Robust analysis of stepped wedge trials using composite likelihood models.

Stepped wedge trials (SWTs) are a type of cluster randomized trial that involve repeated measures on clusters and design-induced confounding between time and treatment. Although mixed models are commonly used to analyze SWTs, they are susceptible to misspecification particularly for cluster-longitudinal designs such as SWTs. Mixed model estimation leverages both "horizontal" or within-cluster information and "vertical" or between-cluster information. To use horizontal information in a mixed model, both the mean model and correlation structure must be correctly specified or accounted for, since time is confounded with treatment and measurements are likely correlated within clusters. Alternative non-parametric methods have been proposed that use only vertical information; these are more robust because between-cluster comparisons in a SWT preserve randomization, but these non-parametric methods are not very efficient. We propose a composite likelihood method that focuses on vertical information, but has the flexibility to recover efficiency by using additional horizontal information. We compare the properties and performance of various methods, using simulations based on COVID-19 data and a demonstration of application to the LIRE trial. We found that a vertical composite likelihood model that leverages baseline data is more robust than traditional methods, and more efficient than methods that use only vertical information. We hope that these results demonstrate the potential value of model-based vertical methods for SWTs with a large number of clusters, and that these new tools are useful to researchers who are concerned about misspecification of traditional models.

Commercial Nafion Membranes for Harvesting Osmotic Energy from Proton Gradients that Exceed the Commercial Goal of 5.0 W/m2.

Osmotic energy from proton gradients in industrial acidic wastewater can be harvested and converted to electricity through membranes, making it a renewable and sustainable power source. However, the currently designed membranes for harvesting proton gradient energy in acidic wastewater cannot simultaneously achieve excellent chemical/mechanical stability and high power density under a large-scale area and require high cost and complex operations. Here, we demonstrate that commercial Nafion membranes with high chemical/mechanical stability and proton transport selectivity can generate a power density of 5.1 W/m2 for harvesting osmotic energy from proton gradients under a test area of 0.2 mm2, which exceeds the commercial goal of 5.0 W/m2. Even under a test area of 12.5 mm2, a power density of 2.1 W/m2 can be achieved under a strong acid condition. In addition, the heat can greatly promote proton transport, and the power density is increased, i.e., 8.1 W/m2 at 333 K (5.1 W/m2 at 293 K) under a test area of 0.2 mm2. By matching membranes with ion selectivity, our work demonstrates the potential of Nafion membranes for harvesting proton gradient energy in acidic wastewater and provides an approach for large-scale conversion of osmotic energy.

Voronoi cell finite element method for heat conduction analysis of composite materials.

In this paper, Voronoi cell finite element method (VCFEM) based on assumed flux hybrid formulation has been presented for heat conduction problem of particle reinforced composites material. The heat fluxes satisfying a priori internal thermal balance are directly approximated independently in the matrix and the inclusion respectively. The temperatures on element boundary and matrix-inclusion interface are interpolated by nodal temperature. The thermal balance on the interelement boundary and matrix-inclusion interface is relaxed and introduced into the functional by taking the temperature as Lagrange multiplier. In this way, a functional containing two variables of heat flux and temperature is proposed. Full field heat flux and effective thermal conductivity are obtained. Feasibility and effectiveness of the proposed approach are verified through several numerical examples.

Trace analysis of 20 antihistamines in milk by ultrahigh performance liquid chromatography coupled with high field quadrupole orbitrap high resolution mass spectrometry followed dispersive micro solid phase extraction.

Ultrahigh-performance liquid chromatography coupled with high-field quadrupole Orbitrap high resolution mass spectrometry was used for the separation and determination of 20 antihistamines, and a dispersive micro solid-phase extraction procedure using high-performance absorbing material was developed as a sample preparation strategy for extracting 20 antihistamines from milk. Instrument conditions and key parameters influencing extraction efficiency were investigated to obtain an optimized method. The limit of detection for 20 antihistamines in milk using this method is 0.05 µg/L to 1.0 µg/L. Recoveries are between 80.7 % and 108.3 %, and the relative standard deviation is less than 15 %. It is suitable for confirmatory monitoring and quantitative analysis of 20 antihistamines in milk. The results show that antihistamines in milk may be noteworthy issues for human health and environmental pollution.

