Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants.

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 µCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

Ursodeoxycholic Acid Modulates the Interaction of miR-21 and Farnesoid X Receptor and NF-κB Signaling.

(1) Background: This study investigates the effects of Ursodeoxycholic acid (UDCA) on NF-κB signaling, farnesoid X receptor (FXR) singling, and microRNA-21 in HepG2 cells. (2) Methods: HepG2 cells were treated with lipopolysaccharide (LPS) to simulate hepatic inflammation. The investigation focused on the expression of NF-κB activation, which was analyzed using Western blot, confocal microscopy, and Electrophoretic Mobility-shift Assays (EMSA). Additionally, NF-κB and farnesoid X receptor (FXR) singling expressions of micro-RNA-21, COX-2, TNF-α, IL-6, cyp7A1, and shp were assessed by RT-PCR. (3) Results: UDCA effectively downregulated LPS-induced expressions of NF-κB/65, p65 phosphorylation, and also downregulated FXR activity by Western blot. Confocal microscopy and EMSA results confirmed UDCA's role in modulating NF-κB signaling. UDCA reduced the expressions of LPS-induced COX-2, TNF-α, and IL-6, which were related to NF-κB signaling. UDCA downregulated LPS-induced cyp7A1 gene expression and upregulated shp gene expression, demonstrating selective gene regulation via FXR. UDCA also significantly decreased micro-RNA 21 levels. (4) Conclusions: This study demonstrates UDCA's potent anti-inflammatory effects on NF-κB and FXR signaling pathways, and thus its potential to modulate hepatic inflammation and carcinogenesis through interactions with NF-κB and FXR. The decrease in micro-RNA 21 expression further underscores its therapeutic potential.

Distinguishing the contributions of different smelting emissions to the spatial risk footprints of toxic elements in soil using PMF, Bayesian isotope mixing models, and distance-based regression.

Toxic element pollution of soils emanating from smelting operations is an escalating global concern due to its severe impact on ecosystems and human health. In this study, soil samples were collected and analyzed to quantify the risk contributions and delineate the spatial risk footprints from smelting emissions for 8 toxic elements. A comprehensive health risk contribution and delineation framework was utilized, consisting of Positive matrix factorization (PMF), spatial interpolation, an advanced Bayesian isotope mixing model via Mixing Stable Isotope Analysis in R (MixSIAR), and distance-based regression. The results showed that the mean concentrations of As, Cd, Cu, Hg, Pb, and Zn exceeded the background levels, indicating substantial contamination. Three sources were identified using the PMF model and confirmed by spatial interpolation and MixSIAR, with contributions ranked as follows: industrial wastewater discharge and slag runoff from the smelter site (48.9 %) > natural geogenic inputs from soil parent materials (26.7 %) > atmospheric deposition of dust particles from smelting operations (24.5 %). Among the identified sources, smelter runoff posed the most significant risk, accounting for 97.9 % of the non-carcinogenic risk (NCR) and 59.9 % of the carcinogenic risk (CR). Runoff also drove NCR and CR exceedances at 7.8 % and 4.7 % of sites near the smelter, respectively. However, atmospheric deposition from smelting emissions affected soils across a larger 0.8 km radius. Although it posed lower risks, contributing just 1.1 % to NCR and 22.6 % to CR due to the limited elevation of toxic elements, deposition reached more distant soils. Spatial interpolation and distance-based regression delineated high NCR and CR exposure hotspots within 1.4 km for runoff and 0.8 km for deposition, with exponentially diminishing risks at further distances. These findings highlight the need for pathway-specific interventions that prioritize localized wastewater containment and drainage controls near the smelter while implementing broader regional air pollution mitigation measures.

A Concise Route to Keto-Bridged Polyphenols by Photo-Fries Rearrangement in Flow.

