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As the main heat and water mass sources, the warm and saline Pacific waters have significant influence on sea ice and intermediate water circulation in the Sea of Okhotsk (SO). However, the long-term history of Pacific warm water intrusion into the SO remains unknown, impeding accurate predictions of its future changes. In this study, provenance proxies (clay mineral assemblages and trace element ratios (<2 μm)) from surface sediments and Site LV87-55-1 were used to investigate the history of Pacific water intrusion into the SO over the past 20 kyr. Provenance analysis indicates that sediments in the central SO primarily originated from the Amur River before 11.7 ka, with a significant rise in sediment input from the Kamchatka Peninsula since that time. By integrating published data on sediment grain size, sea surface temperature (SST), and sea-ice diatoms, we observed that the enhanced inflow of Pacific warm water into the SO led to intensified counterclockwise surface currents and the retreat of sea ice since the early Holocene, which subsequently resulted in a noticeable shift in sediment sources in the central SO. Furthermore, based on modern observation and TraCE-21 model simulations, we deduce that the intensified Aleutian Low (AL) since the early Holocene stimulated the East Kamchatka Current (EKC) through increased Sverdrup transport caused by cyclonic wind patterns. This, in turn, facilitated greater intrusion of Pacific warm water into the SO. Overall, our findings suggest an increase in Pacific warm water intrusion into the SO under future global warming scenarios, potentially posing a significant threat to the marine environment of both the SO and the subarctic Pacific. • Provenance records indicate enhanced intrusion of Pacific water into the SO since 11.7 ka. • Increased warm water intrusion results from enhanced Aleutian Low since 11.7 ka. • Future warming climate would stimulate more Pacific water intrusion into the SO. [ABSTRACT FROM AUTHOR]

• Early antiplatelet use in stroke patients with endovascular treatment was investigated. • Early antiplatelet agents may be safe. • Further studies are required to confirm the efficacy. Endovascular treatment (ET) has been proved as safety and effective in acute ischemic stroke. However, early reocclusion is an inevitable complication following ET. There is uncertainty effect of early antiplatelet therapy on outcomes in patients with acute ischemic stroke undergoing endovascular treatment. We searched major databases for articles published from 2011 to 2019 in the present study. Safety outcomes were any intracranial hemorrhage (ICH), symptomatic intracranial hemorrhage (sICH) and mortality. Efficacy outcomes were recanalization rate and follow-up functional outcome. Review Manager 5.3 and Stata Software Package 14.0 were used to perform the meta-analysis. Seven studies with a total of 1251 patients were included. A total of 451 (36.1%) patients were administrated by antiplatelet agent following ET. Meta-analysis suggested that early antiplatelet did not increase the risk for ICH (OR 1.15; 95% CI 0.56–2.37; P = 0.70), sICH (OR 1.29; 95% CI 0.79–2.09; P = 0.31) and mortality (OR 0.71; 95% CI 0.45–1.12; P = 0.14). There was no association between antiplatelet therapy and recanalization rate (OR 1.03; 95% CI 0.73–1.46; P = 0.30) or functional outcome (OR 0.97; 95% CI 0.55–1.69; P = 0.90). Sensitivity analysis indicated tirofiban did not associated with any ICH and mortality, nor improve the recanalization rate and functional outcome in patients receiving ET or mechanical thrombectomy (all p > 0.05). Early antiplatelet therapy may be safe in acute ischemic stroke patients, further studies are needed to confirm the efficacy. [ABSTRACT FROM AUTHOR]

Background: Recently, the NIHSS STroke Scale score, Age, pre-stroke mRS score, onset-to-treatment Time (START nomogram) predicts 3-month functional outcome after intravenous thrombolysis in ischemic stroke patients. However, this model has not yet been an external validation. We aim to validate the performance of START nomogram.Methods: Data were derived from the stroke center of the Nanjing First Hospital (China). Patients who lacked the necessary data to calculate the nomogram and missed 3-month modified Ranking scale scores were excluded. Modified Rankin Scale score more than 2 at 3-month was assessed as an unfavorable outcome. We used areas under the receiver operator characteristic curves (AUC-ROC) to quantify the prognostic value. Calibration was assessed by calibration plots and Hosmer-Lemeshow (HL) goodness of fit test.Result: The final cohort included 306 eligible patients. For 3-month unfavorable outcome, the AUC-ROC of the START nomogram was .766 (95%CI: .7013-.8304, P < .0001), suggesting good discrimination in the START nomogram. It also showed good calibration (HL goodness of fit test P = .1261) in the external validation sample.Conclusion: The START nomogram with good predictive performance is a reliable and simple clinical instrument to predict unfavorable outcome after acute stroke. [ABSTRACT FROM AUTHOR]