Effect of intraoperative blood transfusion during maternal cesarean section on serum electrolytes and inflammatory response plus cellular immune response: A retrospective study.

Analyzing the effect of intraoperative autotransfusion on serum electrolytes, inflammatory response and cellular immune response in puerperae undergoing cesarean section. This study is a retrospective study of 60 women who underwent cesarean section in our hospital from January 2022 to January 2023. The subjects were divided into 2 groups according to the blood transfusion mode of the patients. The differences in blood transfusion volume, blood transfusion volume, serum electrolyte, inflammatory response, cellular immune function, coagulation function and prognosis were compared between the 2 groups. The intraoperative blood transfusion volume, postoperative feeding time, the activity time since getting out of bed, the time of physical recovery and hospital stay in the observation group were lower compared to those of the control group, but the intraoperative crystal infusion volume and the colloid infusion volume in the observation group were higher compared to those of the control group (P < .05). Ca2+ concentrations of the observation group and the control group were lower compared with those of their same groups before surgery (P < .05), however, there were no statistically significant differences in the comparison of the Ca2+ concentrations between the observation group and the control group (P > .05). At 1d postoperatively, IL-1ß, IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were all higher (P < .05) and CD3+, CD4+ and CD4+/CD8+ were all lower (P < .05) in the observation group and the control group compared with those of their same groups before surgery. The IL-1 ß, IL-6, and GM-CSF of the observation group were decreased compared to those of the control group (P < .05) and CD3+, CD4+, CD4+/CD8+ of the observation group were elevated compared to those of the control group (P < .05). Both autotransfusion and allogeneic blood transfusions during maternal cesarean section can attenuate the inflammatory response and have no significant inhibition of coagulation, and autotransfusion have less effect on the cellular immune response, are more effective in attenuating the inflammatory response, and significantly improve prognosis, although changes in Ca2+ concentration after transfusion require attention.

Karst carbon sink mechanism and its contribution to carbon neutralization under land- use management.

The chemical weathering process of carbonate rocks consumes a large quantity of CO2. This has great potential as a carbon sink, and it is one of a significant pathway for achieving carbon neutrality. However, the control mechanisms of karst carbon sink fluxes are unclear, and there is a lack of effective and accurate accounting. We took the Puding Shawan karst water­carbon cycle test site in China, which has identical initial conditions but different land use types, as the research subject. We used controlled experiments over six years to evaluate the mechanisms for the differences in hydrology, water chemistry, concentrations and fluxes of dissolved organic carbon (DOC) and dissolved inorganic carbon (DIC). We found that the transition from rock to bare soil to grassland led to increases in the DIC concentration by 0.08-0.62 mmol⋅L-1. The inorganic carbon sink flux (CSF) increased by 3.01-5.26 t⋅C⋅km-2⋅a-1, an increase amplitude of 30-70 %. The flux of dissolved organic carbon (FDOC) increase by 0.28 to 0.52 t⋅C⋅km-2⋅a-1, an increase amplitude of 34-90 %. We also assessed the contribution of land use modifications to regional carbon neutrality, it indicate that positive land use modification can significantly regulate the karst carbon sink, with grassland having the greatest carbon sequestration ability. Moreover, in addition to DOC from soil organic matter degradation, DOC production by chemoautotrophic microorganisms utilizing DIC in groundwater may also be a potential source. Thus, coupled studies of the conversion of DIC to DOC processes in groundwater are an important step in assessing karst carbon sink fluxes.

Control of carbon dioxide exchange fluxes by rainfall and biological carbon pump in karst river-lake systems.