Described is a new synthetic route to bis(2-hydroxy-3,5-di-t-butylphenyl)methanone and its derivatives. The combined esterification/photo-Fries rearrangement approach enables a modular preparation of keto-bridged polyphenols. This protecting group-free process is highly atom- and step-economic, and a scalable production was easily achieved in the continuous-flow mode.

An Antibody-Drug Conjugate for Multiple Myeloma Prepared by Multi-Arm Linkers.

First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.

The prediction of the survival in patients with severe trauma during prehospital care: Analyses based on NTDB database.

PURPOSE: Traumas cause great casualties, accompanied by heavy economic burdens every year. The study aimed to use ML (machine learning) survival algorithms for predicting the 8-and 24-hour survival of severe traumas. METHODS: A retrospective study using data from National Trauma Data Bank (NTDB) was conducted. Four ML survival algorithms including survival tree (ST), random forest for survival (RFS) and gradient boosting machine (GBM), together with a Cox proportional hazard model (Cox), were utilized to develop the survival prediction models. Following this, model performance was determined by the comparison of the C-index, integrated Brier score (IBS) and calibration curves in the test datasets. RESULTS: A total of 191,240 individuals diagnosed with severe trauma between 2015 and 2018 were identified. Glasgow Coma Scale (GCS), trauma type, age, SaO2, respiratory rate (RR), systolic blood pressure (SBP), EMS transport time, EMS on-scene time, pulse, and EMS response time were identified as the main predictors. For predicting the 8-hour survival with the complete cases, the C-indexes in the test sets were 0.853 (0.845, 0.861), 0.823 (0.812, 0.834), 0.871 (0.862, 0.879) and 0.857 (0.849, 0.865) for Cox, ST, RFS and GBM, respectively. Similar results were observed in the 24-hour survival prediction models. The prediction error curves based on IBS also showed a similar pattern for these models. Additionally, a free web-based calculator was developed for potential clinical use. CONCLUSION: The RFS survival algorithms provide non-parametric alternatives to other regression models to be of clinical use for estimating the survival probability of severe trauma patients.

Unfolded Von Willebrand Factor Binds Protein S and Reduces Anticoagulant Activity.

Protein S (PS), the critical plasma cofactor for the anticoagulants tissue factor (TF) pathway inhibitor (TFPI) and activated protein C (APC), circulates in two functionally distinct pools: free (anticoagulant) or bound to complement component 4b-binding protein (C4BP) (anti-inflammatory). Acquired free PS deficiency is detected in several viral infections, but its cause is unclear. Here, we identified a shear-dependent interaction between PS and von Willebrand Factor (VWF) by mass spectrometry. Consistently, plasma PS and VWF comigrated in both native and agarose gel electrophoresis. The PS/VWF interaction was blocked by TFPI but not APC, suggesting an interaction with the C-terminal sex hormone binding globulin (SHBG) region of PS. Microfluidic systems, mimicking arterial laminar flow or disrupted turbulent flow, demonstrated that PS stably binds VWF as VWF unfolds under turbulent flow. PS/VWF complexes also localized to platelet thrombi under laminar arterial flow. In thrombin generation-based assays, shearing plasma decreased PS activity, an effect not seen in the absence of VWF. Finally, free PS deficiency in COVID-19 patients, measured using an antibody that binds near the C4BP binding site in SHBG, correlated with changes in VWF, but not C4BP, and with thrombin generation. Our data suggest that PS binds to a shear-exposed site on VWF, thus sequestering free PS and decreasing its anticoagulant activity, which would account for the increased thrombin generation potential. As many viral infections present with free PS deficiency, elevated circulating VWF, and increased vascular shear, we propose that the PS/VWF interaction reported here is a likely contributor to virus-associated thrombotic risk.

Effect of continuous hypertonic saline infusion on clinical outcomes in patients with traumatic brain injury.

