Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.

Monthly-scale hydro-climatic forecasting and climate change impact evaluation based on a novel DCNN-Transformer network.

Climate change has emerged as one of the foremost global challenges confronting humanity today, leading to a heightened frequency and intensity of extreme weather phenomena, including droughts, floods, and erratic rainfall patterns. Accurately predicting changes in runoff patterns under future climate conditions holds significant importance for effective regional water resource planning and management. Recent research on runoff forecast has centered on optimizing hyperparameters of ELM, RNN, LSTM models using PSO, GWO, SSA, and other algorithms. Additionally, key features are extracted through input variable decomposition and preprocessing methods like EMD, EEMD, and VMD. However, these approaches have difficulties in extracting the long-term dependencies information of sequence units, parallel computing, and hyperparameter sensitivity. To address these shortcomings, this study proposes a novel end-to-end deep runoff prediction model based on deep convolutional neural network and Transformer (DCTN). The deep convolutional modules of DCTN employs the deep convolutional operation to extract local features of climate data while the Transformer of DCTN makes full use of self-attention to capture the long-term dependencies, which can achieve more accurate runoff predictions. Experiments on historical runoff forecasting at the Shanjiaodi hydrology station in the Dagu River Basin show that the proposed DCTN obtains a notable improvement of approximately 30.9% compared to traditional models. Based on the prediction results of three shared socioeconomic pathways, the potential impacts of climate change on runoff in Dagu River Basin were evaluated using the DCTN model. The results reveal that the likelihood of spring floods is substantially amplified in the mid-century and late-century, while the probability of extreme summer runoff diminishes. This study advances the understanding of runoff prediction and its implications under changing climate scenarios, paving the way for more informed decision-making and effective water resource management strategies.

Feasibility and efficacy of ultrasound-guided high-intensity focused ultrasound of breast fibroadenoma.

OBJECTIVE: This nonrandomized prospective clinical trial aimed to assess the efficacy, safety and follow-up outcomes of ultrasound-guided high-intensity focused ultrasound (USgHIFU) surgery in patients with breast fibroadenoma. METHODS: With the approval of the institutional ethics committee and written informed consent, a total of 113 patients diagnosed with breast fibroadenoma by core-needle biopsy in our hospital were recruited. USgHIFU surgery was performed under local anesthesia. Contrast-enhanced ultrasound (CEUS) or contrast-enhanced MRI (CEMRI) was performed to evaluate the nonperfused volume (NPV). The patients were followed up with physical examination and ultrasound imaging. RESULTS: The clinical outcome of 85 patients with 147 fibroadenomas with a follow-up time of more than 3 months was analyzed in this study. Fifty-two patients had one lesion, twenty-one patients had two lesions and twelve patients had more than two lesions. During USgHIFU, the median localization time for all fibroadenomas was 3 (interquartile range: 1, 5) min, and the median treatment time was 9 (interquartile range: 5, 15) min. Under local anesthesia, all the patients tolerated the treatment well. No serious epidermal burns were observed in any of the patients. Based on CEUS or CEMRI imaging evaluation, the median NPV ratio was 100% (interquartile range: 79.2%, 116.8%). The VRR were 26.77 ± 50.05%, 50.22 ± 42.01% and 72.74 ± 35.39% at 3-6 months, 6-12 months and >12 months, respectively, which showed significant statistical difference (p < .001). CONCLUSION: Ultrasound-guided HIFU surgery is an effective and safe noninvasive alternative technique for the treatment of breast fibroadenoma.

An inflammatory-related genes signature based model for prognosis prediction in breast cancer.