Water resources constraint intensity (WRCI) refers to the conflict degree between water scarcity and human activities. We provide a comprehensive dynamic assessment index system for WRCI, which is composed of three primary indicators (natural endowment, exploitation and utilization degree, exploitation and utilization efficiency of water resources) and nine secondary indicators. After ascertaining the thresholds and grading standards for each specific indicator and their integrated indexes according to the experience of developed countries and regions, we employ an Analytic Hierarchy Process (AHP) model reformed by entropy technology to calculate their weights, and establish a multi objective fuzzy membership function to calculate the normalized values. Subsequently, we use the statistical data of 51 prefecture level regions in Northwest China during 2000–2014 to analyze the spatiotemporal changes of WRCI and its primary and secondary indicators. The results show that WRCI in the whole region of Northwest China belonged to the less strong or weak constraint type during the period. However, Northwest China was confronted with great disparity in human-water relationship according to the temporal and spatial changes of WRCI and its primary and secondary indicators. About 1/3 of prefecture level regions belonged to the strong and very strong constraint type. About 1/3 belonged to the less strong constraint type. Only about 1/3 belonged to the weak and very weak constraint type. The framework provides a relatively absolute evaluation of the conflict degree between the human-water systems. It might help to scientifically understand the spatiotemporal features of the relationship between water scarcity and human activities for Northwest China, and also has the potential for application in other areas and scales for monitoring and comparison purposes in space and over time. [ABSTRACT FROM AUTHOR]

Sediment core OS03-1 retrieved from the Akademia Nauk Rise in Southern Okhotsk Sea was analyzed for the contents of rare earth elements (REEs) and combined with carbon isotope (δ 13 C) time series of benthic foraminifera to infer changes in terrigenous accumulation and bottom water ventilation on glacial–interglacial timescales in the study area. The age model of OS03-1 was constructed by a combination of foraminifer δ 18 O stratigraphy and 14 C AMS dating, revealing that the 380 cm long core provides a window on climate change in the southern Okhotsk Sea since ∼180 ka. A grain size-controlled-REE content shows strong glacial–interglacial changes. The Cerium and Europium anomalies vary from 0.89 to 1.32 and from 1.14 to 1.37, respectively. The (La/Yb) N values range between 0.55 to 0.92. Both results suggest a significant contribution of volcanic debris in the core sediments. In addition, the relationships between Sm vs. Nd suggest main contribution origin from the Amur River and sea ice during warm intervals and from the sea ice during cold intervals, indicating that the sea ice played an important role in transporting terrigenous materials to the study site in the southern Okhotsk Sea. During the last 180 ka, the mass accumulation rates (MAR) of ∑REEs are relatively higher during glacials and lower during interglacials with a peak accumulation during the early deglacial period. We infer that an intensified Mongolia High is responsible for the first-order accumulation pattern of ∑REEs in the southern Okhotsk Sea by mediating the dynamic changes in sea ice extent. Furthermore, six δ 13 C minima are associated with intensified Asian monsoon (AM) precipitation and maximum MARs of ∑REEs, indicating that the dominance of barrier layer effects by high fresh water input through sea ice melting. The maximum MAR of ∑REEs during the Marine Isotope Stage (MIS) 5c coincides with the minimum of benthic foraminiferal δ 13 C, indicating a major interruption of ventilation in the bottom water in the Okhotsk Sea. The major low ventilation event in the deep water of the Okhotsk Sea appears to be dampened by a cooling condition and a major blooming of surface productivity preceded the event. [ABSTRACT FROM AUTHOR]

Abstract: Background: Glucosamine sulfate is used for the treatment of arthrosis, especially osteoarthritis of the knee joint. The available evidence suggests differences in its pharmacokinetics in Chinese subjects compared with non-Chinese subjects. Objective: The aim of this study was to compare the pharmacokinetics and relative bioavailability of a test and reference formulation of glucosamine sulfate 500 mg after single oral administration in healthy Chinese volunteers. Methods: This open-label, randomized-sequence, single-dose, 2-way crossover study was performed at the First Hospital of Nanjing Medical University, Nanjing, China. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 500-mg dose of the test or reference capsule formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Glucosamine sulfate was assayed using a liquid-chromatography tandem mass spectrometry method. For analysis of pharmacokinetic properties, including Cmax, AUC0−t, and AUC0−∞), blood samples were obtained at intervals over a 14-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (70%–143% for Cmax and 80%–125% for AUC) as established by the State Food and Drug Administration (SFDA) of China. Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). Results: Twenty–two healthy male Chinese subjects were enrolled (mean [range] age, 24 [22–26] years; weight, 63.9 [58.5–69.3] kg; height, 172 [167–177] cm); all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of Cmax, AUC0−t, and AUC0−∞) were 93.4 to 127.3, 92.4 to 114.5, and 92.7 to 114.6, respectively (all, P = NS). The AUC0−∞ of the test and reference formulations was 1.83 (0.66) and 1.77 ( 0.72) μg/h/mL, respectively. No AEs were observed or reported during the study. Conclusions: In this small study in healthy male Chinese volunteers, a single 500-mg dose of the test formulation met the SFDA''s regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated. [Copyright &y& Elsevier]