Osmotic therapy has been recognized as an important treatment option for patients with traumatic brain injury (TBI). Nevertheless, the effect of hypertonic saline (HTS) remains unknown, as findings are primarily based on a large database. This study aimed to elucidate the effect of HTS on the clinical outcomes of patients with TBI admitted to the intensive care unit (ICU). We retrospectively identified patients with moderate-to-severe TBI from two public databases: Medical Information Mart for Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during ICU stay. Trajectory modeling based on the intracranial pressure evolution pattern allowed for the identification of subgroups. Overall, 130 (6.65%) of 1955 eligible patients underwent HTS. MSCM indicated that the HTS significantly associated with higher infection complications (e.g., urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)) and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect of HTS on GCS was found in subgroups with medium and low intracranial pressure. Our study revealed no significant difference in mortality between patients who underwent HTS and those who did not. Increased occurrence rates of infection and electrolyte imbalance are inevitable outcomes of continuous HTS infusion. Although the study suggests slight beneficial effects, including better neurological outcomes, these results warrant further validation.

"Submarine-Shaped" Radial Forearm Flap for Simultaneous Reconstruction of Oral and Lower Lip Defects".

BACKGROUND: Reconstruction of the oral cavity commonly results in trismus and lip incompetence. AIM AND OBJECTIVES: In this study, we aim to describe an innovative design of a radial forearm free flap for resurfacing bilateral buccal defects and simultaneous functional lower lip reconstruction in a single stage. MATERIALS AND METHODS: Between January 2010 and December 2019, 6 males underwent simultaneous buccal and lower lip reconstruction with a radial forearm free flap. The mean age of the patients was 57.3 years (range, 50-68 years). The defects were caused by trismus release and due to previous treatments. The mean size of the defects was 17.9 cm in length and 3.25 cm in width. Flaps were harvested, including the proximal perforators of the radial vessels, and the inset began in the buccal area opposite the anastomosis side. RESULTS: Flap size ranged from 16 to 21 × 2 to 4 cm. The recipient vessels used were the superficial temporal (4) and facial (2). All flaps survived. Lip infection was seen in 2 cases and managed conservatively. The mean follow-up was 19.2 months (range, 12-28 months). The mean increase in the interincisal distance was 10.7 mm. Oral continence was good in all patients. Speech intelligibility was considered total in 4 patients and partial in the remaining 2. CONCLUSION: The radial forearm flap constitutes an option for simultaneous lower lip reconstruction and resurfacing of bilateral buccal areas after trismus release. The procedure provides a thin and pliable reconstruction using only 1 donor site and 1 set of recipient vessels.

Predicting Cd accumulation in rice and identifying nonlinear effects of soil nutrient elements based on machine learning methods.

The spatial mismatch of Cd content in soil and rice causes difficulties in environmental management for paddy soil. To investigate the influence of soil environment on the accumulation of Cd in rice grain, we conducted a paired field sampling in the middle of the Xiangjiang River basin, examining the relationships between soil properties, soil nutrient elements, Cd content, plant uptake factor (PUFCd), and translocation factors in different rice organs (root, shoot, and grain). The total soil Cd (CdT) and available Cd (CdA) contents and PUFCd showed large spatial variability with ranges of 0.31-6.19 mg/kg, 0.03-3.07 mg/kg, and 0.02-3.51, respectively. Soil pH, CdT, CdA, and the contents of soil nutrient elements (Mg, Mn, Ca, P, Si, and B) were linearly correlated with grain Cd content (Cdg) and PUFCd. The decision tree analysis identified nonlinear effects of Si, Zn and Fe on rice Cd accumulation, which suggested that low Si and high Zn led to high Cdg, and low Si and Fe caused high PUFCd. Using the soil nutrient elements as predictor variables, random forest models successfully predicted the Cdg and PUFCd and performed better than multiple linear regressions. It suggested the impacts of soil nutrient elements on rice Cd accumulation should receive more attention.

Thallium content in vegetables and derivation of threshold for safe food production in soil: A meta-analysis.