Background: Breast cancer has become the most common malignant tumor in the world. It is vital to discover novel prognostic biomarkers despite the fact that the majority of breast cancer patients have a good prognosis because of the high heterogeneity of breast cancer, which causes the disparity in prognosis. Recently, inflammatory-related genes have been proven to play an important role in the development and progression of breast cancer, so we set out to investigate the predictive usefulness of inflammatory-related genes in breast malignancies. Methods: We assessed the connection between Inflammatory-Related Genes (IRGs) and breast cancer by studying the TCGA database. Following differential and univariate Cox regression analysis, prognosis-related differentially expressed inflammatory genes were estimated. The prognostic model was constructed through the Least Absolute Shrinkage and Selector Operation (LASSO) regression based on the IRGs. The accuracy of the prognostic model was then evaluated using the Kaplan-Meier and Receiver Operating Characteristic (ROC) curves. The nomogram model was established to predict the survival rate of breast cancer patients clinically. Based on the prognostic expression, we also looked at immune cell infiltration and the function of immune-related pathways. The CellMiner database was used to research drug sensitivity. Results: In this study, 7 IRGs were selected to construct a prognostic risk model. Further research revealed a negative relationship between the risk score and the prognosis of breast cancer patients. The ROC curve proved the accuracy of the prognostic model, and the nomogram accurately predicted survival rate. The scores of tumor-infiltrating immune cells and immune-related pathways were utilized to calculate the differences between the low- and high-risk groups, and then explored the relationship between drug susceptibility and the genes that were included in the model. Conclusion: These findings contributed to a better understanding of the function of inflammatory-related genes in breast cancer, and the prognostic risk model provides a potentially promising prognostic strategy for breast cancer.

Learning Cross-Scale Weighted Prediction for Efficient Neural Video Compression.

Neural video codecs have demonstrated great potential in video transmission and storage applications. Existing neural hybrid video coding approaches rely on optical flow or Gaussian-scale flow for prediction, which cannot support fine-grained adaptation to diverse motion content. Towards more content-adaptive prediction, we propose a novel cross-scale prediction module that achieves more effective motion compensation. Specifically, on the one hand, we produce a reference feature pyramid as prediction sources and then transmit cross-scale flows that leverage the feature scale to control the precision of prediction. On the other hand, for the first time, a weighted prediction mechanism is introduced even if only a single reference frame is available, which can help synthesize a fine prediction result by transmitting cross-scale weight maps. In addition to the cross-scale prediction module, we further propose a multi-stage quantization strategy, which improves the rate-distortion performance with no extra computational penalty during inference. We show the encouraging performance of our efficient neural video codec (ENVC) on several benchmark datasets. In particular, the proposed ENVC can compete with the latest coding standard H.266/VVC in terms of sRGB PSNR on UVG dataset for the low-latency mode. We also analyze in detail the effectiveness of the cross-scale prediction module in handling various video content, and provide a comprehensive ablation study to analyze those important components. Test code is available at https://github.com/USTC-IMCL/ENVC.

New Dimension on Quality of Life Differences among Older Adults: A Comparative Analysis of Digital Consumption in Urban and Rural Areas of China.

The purpose of this study was to compare the variability in quality of life in the area of digital consumption among older adults in urban and rural China during the COVID-19 pandemic. This study proposed a low-cost mixed research method, and the methodology used a quantitative study of a large regional sample combined with a qualitative study of a small regional sample. Data for the large-scale area sample were obtained from the China family panel study (CFPS) dataset, and data for the small-scale regional sample were obtained from Nanjing, China. The quantitative analysis of the large-scale regional sample used the least squares regression analysis (OSL) and propensity score matching (PSM). The qualitative analysis of the small-scale regional sample used the selection optimization and compensation (SOC) model. The findings show that economic income is a direct driver of digital consumption. Digital consumption had a significant positive relationship with the quality of life for urban and rural older adults. In addition, the study established the semantic network relationships of the coping strategies of digital consumption of older adults and their drivers. Finally, the theoretical and practical implications of these findings are discussed in the context of other related studies.

LnNP@ZIF8 Smart System for In Situ NIR-II Ratiometric Imaging-Based Tumor Drug Resistance Evaluation.