Abstract: Background: Cefteram pivoxil (CFTM-PI) is an oral antibiotic available in powder suspension and tablet formulations indicated in China for the treatment of bacterial infections. Although these 2 formulations are marketed in China, published information regarding their pharmacokinetics and bioequivalence in the Chinese population is not available. Objective: The aim of this study was to compare the pharmacokinetics and bioequivalence of the powder suspension (test) and tablet (reference) formulations of CFTM-PI 100 mg available in China. Methods: This single-dose, randomized-sequence, open-label, 2-period crossover study was performed at the Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned at a 1:1 ratio to receive a single 100-mg dose of the test or reference formulation, followed by a 1-week washout period and administration of the alternate formulation. The study drugs were administered after a 12-hour overnight fast. Plasma was assayed using a high-performance liquid chromatography method. For analysis of pharmacokinetic properties, including Cmax, AUC from time 0 (baseline) to 6 hours (AUC0-6), and AUC from baseline to infinity (AUC0-∞), blood samples were obtained at intervals over the 6-hour period after study drug administration. The formulations were considered bioequivalent if the log-transformed ratios of Cmax and AUC were within the predetermined equivalence range (80%-125%) as established by the US Food and Drug Administration (FDA). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis), and by questioning subjects about adverse events (AEs). Results: Twenty-four Chinese male subjects (mean [range]age,24.2 [23-32]years;weight,64.3 [58-67]kg; height, 172 [167-185] cm) enrolled; all completed the study. No period or sequence effect was observed. The 90% CIs for the log-transformed ratios of Cmax, AUC0-6;, and AUC0-∞ were 96.5 to 120.1, 95.7 to 110.2, and 96.2 to 110.4, respectively (all, P > 0.05). Similar results were found for the data without log-transformation. No AEs occurred or were reported during the study. Conclusions: In this small study in healthy Chinese adult male volunteers, a single 100-mg dose of the powder-suspension formulation was bioequivalent to a single 100-mg dose of the tablet formulation based on the US FDA''s regulatory definition (rate and extent of absorption). Both formulations were well tolerated. [Copyright &y& Elsevier]

As an integral part of the Earth's climate system, the Kuroshio Current (KC) plays a crucial role in shaping the regional oceanography and climate in the Northern Hemisphere. However, how the KC dynamics have varied over glacial-interglacial cycles is still under debate. The dynamic transfer and accumulation of submarine hydrothermal source materials by deep-reaching KC offer us a unique opportunity to examine the variations in dynamics of the KC. Here, we used novel proxies of sedimentary mercury (Hg) and antimony (Sb) in core MD01-2404 retrieved from the middle Okinawa Trough (OT) to reconstruct the evolution of the KC hydrodynamics over the last 92,000 years. We infer the enrichments of sedimentary Hg and Sb to signify hydrothermal input, which is delivered laterally to the study site by deep circulation in association with the KC, thus indicating the dynamics of KC. Overall, both the sedimentary Hg and Sb in core MD01-2404 indicate a persistent influence on the KC dynamics within the OT over the last glacial-interglacial cycles. Furthermore, our Hg and Sb proxies suggest a significantly weakened influence during the last deglaciation and last glacial period while a strengthened influence during the Holocene and late Marine Isotope Stage 5. Our studies imply that the orbital-scale dynamics of KC are controlled by tropical atmosphere-ocean interactions induced by sea surface temperature changes and regulated by the extratropical climate conditions. • We reconstructed the first 92,000-year records of sedimentary mercury and antimony from the middle Okinawa Trough. • The extent of hydrothermally-contributed enrichments of sedimentary Hg and Sb reflects the dynamics of Kuroshio Current. • Orbital-scale Kuroshio Current dynamics are controlled by both the tropical and extra-tropical climate. [ABSTRACT FROM AUTHOR]