Soil thallium (Tl) pollution is a serious environmental problem, and vegetables are the primary pathway for human exposure to Tl. Therefore, it is important to investigate the characteristics of soil Tl uptake by vegetables. In this study, the meta-analysis approach was first applied to explore the relationship between Tl content in vegetables and soil environment, as well as key factors influencing soil physical-chemical properties, and to derive soil thresholds for Tl. The results indicated that various types of vegetables have different capabilities for Tl accumulation. Vegetables from contaminated areas showed high Tl accumulation, and the geomean Tl content in different types of vegetables was in the following order: leafy > root-stalk > solanaceous vegetables. Taro and kale had significantly higher capability to accumulate soil Tl among the 35 species studied, with Tl bioconcentration factor values of 0.060 and 0.133, respectively. Pearson correlation analysis and meta-analysis revealed that the Tl content in vegetables was significantly correlated with soil pH and Tl content in soil. The linear predictive model for Tl accumulation in vegetables based on soil Tl content described the data well, and the fitting coefficient R2 increased with soil pH value. According to potential dietary toxicity, the derived soil Tl thresholds for all, leafy and root-stalk vegetables increased with an increase in soil pH, and were in the range of 1.46-6.72, 1.74-5.26 and 0.92-6.06 mg/kg, respectively. The soil Tl thresholds for kale, lettuce and carrot were in the range of 0.24-4.89, 2.94-3.32 and 3.77-14.43 mg/kg, respectively. Ingestion of kale, beet, sweet potato, potato, taro, pepper, turnip, Chinese cabbage, eggplant and carrot poses potential health risks. The study provides scientific guidance for vegetable production in Tl-contaminated areas and can help with the selection of vegetable species suitable for avoiding the absorption of Tl from contaminated soil.

Valorization of spent coffee grounds through integrated bioprocess of fermentable sugars, volatile fatty acids, yeast-based single-cell protein and biofuels production.

Recovering nutrients from waste for biological processes aligns with sustainability principles. This study aimed to convert spent coffee grounds (SCG) into valuable products, including fermentable sugars, volatile fatty acids (VFAs), yeast-based single-cell protein and biofuels. Alkaline pretreatment was conducted before enzymatic hydrolysis, in which the pretreated SCG was hydrolyzed with varying enzyme loadings (20-60 filter paper units (FPU)/g-solid) and solid loadings (3-15 % w/v). The hydrolyzed slurry was utilized for VFAs and hydrogen production, yielding high values of 0.66 g/g-volatile solids (VS) and 109 mL/g-VS, respectively, using an enzyme loading of 50 FPU/g-solid and a solid loading of 3 % (w/v). The derived VFAs were used to cultivate a newly isolated yeast, Candida maltosa KKU-ARY2, resulting in an accumulated protein content of 43.7 % and a biomass concentration of 4.6 g/L. This study highlights the conversion of SCG into essential components, emphasizing the benefits of waste utilization through cascade bioprocesses.

Impacts of land use/cover and slope on the spatial distribution and ecological risk of trace metals in soils affected by smelting emissions.

The soil contamination around smelting sites shows high spatial heterogeneity. This study investigated the impacts of distance, land use/cover types, land slopes, wind direction, and soil properties on the distribution and ecological risk of trace metals in the soil around a copper smelter. The results demonstrated that the average concentrations of As, Cd, Cu, Pb, and Zn were 248.0, 16.8, 502.4, 885.6, and 250.2 g mg kg-1, respectively, higher than their background values. The hotspots of trace metals were primarily distributed in the soil of smelting production areas, runoff pollution areas, and areas in the dominant wind direction. The concentrations of trace metals decreased with the distance to the smelting production area. An exponential decay regression revealed that, depending on the metal species, the influence distances of smelting emissions on trace metals in soil ranged from 450 to 1000 m. Land use/cover types and land slopes significantly affected trace element concentrations in the soil around the smelter. High concentrations of trace metals were observed in farmland, grassland, and flatland areas. The average concentrations of trace metals in the soil decreased in the order of flat land > gentle slope > steep slope. Soil pH values were significantly positively correlated with Cd, Cu, Pb, Zn, and As, and SOM was significantly positively correlated with Cd, Pb, and Zn in the soil. Trace metals in the soil of the study area posed a significant ecological risk. The primary factors influencing the distribution of ecological risk, as determined by the Ctree analysis, were land slope, soil pH, and distance to the source. These results can support the rapid identification of high-risk sites and facilitate risk prevention and control around smelting sites.