Just-in-time evaluation of drug resistance in situ will greatly facilitate the achievement of precision cancer therapy. The rapid elevation of reactive oxygen species (ROS) is the key to chemotherapy. Hence, suppressed ROS production is an important marker for chemotherapy drug resistance. Herein, a NIR-II emission smart nanoprobe (LnNP@ZIF8, consisting of a lanthanide-doped nanoparticle (LnNP) core and metal-organic framework shell (ZIF8)) is constructed for drug delivery and in vivo NIR-II ratiometric imaging of ROS for tumor drug resistance evaluation. The drug-loaded nanoprobes release therapeutic substances for chemotherapy in the acidic tumor tissue. As the level of ROS increases, the LnNPs shows responsively descending fluorescence intensity at 1550 nm excited by 980 nm (F1550, 980Ex), while the fluorescence of the LnNPs at 1060 nm excited by 808 nm (F1060, 808Ex) is stable. Due to the ratiometric F1550, 980Ex/F1060, 808Ex value exhibiting a linear relationship with ROS concentration, NIR-II imaging results of ROS change based on this ratio can be an important basis for determining tumor drug resistance. As the chemotherapy and resistance evaluation are explored continuously in situ, the ratiometric imaging identifies drug resistance successfully within 24 h, which can greatly improve the timeliness of accurate treatment.

Asynchronous Episodic Deep Deterministic Policy Gradient: Toward Continuous Control in Computationally Complex Environments.

Deep deterministic policy gradient (DDPG) has been proved to be a successful reinforcement learning (RL) algorithm for continuous control tasks. However, DDPG still suffers from data insufficiency and training inefficiency, especially, in computationally complex environments. In this article, we propose asynchronous episodic DDPG (AE-DDPG), as an expansion of DDPG, which can achieve more effective learning with less training time required. First, we design a modified scheme for data collection in an asynchronous fashion. Generally, for asynchronous RL algorithms, sample efficiency or/and training stability diminish as the degree of parallelism increases. We consider this problem from the perspectives of both data generation and data utilization. In detail, we redesign experience replay by introducing the idea of episodic control so that the agent can latch on good trajectories rapidly. In addition, we also inject a new type of noise in action space to enrich the exploration behaviors. Experiments demonstrate that our AE-DDPG achieves higher rewards and requires less time consumption than most popular RL algorithms in learning to run task which has a computationally complex environment. Not limited to the control tasks in the computationally complex environments, AE-DDPG also achieves higher rewards and two-fold to four-fold improvement in sample efficiency on average compared with other variants of DDPG in MuJoCo environments. Furthermore, we verify the effectiveness of each proposed technique component through abundant ablation study.

[Etiological, clinical and imaging characters of reversible posterior encephalopathy syndrome].

OBJECTIVE: To elucidate the clinical and imaging characters of reversible posterior encephalopathy syndrome (PRES) and to discuss the etiological factors and the probable pathogenesis. METHOD: Retrospective analysis of basal diseases, clinical manifestations and imaging characters of 13 PRES patients was conducted with follow-ups. RESULTS: The common associated diseases are various kinds of kidney disease and renal inadequacy, eclampsia of gravidity and postpartum, connective tissue disease and immunosuppressives, et al. The main clinical manifestations are headache, convulsion, poor vision, changes of psychology or consciousness. The radiological findings are multifocal, symmetrical and posteriorly distributed in the cerebral hemispheres involving bilateral grey and white matter abnormalities in occipital, parietal and frontal regions. The majority of patients with PRES have an excellent prognosis. CONCLUSION: The etiological factors and pathogenesis of PRES are different and not all of them are reversible. Thus it is decisive to take specific and appropriate measures.

An integrated microwell array platform for cell lasing analysis.