Understanding past changes in oceanic circulation and the corresponding heat, salt delivery variations are essential for assessing the climatic roles of ocean dynamic processes since the last glacial period. Unravelling salinity budget variation in the North Pacific and its controls is important to better understand the North Pacific Intermediate/Deep Water formation and associated climate impacts. The Tsushima Warm Current (TWC), the northernmost Kuroshio branch entering the semi-closed Japan Sea through the shallow strait, is regarded as a fundamental component for oceanographic changes in the Japan Sea. To obtain a comprehensive history of the Japan Sea salinity budget, this study reconstructed the evolution history of the TWC inflow by compiling paleo-hydrographic records in the Japan Sea. Following a persistent but weakened TWC inflow during Marine Isotope Stage 3, radiolarian assemblage data revealed that the TWC taxa disappeared since ∼30 thousand years ago (ka). The synchronous onset of the low salinity anomaly event was in response to the cutoff of saline TWC inflow due to the rapid fall in global sea level at 30 ka. Extreme restriction of seawater exchange caused a persistent freshening of the glacial Japan Sea and formed a low-salinity water mass in the upper ocean. The compiled paleodata confirmed that the Japan Sea accumulated excess freshwater during the glacial sea-level lowstands and the low-salinity pool extended downward to ∼900 m depths. Coinciding with the peak of the low salinity anomaly event, re-emerging TWC inflow after 19 ka reflected the reconnection of the open ocean to the Japan Sea. The persistent TWC inflow mainly drove the reduction in magnitude of the deep low-salinity pool during the last deglaciation. As a large and isolated freshwater sink for the glacial North Pacific, the deep low-salinity pool evolution could potentially have strong impacts on the North Pacific salinity budget and subsequent large-scale circulation. • Radiolarian reconstruction indicates a persistent but weakened influence of the TWC inflow in the Japan Sea during MIS 3. • The low-salinity pool extended downward to ∼900 m depths in the Japan Sea during the LGM. • The link between global sea-level change and deep low-salinity pool evolution is sought. [ABSTRACT FROM AUTHOR]

Accurate assessment of future liver remnant growth after partial hepatectomy (PH) in patients with different liver backgrounds is a pressing clinical issue. Amino acid (AA) metabolism plays a crucial role in liver regeneration. In this study, we combined metabolomics and machine learning (ML) to develop a generalized future liver remnant assessment model for multiple liver backgrounds. The liver index was calculated at 0, 6, 24, 48, 72 and 168 h after 70 % PH in healthy mice and mice with nonalcoholic steatohepatitis or liver fibrosis. The serum levels of 39 amino acids (AAs) were measured using UPLC–MS/MS. The dataset was randomly divided into training and testing sets at a 2:1 ratio, and orthogonal partial least squares regression (OPLS) and minimally biased variable selection in R (MUVR) were used to select a metabolite signature of AAs. To assess liver remnant growth, nine ML models were built, and evaluated using the coefficient of determination (R2), mean absolute error (MAE), and root mean square error (RMSE). The post-Pareto technique for order preference by similarity to the ideal solution (TOPSIS) was employed for ranking the ML algorithms, and a stacking technique was utilized to establish consensus among the superior algorithms. Compared with those of OPLS, the signature AAs set identified by MUVR (Thr, Arg, EtN, Phe, Asa, 3MHis, Abu, Asp, Tyr, Leu, Ser, and bAib) are more concise. Post-Pareto TOPSIS ranking demonstrated that the majority of ML algorithm in combinations with MUVR outperformed those with OPLS. The established SVM-KNN consensus model performed best, with an R2 of 0.79, an MAE of 0.0029, and an RMSE of 0.0035 for the testing set. This study identified a metabolite signature of 12 AAs and constructed an SVM-KNN consensus model to assess future liver remnant growth after PH in mice with different liver backgrounds. Our preclinical study is anticipated to establish an alternative and generalized assessment method for liver regeneration. • Amino acid metabolism closely correlates with future liver remnant growth. • MUVR selects a more concise set of amino acids compared to OPLS-VIP. • The SVM and KNN consensus is superior to all base estimators and other consensuses. [ABSTRACT FROM AUTHOR]

[Display omitted] • Sediments in OCVB and Kamchatka Peninsula were supplied to Okhotsk Sea shelf. • Intensive chemical weathering occurred on Okhotsk Sea shelf during glaciation. • Changes of sediment provenances affected the weathering records in the Holocene. • Climates and sea level were role factors on weathering patterns during glaciation. The Okhotsk Sea, a subarctic marginal sea with a wide shelf and abundant weathering products, provides ample information about the chemical weathering in the geological past. However, insufficient investigation in the Okhotsk Sea, especially in its shelf, limits our knowledge of the intensity of chemical weathering in high-latitudes. In this study, high-resolution geochemical elements compositions of the core LV87-54-1 were measured to reveal the provenance change in the Northern Okhotsk Sea Shelf since the Last Glacial Maximum (LGM) and to discuss the influential factors of the deep-sea weathering records. The elemental ratios suggested that the sediment provenance remained stable during 23–11.4 ka, mainly transported from the Okhotsk-Chukotka volcanic belt; whereas the sediment input from the Kamchatka Peninsula to the study area has been enhanced since 11.4 ka. During 23–14 ka, the chemical index of alteration (CIA) was observed to align with climatic changes in the Northern Hemisphere. Synchronized climatic deterioration (i.e., cooling and drying) in the Northern Hemisphere mainly contributed to the reduced alteration of the sediments eroded from the Okhotsk-Chukotka volcanic belt. During 14–11.4 ka, the reworking of older weathered sediments caused by sea-level rise overwhelmed climates in controlling silicate weathering, resulting in an increased alteration of sediments. During the Holocene, the core sediment witnessed a lower weathering degree, compared to the LGM–Deglaciation. We attribute this to an increased sediment input from the Kamchatka Peninsula that supplied more weaker weathered sediments to the study area. [ABSTRACT FROM AUTHOR]