[Vertical Migration Characteristics and Fate of Heavy Metals from Zinc Smelting Slag in Soil Profile].

To investigate the influence of heavy metals in smelting waste residue on the quality of soil and groundwater, a simulation column experiment was conducted to study the migration characteristics of heavy metals from the leaching solution of zinc volatilizing kiln residue in the site soil profile under continuous or intermittent leaching for 90 days. The concentrations of Cd, Cu, Pb, and Zn in leachate and their accumulation, chemical fractions, and particle size distribution characteristics in the soil profile were analyzed, and the retention mechanism of heavy metals was also discussed. The results showed that the concentration of heavy metals in the soil column leachate decreased rapidly after reaching the peak at the earlier leaching stage, and the Cd concentration far exceeded the threshold limit of 0.1 mg·L-1(class Ⅳ) of the Quality Standard for Groundwater(GB/T 14848-2017), indicating that there was Cd pollution risk of groundwater. The soil profile had a great adsorption capacity for heavy metals in the waste residue. Cd, Cu, Pb, and Zn were predominately accumulated in the shallow soil depth(0-10 cm), which was 237-429, 1.25-16.2, 1.38-2.31, and 1.79-3.17 times of the content of corresponding heavy metals in the soil profile before leaching, respectively. The migration distance of heavy metals in the slag under continuous leaching was longer than that under intermittent leaching, and Cd was significantly accumulated in the deep layer of the soil column. The contribution of soil coarse particles(0.5-2.0 mm) to the total cumulative amount of Cd, Cu, and Zn was larger, whereas Pb was more prone to accumulate in the particle size of<0.25 mm. The results of BCR sequential extraction fraction showed that the accumulated Cd, Cu, and Zn in shallow soil depth were mainly present in the weak acid extraction, accounting for 62.4%-76.7%, 72.0%-95.8%, and 67.6%-85.8% of total content, respectively. The X-ray diffraction(XRD) and Fourier transform infrared spectroscopy(FTIR) analysis showed that exogenous heavy metals in slag entering the soil would not form a stable mineral phase within 90 days, and the soil hydroxyl(-OH) and carbonyl(C=O) functional groups and iron aluminum silicate oxides were the main retention factors.

Deep learning, 3D ultrastructural analysis reveals quantitative differences in platelet and organelle packing in COVID-19/SARSCoV2 patient-derived platelets.

Platelets contribute to COVID-19 clinical manifestations, of which microclotting in the pulmonary vasculature has been a prominent symptom. To investigate the potential diagnostic contributions of overall platelet morphology and their α-granules and mitochondria to the understanding of platelet hyperactivation and micro-clotting, we undertook a 3D ultrastructural approach. Because differences might be small, we used the high-contrast, high-resolution technique of focused ion beam scanning EM (FIB-SEM) and employed deep learning computational methods to evaluate nearly 600 individual platelets and 30 000 included organelles within three healthy controls and three severely ill COVID-19 patients. Statistical analysis reveals that the α-granule/mitochondrion-to-plateletvolume ratio is significantly greater in COVID-19 patient platelets indicating a denser packing of organelles, and a more compact platelet. The COVID-19 patient platelets were significantly smaller -by 35% in volume - with most of the difference in organelle packing density being due to decreased platelet size. There was little to no 3D ultrastructural evidence for differential activation of the platelets from COVID-19 patients. Though limited by sample size, our studies suggest that factors outside of the platelets themselves are likely responsible for COVID-19 complications. Our studies show how deep learning 3D methodology can become the gold standard for 3D ultrastructural studies of platelets.