Biological cell lasers are emerging as a novel technology in biological studies and biomedical engineering. The heterogeneity of cells, however, can result in various lasing behaviors from cell to cell. Thus, the capability to track individual cells during laser investigation is highly desired. In this work, a microwell array was integrated with high-quality Fabry-Pérot cavities for addressable and automated cell laser studies. Cells were captured in the microwells and the corresponding cell lasing was achieved and analyzed using SYTO9-stained Sf9 cells as a model system. It is found that the presence of the microwells does not affect the lasing performance, but the cell lasers exhibit strong heterogeneity due to different cell sizes, cycle stages and polyploidy. Time series laser measurements were also performed automatically with the integrated microarray, which not only enables the tracking and multiplexed detection of individual cells, but also helps identify "abnormal" cells that deviate from a large normal cell population in their lasing performance. The microarrayed cell laser platform developed here could provide a powerful tool in single cell analysis using lasing emission that complements conventional fluorescence-based cell analysis.

Differential effect of PARP-2 deletion on brain injury after focal and global cerebral ischemia.

Poly(ADP-ribose) polymerase-2 (PARP-2) is a member of the PARP enzyme family, and, similarly to PARP-1, catalyzes the formation of ADP-ribose polymers in response to DNA damage. While PARP-1 overactivation contributes to ischemic cell death, no information is available regarding the role of PARP-2. In this study, we evaluated the impact of PARP-2 deletion on histopathological outcome from two different experimental models of cerebral ischemia. Male PARP-2-/- mice and wild-type (WT) littermates were subjected to either 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h reperfusion, or underwent 10 mins of KCl-induced cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) and 3-day survival. After MCAO, infarct volume was reduced in PARP-2-/- mice (38%+/-12% of contralateral hemisphere) compared with WT (64%+/-16%). After CA/CPR, PARP-2 deletion significantly increased neuronal cell loss in the hippocampal CA1 field (65%+/-36% ischemic neurons) when compared with WT mice (31%+/-33%), with no effect in either striatum or cortex. We conclude that PARP-2 is a novel executioner of cell death pathways in focal cerebral ischemia, but might be a necessary survival factor after global ischemia to mitigate hippocampal delayed cell death.

Age-dependent effects of testosterone in experimental stroke.

Although male sex is a well-recognized risk factor for stroke, the role of androgens in cerebral ischemia remains unclear. Therefore, we evaluated effects of testosterone on infarct size in both young adult and middle-aged rats (Wistar, 3-month versus 14-month old) and mice (C57/BL6, 3-month versus 12-month old) subjected to middle cerebral artery occlusion. In young adult groups, castrates displayed less ischemic damage as compared with intact males and castrates with testosterone replacement (Cortex: 24% in castrates versus 42% in intact versus 40% with testosterone; Striatum: 45% versus 73% versus 70%) at 22 h reperfusion. Surprisingly, supplementing testosterone in middle-aged rats to the physiologic levels ordinarily seen in young males reduced infarction (Cortex: 2% with testosterone versus 31%; Striatum: 38% with testosterone versus 68%). Testosterone effects on infarct size were blocked by the androgen receptor (AR) antagonist flutamide and further confirmed in young versus middle-aged mice. Baseline cerebral aromatase mRNA levels and activity were not different between young and middle-aged rats. Aromatase activity increased in ischemic tissue, but only in young males. Lastly, stroke damage was not different in aging aromatase knockout mice versus wild-type controls. Our findings indicate that testosterone's effects in experimental stroke are age dependent, mediated via AR, but not cerebral aromatase.

Poly(ADP-ribose) (PAR) polymer is a death signal.

Excessive activation of the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) plays a prominent role in various of models of cellular injury. Here, we identify poly(ADP-ribose) (PAR) polymer, a product of PARP-1 activity, as a previously uncharacterized cell death signal. PAR polymer is directly toxic to neurons, and degradation of PAR polymer by poly(ADP-ribose) glycohydrolase (PARG) or phosphodiesterase 1 prevents PAR polymer-induced cell death. PARP-1-dependent, NMDA excitotoxicity of cortical neurons is reduced by neutralizing antibodies to PAR and by overexpression of PARG. Neuronal cultures with reduced levels of PARG are more sensitive to NMDA excitotoxicity than WT cultures. Transgenic mice overexpressing PARG have significantly reduced infarct volumes after focal ischemia. Conversely, mice with reduced levels of PARG have significantly increased infarct volumes after focal ischemia compared with WT littermate controls. These results reveal PAR polymer as a signaling molecule that induces cell death and suggests that interference with PAR polymer signaling may offer innovative therapeutic approaches for the treatment of cellular injury.