The alkenone unsaturation index (U 37 k ′ ) as proxy for sea surface temperature (SST) is an important tool in paleoclimatology for reconstructing past ocean temperature variability. Typically, U 37 k ′ recorded in marine surface sediments shows a linear correlation with modern mean annual SST. However, in high-latitude oceanic regions, such as the subpolar Pacific, U 37 k ′ -based SSTs do overestimate the mean annual temperature by up to 6 °C, potentially leading to obscured paleoclimatic information drawn from stratigraphic U 37 k ′ -records. The reason for this "warm bias" is still not well understood. Here, we present a compilation of 97 sediment surface samples from Multicores collected in the Bering Sea, the Okhotsk Sea and the North Pacific to evaluate the alkenone-temperature proxy against observational data from the North Pacific. Sediment surface samples were analysed for alkenones and the derived U 37 k ′ -indices converted to water temperatures using different calibration equations established in the literature. U 37 k ′ -based SSTs were then compared to instrumental SST data, as well as modern alkenone flux data from sediment traps in the North Pacific. Our results confirm that most U 37 k ′ -based SSTs from the subpolar Pacific are 2–6 °C too warm compared to instrumental mean annual SSTs for calibrations applied. However, with an uncertainty at the level of ±1.5 °C or less reconstructed SSTs fit quite well to modern autumn temperatures north of the Subarctic Front (SAF), when maximum export flux of alkenones to the seafloor is indicated by sediment trap data. South of the SAF, reconstructed SSTs largely mimic the modern mean annual SST signal with an uncertainty of ±1.5 °C or less, which is likely due to the attenuation of seasonality and longer growth season of coccolithophorids according to sediment trap data. Our study further demonstrates that U 37 k ′ , when seasonality in alkenone production and export are known and considered, is able to provide reasonable estimates of SSTs in modern high-latitude ocean settings. We conduct a case study using available alkenone time-series derived from a sediment core collected from the south-western Okhotsk Sea to better understand the potential effect of seasonality in alkenone production on stratigraphic U 37 k ′ -record in the subpolar Pacific. The case study from the Okhotsk Sea indicates that even a small shift in seasonality may lead to strongly biased SSTs with broader regional implications for paleoclimate reconstructions in high-latitude ocean settings. • Compilation of 97 sediment surface samples from Multicores collected in the Bering Sea, Okhotsk Sea and North Pacific. • U 37 k ′ , when seasonality in alkenone production and export in the subpolar Pacific are considered, provides reasonable SSTs. • Past shifts in bloom season may lead to strongly biased SST reconstructions in high-latitude ocean settings. [ABSTRACT FROM AUTHOR]

Background: Blocking the interaction between PD-1 and its ligands is a promising treatment strategy for advanced hepatocellular carcinoma. This study aimed to assess the antitumour activity and safety of the anti-PD-1 inhibitor camrelizumab in pretreated patients with advanced hepatocellular carcinoma.Methods: This is a multicentre, open-label, parallel-group, randomised, phase 2 trial done at 13 study sites in China. Eligible patients were aged 18 years and older with a histological or cytological diagnosis of advanced hepatocellular carcinoma, had progressed on or were intolerant to previous systemic treatment, and had an Eastern Cooperative Oncology Group performance score of 0-1. Patients were randomly assigned (1:1) to receive camrelizumab 3 mg/kg intravenously every 2 or 3 weeks, via a centralised interactive web-response system using block randomisation (block size of four). The primary endpoints were objective response (per blinded independent central review) and 6-month overall survival, in all randomly assigned patients who had at least one dose of study treatment. Safety was analysed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02989922, and follow-up is ongoing, but enrolment is closed.Findings: Between Nov 15, 2016, and Nov 16, 2017, 303 patients were screened for eligibility, of whom 220 eligible patients were randomly assigned and among whom 217 received camrelizumab (109 patients were given treatment every 2 weeks and 108 every 3 weeks). Median follow-up was 12·5 months (IQR 5·7-15·5). Objective response was reported in 32 (14·7%; 95% CI 10·3-20·2) of 217 patients. The overall survival probability at 6 months was 74·4% (95% CI 68·0-79·7)]. Grade 3 or 4 treatment-related adverse events occurred in 47 (22%) of 217 patients; the most common were increased aspartate aminotransferase (ten [5%]) and decreased neutrophil count (seven [3%]). Two deaths were judged by the investigators to be potentially treatment-related (one due to liver dysfunction and one due to multiple organ failure).Interpretation: Camrelizumab showed antitumour activity in pretreated Chinese patients with advanced hepatocellular carcinoma, with manageable toxicities, and might represent a new treatment option for these patients.Funding: Jiangsu Hengrui Medicine. [ABSTRACT FROM AUTHOR]