COVID-19 patients exhibit a range of symptoms including microclotting. Clotting is a complex process involving both circulating proteins and platelets, a cell within the blood. Increased clotting is suggestive of an increased level of platelet activation. If this were true, we reasoned that parts of the platelet involved in the release of platelet contents during clotting would have lost their content and appear as expanded, empty "ghosts." To test this, we drew blood from severely ill COVID-19 patients and compared the platelets within the blood draws to those from healthy volunteers. All procedures were done under careful attention to biosafety and approved by health authorities. We looked within the platelets for empty ghosts by the high magnification technique of electron microscopy. To count the ghosts, we developed new computer software. In the end, we found little difference between the COVID patient platelets and the healthy donor platelets. The results suggest that circulating proteins outside of the platelet are more important to the strong clotting response. The software developed will be used to analyze other disease states.

Stack versus Te technique for central slip reconstruction during vascularized toe proximal interphalangeal joint transfer.

BACKGROUND: Significant extension deficit is a common problem after a vascularized toe proximal interphalangeal joint transfer. One of the main causes related to extensor lag is central slip deficiency of the donor toes. In our clinical practice, we performed both the Stack and Te technique to reconstruct central slip function during a joint transfer. The aim of this study was to compare the long-term outcomes of vascularized joint transfers between these two techniques. PATIENTS AND METHODS: From May 2009 to October 2021, 38 digits in 36 patients (28 men and 8 women) underwent free vascularized toe joint transfer requiring central slip reconstruction. Eight and 30 digits were reconstructed with the Stack and Te technique, respectively. RESULTS: The median length of follow-up was 19 months (range, 5 to 78 months). The overall median extension lag was 20±20 degrees and the flexion was 80±20 degrees. There were no significant differences in extension lag (25±29 vs. 20±15 degrees, p = 0.281), flexion (75±10 vs. 85±20 degrees, p = 0.13), and range of motion (53±23 vs. 63±15 degrees, p = 0.076) of the joints between the Stack and Te techniques after the transfers. CONCLUSIONS: From the limited number of cases, both the Stack and Te techniques provided similar outcomes in correcting extension lag in vascularized joint transfers. The Te technique is a simplified and effective method for central slip reconstruction, while caution is advised when using the Stack technique due to potential complications.Clinical question/level of evidence: Therapeutic, IV.

Effects of Simulated Reclaimed Water on Soil Particle Sizes and Cd Adsorption and Migration in Soils at Smelting Sites.

This work studied the vertical migration characteristics of Cd in soil profiles from a zinc smelting site under the influence of simulated reclaimed water containing NaCl and Na2SO4. The isothermal adsorption curves of Cd in the soils of miscellaneous fill and weathered slate well fitted the Freundlich and Langmuir models, with R2 ranging from 0.991 to 0.998. The maximum adsorption capacity of Cd in the soils decreased significantly under the salt ion treatments with NaCl and Na2SO4. After leaching, the Cd concentrations in the leachates and Cd contents in the subsoil layers of 10-60 cm followed the order NaCl treatment > Na2SO4 treatment > CK (p < 0.05), suggesting that the salt ions promoted the vertical migration of exogenous Cd. The proportion of coarse particles (> 0.02 mm) decreased, while that of fine particles (< 0.02 mm) increased under salt ion treatments (p < 0.05). The morphological characterization indicated that salt ions accelerated the erosion and fragmentation of coarse particles to form fine particles. The use of reclaimed water to flush smelting sites may increase the risk of Cd migration with small-sized soil particles from the soil to groundwater.

Effect of multiple-digit replantation in patients with amputated digits.