As an important component of inland water, the primary factors affecting the carbon cycle in karst river-lake systems require further investigation. In particular, the impacts of climatic factors and the biological carbon pump (BCP) on carbon dioxide (CO2) exchange fluxes in karst rivers and lakes deserve considerable attention. Using quarterly sampling, field monitoring, and meteorological data collection, the spatiotemporal characteristics of CO2 exchange fluxes in Erhai Lake (a typical karst lake in Yunnan, SW China) and its inflow rivers were investigated and the primary influencing factors were analyzed. The average river CO2 exchange flux reached 346.80 mg m-2 h-1, compared to -6.93 mg m-2 h-1 for the lake. The carbon cycle in rivers was strongly influenced by land use within the basin; cultivated and construction land were the main contributors to organic carbon (OC) in the river (r = 0.66, p < 0.01) and the mineralization of OC was a major factor in CO2 oversaturation in most rivers (r = 0.76, p < 0.01). In addition, the BCP effect of aquatic plants and the high pH in karst river-lake systems enhance the ability of water body to absorb CO2, resulting in undersaturated CO2 levels in the lake. Notably, under rainfall regulation, riverine OC and dissolved inorganic carbon (DIC) flux inputs controlled the level of CO2 exchange fluxes in the lake (rOC = 0.78, p < 0.05; rDIC = 0.97, p < 0.01). We speculate that under future climate and human activity scenarios, the DIC and OC input from rivers may alleviate the CO2 limitation of BCP effects in karst eutrophication lakes, possibly enabling aquatic plants to convert more CO2 into OC for burial. The results of this research can help advance our understanding of CO2 emissions and absorption mechanisms in karst river-lake systems.

A Self-Powered Biochemical Sensor for Intelligent Agriculture Enabled by Signal Enhanced Triboelectric Nanogenerator.

Precise agriculture based on intelligent agriculture plays a significant role in sustainable development. The agricultural Internet of Things (IoTs) is a crucial foundation for intelligent agriculture. However, the development of agricultural IoTs has led to exponential growth in various sensors, posing a major challenge in achieving long-term stable power supply for these distributed sensors. Introducing a self-powered active biochemical sensor can help, but current sensors have poor sensitivity and specificity making this application challenging. To overcome this limitation, a triboelectric nanogenerator (TENG)-based self-powered active urea sensor which demonstrates high sensitivity and specificity is developed. This device achieves signal enhancement by introducing a volume effect to enhance the utilization of charges through a novel dual-electrode structure, and improves the specificity of urea detection by utilizing an enzyme-catalyzed reaction. The device is successfully used to monitor the variation of urea concentration during crop growth with concentrations as low as 4 µm, without being significantly affected by common fertilizers such as potassium chloride or ammonium dihydrogen phosphate. This is the first self-powered active biochemical sensor capable of highly specific and highly sensitive fertilizer detection, pointing toward a new direction for developing self-powered active biochemical sensor systems within sustainable development-oriented agricultural IoTs.

Scalable Fabrication of Ionic-Conductive Covalent Organic Framework Fibers for Capturing of Sustainable Osmotic Energy.

High-performance covalent organic framework (COF) fibers are demanded for an efficient capturing of blue osmotic power because of their excellent durability, simple integration, and large scalability. However, the scalable production of COF fibers is still very challenging due to the poor solubility and fragile structure of COFs. Herein, for the first time, it is reported that COF dispersions can be continuously processed into macroscopic, meter-long, and pure COF fibers using a wet spinning approach. The two presented COF fibers can be directly used for capturing of osmotic energy, avoiding the production of composite materials that require other additives and face challenges such as phase separation and environmental issues induced by the additives. A COF fiber exhibits power densities of 70.2 and 185.3 W m-2 at 50-fold and 500-fold salt gradients, respectively. These values outperform those of most reported systems, which indicate the high potential of COF fibers for capturing of blue osmotic energy.

Long COVID and its association with neurodegenerative diseases: pathogenesis, neuroimaging, and treatment.