Postoperative delirium (POD) is strongly associated with poor early and long-term prognosis in cardiac surgery patients with cardiopulmonary bypass (CPB). This study aimed to develop dynamic prediction models for POD after cardiac surgery under CPB using machine learning (ML) algorithms. From July 2021 to June 2022, clinical data were collected from patients undergoing cardiac surgery under CPB at Nanjing First Hospital. A dataset from the same center (October 2022 to November 2022) was also used for temporal external validation. We used ML and deep learning to build models in the training set, optimized parameters in the test set, and finally validated the best model in the validation set. The SHapley Additive exPlanations (SHAP) method was introduced to explain the best models. Of the 885 patients enrolled, 221 (25.0%) developed POD. 22 (22.0%) of 100 validation cohort patients developed POD. The preoperative and postoperative artificial neural network (ANN) models exhibited optimal performance. The validation results demonstrated satisfactory predictive performance of the ANN model, with area under the receiver operator characteristic curve (AUROC) values of 0.776 and 0.684 for the preoperative and postoperative models, respectively. Based on the ANN algorithm, we constructed dynamic, highly accurate, and interpretable web risk calculators for POD. We successfully developed online interpretable dynamic ANN models as clinical decision aids to identify patients at high risk of POD before and after cardiac surgery to facilitate early intervention or care. • Prediction models were temporally validated and had good prediction effect. • Dynamic prediction promoted clinical decision-making and guided interventions. • Our web risk calculators can output patient's risk probability and SHAP plot. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Previous studies reported that Ginsenoside Rd (Rd) had anti-inflammatory and anti-cancer effects. However, the molecular mechanism underlying the inhibition effect of Rd on colitis in mice hasn’t been clarified clearly. Here, in our study, we detected the effects of Rd on dextran sulfate sodium (DSS)-induced murine colitis, and found that oral administration of Rd dose-dependently alleviated DSS-induced body weight loss, colon length shortening and colonic pathological damage with lower myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities and higher glutathione level. In addition, the production of pro-inflammatory cytokines (IL-1β, TNF-a and IL-6) in both serum and colonic tissues were significantly down-regulated by Rd administration. The activation of NLRP3 inflammasome was also suppressed in Rd-treated group, resulting in reduced caspase-1 production and IL-1β secretion. In vitro, Rd remarkably inhibited NLRP3 inflammasome activation which was mostly dependent on the mitochondrial translocation of p62 and mitophagy. Importantly, Rd-driven inhibition of the NLRP3 inflammasome was significantly blocked by various autophagy inhibitors. Furthermore, upregulation of AMPK/ULK1 signaling pathway accounted for Rd-induced autophagy, which was also seen in vivo. In conclusion, our results demonstrated the function of Rd on the inhibition NLRP3 inflammasome and its potential application for the treatment of NLRP3-associated diseases. [ABSTRACT FROM AUTHOR]

The pollen and algae records derived from core KCES-1 in the East Sea (Japan Sea) reveal vegetation and climate changes during the past 44 ka. From 44 to 36 cal ka BP, forest vegetation in the coastal regions of Ulleung Basin was composed predominantly of subalpine conifer forest, open grassland covered the exposed continental shelves, indicating a cool and dry climate. During the period of 36–28.3 cal ka BP, a warmer and wetter climate caused the contraction of subalpine conifer forest in the coastal regions of Ulleung Basin, and the expansion of marsh in the exposed continental shelves. From 28.3 to 17.6 cal ka BP, the sea-level decline restricted the herbs pollen originates in the exposed shelf of East China Sea and Yellow Sea inflow into the East Sea (Japan Sea), and caused the reduction of herbs pollen in the site location. During the time interval of 17.6–15.1 cal ka BP, a great expansion of subalpine conifer forest can be regarded as the consequence of enhanced East Asian winter monsoon (EAWM). The obvious increase in temperate deciduous broadleaved trees, spores and algae can be attributable to the rising of sea level and the warming of climate from 15.1 to 12.1 cal ka BP. During the period of 12.1 to 5.3 cal ka BP, broadleaved taxa increased, especially during the time period of 9.5–5.3 cal ka BP, evergreen broadleaved trees pollen reach the highest values throughout the core, as a result of the Holocene climate optimum condition. Vegetation changes controlled by humid impacts occurred at the late Holocene, as indicated by an increase in Pinus pollen. [ABSTRACT FROM AUTHOR]

In order to reconstruct the history of primary paleoproductivity changes during the last 160 kyr in the Okhotsk Sea (OS), the high-resolution down-core analyses of chlorin content were performed on 11 sediment cores obtained from various part of the studied area with wide ranged depths. Spatial and temporal distributions of the marine phytoplankton paleoproductivity depend on sea ice condition and nutrient supply. The observed discrepancies among the reconstructed records allow us to separate out three main regions with specific environmental conditions. During glacial stages the paleoproductivity was depressed and vice versa. Productivity in the central region is low comparing to other regions due to nutrient limitation. Increased paleoproductivity in the southeastern area was affected by influence of nutrient-rich Pacific waters. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ti/Al molar ratios of sediments declines during transportation. [•] Lake and pelagic sediments show relative low Ti/Al ratios. [•] The declined Ti/Al ratio in aerosol particles indicates Asian dust storm episode. [•] Ti/Al molar ratios of a deep marine core can estimate sea level changes. [Copyright &y& Elsevier]

