. In this review, we first summarize the progress of using rodent astrocytes as the primary step for spinal repair. Rodent astrocytes can survive well, migrate extensively, and mature in spinal injury; they can also inhibit host reactive glial scar formation, stimulate host axon regeneration, and promote motor, sensory, respiratory, and autonomic functional recovery. Then, we review the progress in spinal repair by using human astrocytes of various origins, including the fetal brain, fetal spinal cord, and pluripotent stem cells. Finally, we introduce some key questions that merit further research in the future, including rapid generation of large amounts of human astrocytes with high purity, identification of the right origins of astrocytes to maximize neural function improvement while minimizing side effects, testing human astrocyte transplantation in chronic SCI, and verification of the long-term efficacy and safety in large animal models.

Polymerized Naphthalimide Derivatives as Remarkable Electron-Transport Layers for Inverted Organic Solar Cells.

Two polymerized naphthalimide derivatives, named as N-TBHOB and N-DBH, are prepared by quaternization. They exhibit excellent performance as electron-transport layers (ETLs) in inverted organic solar cells (i-OSCs). The results indicate N-TBHOB with a reticulated structure owns a superior performance on electron extraction, electron transport, thickness tolerance, and less carrier recombination compared with N-DBH with linear structure. The i-OSCs based on N-TBHOB with PTB7-Th:PC71 BM as the active layer achieve power conversion efficiencies (PCEs) of 10.72% and 10.03% under the thickness of 11 and 48 nm respectively, which indicates N-TBHOB possesses better thickness tolerance than most of organic ETLs in i-OSCs. N-TBHOB also shows more competent performance than N-DBH and ZnO in nonfullerene i-OSCs for comprehensively improved Jsc , Voc , and fill factor (FF) values. Its i-OSC with PM6:Y6 blend presents a high PCE of 16.78%. The study provides an efficient strategy to prepare ETLs by combining conjugated and nonconjugated units with a reticulated structure in the backbone for high-performance i-OSCs.

The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain. METHODS: A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS). RESULTS: The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022). CONCLUSIONS: Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

The Two-Pore Domain Potassium Channel TREK-1 Promotes Blood-Brain Barrier Breakdown and Exacerbates Neuronal Death After Focal Cerebral Ischemia in Mice.

Earlier studies have shown the neuroprotective role of TWIK-related K+ channel 1 (TREK-1) in global cerebral and spinal cord ischemia, while its function in focal cerebral ischemia has long been debated. This study used TREK-1-deficient mice to directly investigate the role of TREK-1 after focal cerebral ischemia. First, immunofluorescence assays in the mouse cerebral cortex indicated that TREK-1 expression was mostly abundant in astrocytes, neurons, and oligodendrocyte precursor cells but was low in myelinating oligodendrocytes, microglia, or endothelial cells. TREK-1 deficiency did not affect brain weight and morphology or the number of neurons, astrocytes, or microglia but did increase glial fibrillary acidic protein (GFAP) expression in astrocytes of the cerebral cortex. The anatomy of the major cerebral vasculature, number and structure of brain micro blood vessels, and blood-brain barrier integrity were unaltered. Next, mice underwent 60 min of focal cerebral ischemia and 72 h of reperfusion induced by the intraluminal suture method. TREK-1-deficient mice showed less neuronal death, smaller infarction size, milder blood-brain barrier (BBB) breakdown, reduced immune cell invasion, and better neurological function. Finally, the specific pharmacological inhibition of TREK-1 also decreased infarction size and improved neurological function. These results demonstrated that TREK-1 might play a detrimental rather than beneficial role in focal cerebral ischemia, and inhibition of TREK-1 would be a strategy to treat ischemic stroke in the clinic.

UV-enhanced NO2gas sensors based on In2O3/ZnO composite material modified by polypeptides.

This present study reported a high-performance gas sensor, based on In2O3/ZnO composite material modified by polypeptides, with a high sensibility to NO2, where the In2O3/ZnO composite was prepared by a one-step hydrothermal method. A series of results through material characterization technologies showed the addition of polypeptides can effectively change the morphology and size of In2O3/ZnO crystals, and effectively improve the sensing performance of the gas sensors. Due to the single shape and small size, In2O3/ZnO composite modified by polypeptides increased the active sites on the surface. At the same time, the gas sensing properties of four different ratios of polypeptide-modified In2O3/ZnO gas sensors were tested. It was found that the In2O3/ZnO-10 material showed the highest response, excellent selectivity, and good stability at room temperature under UV light. In addition, the response of the In2O3/ZnO-10 gas sensor showed a strong linear relationship with the NO2gas concentration. When the NO2gas concentration was 20 ppm, the response time was as quick as 19 s, and the recovery time was 57 s. Finally, based on the obtained experimental characterization results and energy band structure analysis, a possible gas sensing mechanism is proposed.

Improving the Energy Density and Efficiency of the Linear Polymer PMMA with a Double-Bond Fluoropolymer at Elevated Temperatures.

A variety of applications can be found for high-temperature film capacitors, including energy storage components and pulsed power sources. In this work, in order to increase the energy density (U e), poly(vinylidene fluoride-chlorotrifluoroethylene-double bond) (P-DB) is introduced into poly(methyl methacrylate) (PMMA) to manufacture composite films by a solution casting process. In the case of the pure PMMA film, there is significant improvement in the polarization (P max) and breakdown field (E b) of the composite film. These improvements can effectively increase the U e of the composite film at room temperature and the elevated temperature. The results show that at an elevated temperature of 90 °C and at 350 MV/m, the U e of 40 vol % P-DB reaches 8.7 J/cm3, and the efficiency (η) of 77% is also considerable. Compared with biaxially oriented polypropylene (2.0 J/cm3), the proposed film exhibits 4 times enhancement in the energy storage density, meaning that it can be an energy storage capacitor with huge potential at high temperatures.