Corona Virus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has presented unprecedented challenges to the world. Changes after acute COVID-19 have had a significant impact on patients with neurodegenerative diseases. This study aims to explore the mechanism of neurodegenerative diseases by examining the main pathways of central nervous system infection of SARS-CoV-2. Research has indicated that chronic inflammation and abnormal immune response are the primary factors leading to neuronal damage and long-term consequences of COVID-19. In some COVID-19 patients, the concurrent inflammatory response leads to increased release of pro-inflammatory cytokines, which may significantly impact the prognosis. Molecular imaging can accurately assess the severity of neurodegenerative diseases in patients with COVID-19 after the acute phase. Furthermore, the use of FDG-PET is advocated to quantify the relationship between neuroinflammation and psychiatric and cognitive symptoms in patients who have recovered from COVID-19. Future development should focus on aggressive post-infection control of inflammation and the development of targeted therapies that target ACE2 receptors, ERK1/2, and Ca2+.

Intestinal Barrier Dysfunction and Gut Microbiota in Non-Alcoholic Fatty Liver Disease: Assessment, Mechanisms, and Therapeutic Considerations.

Non-alcoholic fatty liver disease (NAFLD) is a type of metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility without alcohol consumption, which encompasses a spectrum of liver disorders ranging from simple hepatic lipid accumulation, known as steatosis, to the more severe form of steatohepatitis (NASH). NASH can progress to cirrhosis and hepatocellular carcinoma (HCC), posing significant health risks. As a multisystem disease, NAFLD is closely associated with systemic insulin resistance, central obesity, and metabolic disorders, which contribute to its pathogenesis and the development of extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain extrahepatic cancers. Recent evidence highlights the indispensable roles of intestinal barrier dysfunction and gut microbiota in the onset and progression of NAFLD/NASH. This review provides a comprehensive insight into the role of intestinal barrier dysfunction and gut microbiota in NAFLD, including intestinal barrier function and assessment, inflammatory factors, TLR4 signaling, and the gut-liver axis. Finally, we conclude with a discussion on the potential therapeutic strategies targeting gut permeability and gut microbiota in individuals with NAFLD/NASH, such as interventions with medications/probiotics, fecal transplantation (FMT), and modifications in lifestyle, including exercise and diet.

Automatic ultrasensitive lateral flow immunoassay based on a color-enhanced signal amplification strategy.

Lateral flow immunoassays (LFIAs) are an essential and widely used point-of-care test for medical diagnoses. However, commercial LFIAs still have low sensitivity and specificity. Therefore, we developed an automatic ultrasensitive dual-color enhanced LFIA (DCE-LFIA) by applying an enzyme-induced tyramide signal amplification method to a double-antibody sandwich LFIA for antigen detection. The DCE-LFIA first specifically captured horseradish peroxidase (HRP)-labeled colored microspheres at the Test line, and then deposited a large amount of tyramide-modified signals under the catalytic action of HRP to achieve the color superposition. A limit of detection (LOD) of 3.9 pg/mL and a naked-eye cut-off limit of 7.8 pg/mL were achieved for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein. Additionally, in the inactivated virus detections, LOD equivalent to chemiluminescence (0.018 TCID50/mL) was obtained, and it had excellent specificity under the interference of other respiratory viruses. High sensitivity has also been achieved for detection of influenza A, influenza B, cardiac troponin I, and human chorionic gonadotrophin using this DCE-LFIA, suggesting the assay is universally applicable. To ensure the convenience and stability in practical applications, we created an automatic device. It provides a new practical option for point-of-care test immunoassays, especially ultra trace detection and at-home testing.

Addressing Challenges in Ion-Selectivity Characterization in Nanopores.