Abstract: Background: Nateglinide, N-(trans-4-isopropylcyclohexyl-carbonyl)-d-phenylalanine, is a potent insulin secretagogue designed to restore early-phase insulin secretion. It increases pancreatic insulin secretion by competitively binding to sulfonylurea receptors inhibiting adenosine triphosphate–sensitive potassium channels and thus reducing blood glucose levels. The drug has a rapid onset (causing immediate insulin release) and a short duration (allowing insulin to return to baseline levels between meals) of insulinotropic action. Objective: To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic parameters and relative fasting bioavailability of new generic (test) formulation of nateglinide with the reference formulation of nateglinide in healthy Chinese male volunteers. Methods: This open-label, single-dose, randomized-sequence, 2-way crossover study was performed at Nanjing First Hospital of Nanjing Medical University. Eligible subjects were healthy male volunteers who were randomly assigned in a 1:1 ratio to receive a single 60-mg (0.88 mg/kg) dose of the 2 formulations, followed by a 1-week washout period and then administration of the alternate formulation. Study drugs were administered after a 10-hour overnight fast. Concentrations of nateglinide were determined by using a validated LC-MS method. For analysis of pharmacokinetic properties, including Cmax, AUC0–10, and AUC0–∞, blood samples were obtained at intervals over the 10-hour period after study drug administration. As established by the State Food and Drug Administration, the formulations were assumed bioequivalent if 90% CIs for the test/reference ratios of ln-transformed values of Cmax and AUC (obtained by using ANOVA) were within the predetermined equivalence range (80%–125%). Tolerability was assessed by monitoring vital signs and laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and by questioning subjects about adverse events. Results: The 90% CIs for nateglinide were as follows: Cmax, 98.4% to 118.6%; AUC0–10, 99.5% to 110.3%. Both Cmax and AUC0–10 met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation was estimated to be 102.1% (13.5%). One volunteer (5%) experienced a headache after administration of the test formulation. This resolved spontaneously within 1 hour and was considered by the investigators to be mild. No serious adverse events were reported. No period or sequence effects were observed. Conclusions: In this study of healthy Chinese male volunteers, a single 60-mg dose of nateglinide (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TRC-11001754. [Copyright &y& Elsevier]

Abstract: Background: Nevirapine was the first member of the nonnucleoside reverse transcriptase inhibitor class to be approved for the treatment of HIV infection. It binds directly to the allosteric site on the reverse transcriptase and inhibits the activity of both RNA- and DNA-dependent DNA polymerases. Objective: This study compared the pharmacokinetics and relative bioavailability of a test and reference formulation of nevirapine 200-mg tablets after single oral doses in healthy Chinese men to meet regulatory criteria for marketing of the new generic formulation. Methods: This single-dose, randomized-sequence, open-label, 2-way crossover study was conducted at the Nanjing First Hospital of Nanjing Medical University, Nanjing, China. Healthy male Chinese volunteers were randomized in a 1∶1 ratio to receive a single 200-mg (3.2-mg/kg) tablet of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Concentrations of nevirapine were assayed using an HPLC-UV method. For analysis of nevirapine pharmacokinetic parameters, blood samples were obtained before dosing and at regularly scheduled intervals over 168 hours after administration. The 2 formulations would be assumed to be bioequivalent for regulatory purposes if the 90% CIs for the log-transformed ratios of nevirapine AUC and Cmax were within the range established by the US Food and Drug Administration (0.80–1.25). Tolerability was evaluated throughout the study based on vital signs, physical examinations, 12-lead ECGs, and subject interviews concerning adverse events (AEs). Results: Twenty Chinese male subjects were enrolled in and completed the study. Their mean age was 23 years (range, 21–25 years), mean weight was 63 kg (range, 56–70 kg), and mean height was 171 cm (range, 166–176 cm). No period or sequence effect was observed. The mean (SD) t½ was 38.12 (2.23) hours for the test tablet and 36.79 (5.06) hours for the reference tablet; Tmax was 3.1 (0.7) and 3.0 (0.7) hours, respectively; Cmax was 2.52 (0.31) and 2.60 (0.48) mg · L−1; AUC0–168 was 155.66 (22.41) and 150.66 (22.11) mg · h · L−1; and AUC0–∞ was 163.30 (22.88) and 157.75 (22.87) mg · h · L−1. Mean relative bioavailability was 103.6% (8.6%). The 90% CIs for the log-transformed ratios of Cmax (93.51–102.13) and AUC0–168 ( 99.84–106.74) were within the predetermined range for the assumption of bioequivalence. One subject reported mild headache after receiving the test formulation; the relationship of this AE to study drug was considered uncertain. No serious or clinically significant AEs were observed or reported during the study. Conclusions: In this single-dose study in healthy fasted Chinese males, the test tablet met the regulatory criterion for assumption of bioequivalence to the reference tablet. Both formulations were well tolerated in the population studied. SFDA registration no: 2009L04358. [Copyright &y& Elsevier]