Kappa-opioid receptor selectivity for ischemic neuroprotection with BRL 52537 in rats.

UNLABELLED: Kappa-opioid receptors (KOR) have been implicated in neuroprotection from ischemic neuronal injury, but less work has been performed with transient focal cerebral ischemia to determine the role of KOR during reperfusion. We tested the effects of a selective and specific KOR agonist, BRL 52537 hydrochloride [(+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine], and the standard KOR antagonist, nor-binaltorphimine dihydrochloride [nor-BNI; 17,17'-(dicyclopropylmethyl)-6,6',7,7'-6,6'-imino-7,7'-binorphinan-3,4',14,14'-tetrol], on functional and histological outcome after transient focal ischemia in the rat. By use of the intraluminal filament technique, halothane-anesthetized adult male Wistar rats were subjected to 2 h of middle cerebral artery occlusion confirmed by laser Doppler flowmetry. In a blinded, randomized fashion, rats were treated with 1). saline (vehicle) 15 min before reperfusion followed by saline at reperfusion for 22 h, 2). saline 15 min before reperfusion followed by BRL 52537 (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, 3). saline 15 min before reperfusion followed by nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h, or 4) nor-BNI (1 mg/kg) 15 min before reperfusion followed by BRL 52537 (1 mgx kg(-1)x h(-1)) and nor-BNI (1 mg x kg(-1) x h(-1)) at reperfusion for 22 h. Infarct volume (percentage of ipsilateral structure) analyzed at 4 days of reperfusion was significantly attenuated in saline/BRL 52537 rats (n = 8; cortex, 10.2% +/- 4.3%; caudoputamen [CP], 23.8% +/- 6.7%) (mean +/- SEM) compared with saline/saline treatment (n = 8; cortex, 28.6% +/- 4.9%; CP, 53.3% +/- 5.8%). Addition of the specific KOR antagonist nor-BNI to BRL 52537 completely prevented the neuroprotection (n = 7; cortex, 28.6% +/- 5.3%; CP, 40.9% +/- 6.2%) conferred by BRL 52537. BRL 52537 did not produce postischemic hypothermia. These data demonstrate that KORs may provide a therapeutic target during early reperfusion after ischemic stroke. IMPLICATIONS: The neuroprotective effect of selective kappa-opioid agonists in transient focal ischemia is via a selective action at the kappa-opioid receptors.

Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies.

Fatty acid synthase (FAS) has been identified as a potential antifungal target. FAS prepared from Saccharomyces cerevisiae was employed for bioactivity-guided fractionation of Chlorophora tinctoria,Paspalum conjugatum, Symphonia globulifera, Buchenavia parviflora, and Miconia pilgeriana. Thirteen compounds (1-13), including three new natural products (1, 4, 12), were isolated and their structures identified by spectroscopic interpretation. They represented five chemotypes, namely, isoflavones, flavones, biflavonoids, hydrolyzable tannin-related derivatives, and triterpenoids. 3'-Formylgenistein (1) and ellagic acid 4-O-alpha-l-rhamnopyranoside (9) were the most potent compounds against FAS, with IC(50) values of 2.3 and 7.5 microg/mL, respectively. Furthermore, 43 (14-56) analogues of the five chemotypes from our natural product repository and commercial sources were tested for their FAS inhibitory activity. Structure-activity relationships for some chemotypes were investigated. All these compounds were further evaluated for antifungal activity against Candida albicans and Cryptococcus neoformans. Although there were several antifungal compounds in the set, correlation between the FAS inhibitory activity and antifungal activity could not be defined.