Ion selectivity is the basis for designing smart nanopore/channel-based devices, e.g., ion separators and biosensors. Quantitative characterization of ion selectivities in nanopores often employs the Nernst or Goldman-Hodgkin-Katz (GHK) equation to interpret transmembrane potentials. However, the direction of the measured transmembrane potential drop is not specified in these equations, and selectivity values calculated using absolute values of transmembrane potentials do not directly reveal the ion for which the membrane is selective. Moreover, researchers arbitrarily choose whether to use the Nernst or GHK equation and overlook the significant differences between them, leading to ineffective quantitative comparisons between studies. This work addresses these challenges through (a) specifying the transmembrane potential (sign) and salt concentrations in terms of working and reference electrodes and the solutions in which they reside when using the Nernst and GHK equations, (b) reporting of both Nernst-selectivity and GHK-selectivity along with solution compositions and transmembrane potentials when comparing different nanopores/channels, and (c) performing simulations to define an ideal selectivity for nanochannels. Experimental and modeling studies provide significant insight into these fundamental equations and guidelines for the development of nanopore/channel-based devices.

Dual-Activated H2O2-Responsive AIE Probes for Oocyte Quality Assessment.

Nonobstructive azoospermia (NOA) is an important cause of infertility, and intracytoplasmic sperm injection (ICSI) is the mainstay of treatment for these patients. In cases where a sufficient number of sperm (usually 1-2) is not available, the selection of oocytes for ICSI is a difficult problem that must be solved. Here, we constructed a dual-activated oxidative stress-responsive AIE probe, b-PyTPA. The strong donor-acceptor configuration of b-PyTPA leads to twisted intramolecular charge transfer (TICT) effect that quenches the fluorescence of the probe, however, H2O2 would specifically remove the boronatebenzyl unit and release a much weaker acceptor, which inhibits TICT and restores the fluorescence. In addition, the presence of a pyridine salt makes b-PyTPA more hydrophilic, whereas removal of the pyridine salt increases the hydrophobicity of PyTPA, which triggers aggregation and further enhances fluorescence. Thus, the higher the intracellular level of oxidative stress, the stronger the fluorescence. In vitro, this dual-activated fluorescent probe is capable of accurately detecting senescent cells (high oxidative stress). More importantly, b-PyTPA was able to characterize senescent oocytes, as assessed by the level of oxidative stress. It is also possible to identify high quality oocytes from those obtained for subsequent ICSI. In conclusion, this dual-activated oxidative stress-assessment probe enables the quality assessment of oocytes and has potential application in ICSI.

Source-free active domain adaptation for diabetic retinopathy grading based on ultra-wide-field fundus images.

Domain adaptation (DA) is commonly employed in diabetic retinopathy (DR) grading using unannotated fundus images, allowing knowledge transfer from labeled color fundus images. Existing DAs often struggle with domain disparities, hindering DR grading performance compared to clinical diagnosis. A source-free active domain adaptation method (SFADA), which generates features of color fundus images by noise, selects valuable ultra-wide-field (UWF) fundus images through local representation matching, and adapts models using DR lesion prototypes, is proposed to upgrade DR diagnostic accuracy. Importantly, SFADA enhances data security and patient privacy by excluding source domain data. It reduces image resolution and boosts model training speed by modeling DR grade relationships directly. Experiments show SFADA significantly improves DR grading performance, increasing accuracy by 20.90% and quadratic weighted kappa by 18.63% over baseline, reaching 85.36% and 92.38%, respectively. This suggests SFADA's promise for real clinical applications.

Pore-Size-Dependent Role of Functional Elements at the Outer Surface and Inner Wall in Single-Nanochannel Biosensors.