The Sea of Japan, located in the humid zone, was subjected to significant freshening of surface waters and a decrease in ventilation of deep waters during the glacial eustatic drop in relative sea level (RSL) and a decrease in water exchange with Pacific due to the shallowness of its straits. As a result, the δ18O values of planktic foraminifera (δ18O pf) decreased by several ppm, in contrast to the increase of ones in the Red Sea, depending on the degree of RSL drop. The good preservation of planktic foraminifera in the sediments of the Sea of Japan during the Last Glacial Maximum (LGM) and deglaciation allows us to significantly refine and supplement the available evidences of the global sea level changes over the 33–15 ka. Based on the obtained and published records of δ18O pf of five cores from different parts of the sea and the general chronology of the accumulation of dark layers in the sediments of the Sea of Japan, we calculated the δ18O pf stacks with high and low resolution (0.13 kyr for two cores and 0.5 kyr for other three cores) for the time 33–15 ka. Both stacks showed significant RSL falls at the onset of LGM (32–29 ka), during 21.8–20.3 ka, and an abrupt rise at 17 ka consistently with previously published data. The higher resolution stack additionally showed two phases of RSL falls at the onset of the LGM followed by a slow decrease until 22 ka, with a short and abrupt descent at around 25 ka. According to both stacks the lowest sea level around 18.5–17.5 ka was preceded by a short rise just before 19 ka. A significant RSL rise at 17 ka was followed by an abrupt and short fall at nearly 16.5 ka and then prolonged rise since around 16.2 ka. • Two stacks of planktic foraminifera δ18O records were calculated over the 33-15 ka with a higher and lower resolution. • Chronology was based on synchronicity of dark layers formation ruled by surface water salinity and ventilation changes. • Both stacks showed significant relative sea level (RSL) falls at 32–29 ka, during 21.8-20.3 ka, and abrupt rise at 17 ka. • A higher resolution stack additionally showed millennial-centennial RSL changes over Last Glacial Maximum and since 17 ka. [ABSTRACT FROM AUTHOR]

Evidence of meltwater and ice rafted debris from the Tenji and Detroit seamounts in the northwestern corner of the North Pacific are key to understanding ice sheet dynamics across the Kamchatka Region. Marine isotopic stages 6.5–1 were established in this study for the Tenji Seamount sediment core based on accelerator mass spectrometry (AMS) 14C data, benthic foraminifera δ18O stratigraphy, and relative paleointensity excursions. Records of planktic foraminifera δ18O and ice rafted debris (IRD) in sediment cores pertaining to the last 190 kyr were used to outline several periods of surface water freshening and increased accumulation of coarse terrigenous grains induced by iceberg supply and melting in the northwest Pacific. Iceberg discharge events (IDEs) were reconstructed over the last and penultimate glacial periods in the central and eastern parts of the Okhotsk Sea and southwestern part of the Bering Sea using relevant published proxies. Similar reconstructions of IDEs were also performed for two published sediment cores from the Detroit Seamount. Synthesis of planktic foraminifera δ18O and IRD records along with other related proxies from the studied areas concordantly revealed five IDEs in the northwest Pacific and its marginal seas during the last 190 kyr: IDE 1 (42–29 ka), IDE 2 (76–57 ka), IDE 3 (118–110 ka), IDE 4 (152–141 ka), and IDE 5 (179–160 ka). Data showed that IDEs 4–1 occurred at low values of Earth obliquity and under a weak Aleutian Low, facilitating snowfall precipitation and enhancing glacier formation at Kamchatka, which is a priority area for capturing atmospheric moisture transferred into northeast Asia. Compared with the other IDEs, IDEs 2 and 5 were more pronounced and prolonged events over the last 190 kyr. In addition, IDE 2 was also characterised by a catastrophic and short IRD peak that was probably forced by the influx of lake water from the Central Kamchatka Depression. It is likely that IDEs 2 and 1 occurred during phases I (more extensive) and II (less extensive) of the published Kamchatka glaciations during the Late Pleistocene. • Planktic δ18O and ice rafted debris as tools for iceberg discharge in the NW Pacific. • Dated records of iceberg evidences in sediments of NW Pacific and marginal Seas. • Five dated iceberg discharge events (IDE) in NW Pacific inferred by data synthesis. • Five periods of Kamchatka glaciations related with NW Pacific IDEs over last 190 ka. [ABSTRACT FROM AUTHOR]