PURPOSE: The replantation of multiple amputated digits is a technically challenging procedure for reconstructive surgeons that requires more time than the replantation of a single digit. We evaluated the effect of multiple-digit replantation on the success of digital replantation. METHODS: Patients who experienced digital amputation and underwent digital replantation from January 2018 to December 2021 were studied retrospectively. Patients who experienced successful and failed replantation were compared, as were digits that survived or became necrotic after replantation. A multivariate logistic regression (MLR) analysis was performed to evaluate the independent factors of replanted digit survival. RESULTS: There were 378 patients with 497 amputated digits who underwent digital replantation. Of all 378 patients, 298 underwent single-digit replantation, and the other 80 patients underwent multiple-digit replantation. A total of 83.3% of the replanted digits survived (414 of 497). Compared with patients with surviving replanted digits, significantly more patients with necrotic replanted digits underwent multiple-digit replantation (37.7% vs. 17.5%, p < 0.001). On the other hand, a digit that developed necrosis after replantation was more likely to have been involved in the replantation of three or more digits (16% vs. 29%, p = 0.005). The subsequent MLR analysis revealed that the likelihood of necrosis was 2.355 (p = 0.003) times higher in the replantation of three or more digits than in the replantation of one or two digits. CONCLUSION: Patients who underwent multiple-digit replantation exhibited a higher incidence of necrosis in the replanted digits. In cases involving patients with multiple-digit amputation, it is crucial to prioritize and perform selective replantation based on the amputated digits.

Site-specific Conjugation of 6 DOTA Chelators to a CA19-9-targeting scFv-Fc Antibody for Imaging and Therapy.

Antibodies conjugated with diagnostic/therapeutic radionuclides are attractive options for inoperable cancers lacking accurate imaging methods and effective therapeutics, such as pancreatic cancer. Hence, we have produced an antibody radionuclide conjugate termed TE-1132 comprising a α-CA19-9 scFv-Fc that is site-specifically conjugated at each C-terminus to 3 DOTA chelators via a cysteine-containing peptide linker. The smaller scFv-Fc size facilitates diffusivity within solid tumors, whereas the chelator-to-antibody ratio of six enabled 177Lu-radiolabeled TE-1132 to exhibit high radioactivity up to 520 MBq/nmol. In mice bearing BxPC3 tumors, immuno-SPECT/CT imaging of [111In]In-TE-1132 and the biodistribution of [177Lu]Lu-TE-1132 showed selective tumor accumulation. Single and multiple doses of [177Lu]Lu-TE-1132 effectively inhibited the BxPC3 tumor growth and prolonged the survival of mice with no irreversible body weight loss or hematopoietic damage. The adequate pharmacokinetic parameters, prominent tumor accumulation, and efficacy with good safety in mice encourage the further investigation of theranostic TE-1132 for treating pancreatic cancer.

Regulating cathode surface hydroxyl chemistry enables superior potassium storage.

Potassium vanadium fluorophosphate (KVPO4F) is regarded as a promising cathode candidate for potassium-ion batteries due to its high working voltage and satisfactory theoretical capacity. However, the usage of electrochemically inactive binders and redundant current collectors typically results in inferior electrochemical performance and low energy density, thus implying the important role of rational electrode structure design. Herein, we have reported a scalable and cost-effective synthesis of a cellulose-derived KVPO4F self-supporting electrode, which features a special surface hydroxyl chemistry, three-dimensional porous and conductive framework, as well as super flexible and stable architecture. The cellulose not only serves as a flexible substrate, a pore-forming agent, and a versatile binder for KVPO4F/conductive carbon but also enhances the K-ion migration ability. Benefiting from the special hydroxyl chemistry-induced storage mechanism and electrode structural stability, the flexible freestanding KVPO4F cathode exhibits high-rate performance (53.0% capacity retention with current densities increased 50-fold, from 0.2 C to 10 C) and impressive cycling stability (capacity retention up to 74.9% can be achieved over 1,000 cycles at a rate of 5 C). Such electrode design and surface engineering strategies, along with a deeper understanding of potassium storage mechanisms, provide invaluable guidance for better electrode design to boost the performance of potassium-ion energy storage systems.