Biological nanopores feature functional elements on the outer surfaces (FEOS) and inner walls (FEIW), enabling precise control over ions and molecules with exceptional sensitivity and specificity. This provides valuable inspiration to scientists for the development of intelligent artificial nanochannel-based platforms, with a wide range of potential applications, including biosensors. Much effort has been dedicated to investigating the distinct contribution of FEOS and FEIW of multichannel membrane biosensors. However, the intricate interactions among neighboring pores in multichannel biosensors have presented challenges. This underscores the untapped potential of single nanochannels as ideal candidates in this field. Here, we employed single nanochannel membranes with different pore sizes to investigate the distinct contributions of FEIW and FEOS to single-nanochannel biosensors, combined with numerical simulations. Our findings revealed that alterations in the negative charges of FEIW and FEOS, induced by target binding, have differential effects on ion transport, contingent upon the degree of nanoconfinement. In the case of smaller pores, such as 20 nm, the ion concentration polarization driven by FEIW can independently control ion transport through the surface's electric double layer. However, as the pore size increases to 40-60 nm, both FEIW and FEOS become essential for effective ion concentration polarization. When the pore size reaches 100 nm, both FEIW and FEOS are ineffective and thus unsuitable for biosensors. Simulations demonstrate that the observed phenomena can be attributed to the interactions between the charges of FEIW and FEOS within the overlapping electric double layer under confinement. These results underscore the critical role of pore size as a key parameter in governing the functionality of probes within or on nanopore-based biosensors as well as in the design of nanopore-based devices.

Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma.

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal-tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high-tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.

Low-dose radiotherapy synergizes with iRGD-antiCD3-modified T cells by facilitating T cell infiltration.

BACKGROUND AND PURPOSE: Poor penetration of transferred T cells represents a critical factor impeding the development of adoptive cell therapy in solid tumors. We demonstrated that iRGD-antiCD3 modification promoted both T cell infiltration and activation in our previous work. Interest in low-dose radiotherapy has recently been renewed due to its immuno-stimulatory effects including T cell recruitment. This study aims to explore the synergistic effects between low-dose radiotherapy and iRGD-antiCD3-modified T cells. MATERIALS AND METHODS: Flow cytometry was performed to assess the expression of iRGD receptors and chemokines. T cell infiltration was evaluated by immunohistofluorescence and in vivo real-time fluorescence imaging and antitumor effects were investigated by in vivo bioluminescence imaging in the gastric cancer peritoneal metastasis mouse model. RESULTS: We found that 2 Gy irradiation upregulated the expression of all three iRGD receptors and T-cell chemokines. The addition of 2 Gy low-dose irradiation boosted the accumulation and penetration of iRGD-antiCD3-modified T cells in peritoneal tumor nodules. Combining 2 Gy low-dose irradiation with iRGD-antiCD3-modified T cells significantly inhibited tumor growth and prolonged survival in the peritoneal metastasis mouse model with a favorable safety profile. CONCLUSION: Altogether, we demonstrated that low-dose radiotherapy could improve the antitumor potency of iRGD-antiCD3-modified T cells by promoting T cell infiltration, providing a rationale for exploring low-dose radiotherapy in combination of other adoptive T cell therapies in solid tumors.

Outer-Surface Functionalized Solid-State Nanochannels for Enhanced Sensing Properties: Progress and Perspective.

Solid-state nanochannel-based sensing systems have been established as vigorous tools for sensing plentiful biomarkers due to their label-free, highly sensitive, and high-throughput screening. However, research on solid-state nanochannels has predominantly centered on the functional groups modified on the inner wall, neglecting investigations into the outer surface. Actually, the outer surface, as a part of the nanochannels, also plays a key role in regulating ionic current. When the target nears the entrance of the nanochannel and prepares to pass through, it would also interact with functional groups located on the nanochannel's outer surface, leading to subsequent alterations in the ionic current. Recently, the probes on the outer surface have experimentally demonstrated their ability to independently regulate ionic current, unveiling advantages in in situ target detection, especially for targets larger than the diameter of the nanochannels that cannot pass through them. Here, we review the progress over the past decade in nanochannels featuring diverse outer-surface functionalization aimed at enhanced sensing performance, including charge modification, wettability adjustment, and probe immobilization. In addition, we present the promises and challenges posed by outer-surface functionalized nanochannels and discuss possible directions for their future deployments.