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The ocean is the largest active carbon reservoir on Earth. Organic carbon (OC), as the primary species of carbon sequestration in the ocean, plays an important role in the global carbon cycle through its deposition and burial. In this study, sedimentary OC data from 5796 stations, together with relevant geochemical and sedimentological parameters in the Bohai Sea, Yellow Sea, and East China Sea (BYES) were used to summarize and elucidate the distribution and burial patterns of sedimentary OC, and assess carbon sink effect of sedimentary OC burial. The results show that the OC content in the sediments of the BYES ranges from 0.00% to 2.12%, with an average content of 0.47%±0.26%. OC content is significantly correlated with finegrained sediments, with an average OC content in mud areas being 39% higher than that in non-mud areas. Modern OC buried in the BYES are mainly deposited in 7 major mud areas, with a total sedimentary OC burial flux of approximately 8.20 Mt C yr−1. Among them, the burial flux of biospheric OC is 6.92 Mt C yr−1, equivalent to the OC consumption amount of silicate weathering of the 9 major river basins in the eastern China. In its natural state, the annually sequestered OC in the sediments of the eastern China seas is equivalent to 25.37 Mt of atmospheric CO2, indicating a significant carbon sink effect. The distribution and burial of terrigenous OC in the BYES are mainly influenced by the large river inputs and complex marine hydrodynamic environment, while human activities such as dam construction have significantly altered the OC burial in these coastal mud areas. [ABSTRACT FROM AUTHOR]

Background: Early identification of elderly patients undergoing non-cardiac surgery who may be at high risk for postoperative cognitive dysfunction (POCD) can increase the chances of prevention for them, as extra attention and limited resources can be allocated more to these patients. Aim: We performed this analysis with the aim of developing a simple, clinically useful machine learning (ML) model to predict the probability of POCD at 3 months in elderly patients after non-cardiac surgery. Methods: We collected information on patients who received surgical treatment at Nanjing First Hospital from May 2020 to May 2021. We used LASSO regression to select key features and built 5 ML models to assess the risk of POCD at 3 months in elderly patients after non-cardiac surgery. The Shapley Additive exPlanations (SHAP) and methods were introduced to interpret the best model. Results: A total of 415 patients with non-cardiac surgery were included. The support vector machine (SVM) was the best-performing model of the five ML models. The model showed excellent performance compared to the other four models. The SHAP results showed that VAS score, age, intraoperative hypotension, and preoperative hemoglobin were the four most important features, indicating that the SVM model had good interpretability and reliability. The website of the web-based calculator was https://modricreagan-non-3-pocd-9w2q78.streamlit.app/. Conclusion: Based on six important perioperative variables, we successfully established a series of ML models for predicting POCD occurrence at 3 months after surgery in elderly non-cardiac patients, with SVM model being the best-performing model. Our models are expected to serve as decision aids for clinicians to monitor screened high-risk patients more closely or to consider further interventions. [ABSTRACT FROM AUTHOR]

Background: Aneurysmal subarachnoid hemorrhage (aSAH) causes long-term functional dependence and death. Early prediction of functional outcomes in aSAH patients with appropriate intervention strategies could lower the risk of poor prognosis. Therefore, we aimed to develop pre- and post-operative dynamic visualization nomograms to predict the 1-year functional outcomes of aSAH patients undergoing coil embolization. Methods: Data were obtained from 400 aSAH patients undergoing endovascular coiling admitted to the People's Hospital of Hunan Province in China (2015–2019). The key indicator was the modified Rankin Score (mRS), with 3–6 representing poor functional outcomes. Multivariate logistic regression (MLR)-based visual nomograms were developed to analyze baseline characteristics and post-operative complications. The evaluation of nomogram performance included discrimination (measured by C statistic), calibration (measured by the Hosmer–Lemeshow test and calibration curves), and clinical usefulness (measured by decision curve analysis). Results: Fifty-nine aSAH patients (14.8%) had poor outcomes. Both nomograms showed good discrimination, and the post-operative nomogram demonstrated superior discrimination to the pre-operative nomogram with a C statistic of 0.895 (95% CI: 0.844–0.945) vs. 0.801 (95% CI: 0.733–0.870). Each was well calibrated with a Hosmer–Lemeshow p-value of 0.498 vs. 0.276. Moreover, decision curve analysis showed that both nomograms were clinically useful, and the post-operative nomogram generated more net benefit than the pre-operative nomogram. Web-based online calculators have been developed to greatly improve the efficiency of clinical applications. Conclusions: Pre- and post-operative dynamic nomograms could support pre-operative treatment decisions and post-operative management in aSAH patients, respectively. Moreover, this study indicates that integrating post-operative variables into the nomogram enhanced prediction accuracy for the poor outcome of aSAH patients. [ABSTRACT FROM AUTHOR]

Simple Summary: CPUL1 exhibits antitumor properties against hepatocellular carcinoma (HCC), although the underlying mechanisms remain unclear. Our study provides a comprehensive overview of the properties and molecular mechanisms of CPUL1 anti-HCC using transcriptomics and metabolomics and highlights the significance of progressive metabolic failure. This may be partially attributable to autophagy blockage, which is presumed to contribute to nutrient deprivation and increased cell susceptibility to stress. Therefore, the attractive properties of CPUL1 may endow this compound with the potential of becoming a promising anti-HCC agent. Background: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. Methods: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. Results: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. Conclusions: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress. [ABSTRACT FROM AUTHOR]

Background: Medication safety among children represents an underrecognized public health concern worldwide, yet little evidence was found in China. This study aimed to examine trends in rates of pediatric adverse drug reaction (ADR) reports in Jiangsu Province of China with a catchment population of more than 11 million children. Methods: Data for children aged under 15 years were extracted from the spontaneous reporting system of ADR surveillance in Jiangsu Province. Suspected therapeutic agents for ADRs were coded using the Anatomical Therapeutic Chemical classification system. We used the Chinese modification of the International Classification of Diseases, Tenth Revision, to group primary diseases, and the Medical Dictionary for Regulatory Activities to classify the manifestation of ADRs. We used Joinpoint to estimate age-adjusted ADR rates stratified by sex from July 2010 to June 2019, and further by specific features, including patient characteristics, main suspected therapeutic medications, primary diseases, and ADRs. We used the percentage change annualized estimator to evaluate trends over time. Results: A total of 79,903 ADR reports were identified among children aged under 15 years, which accounted for 11.4% of all ADRs reported in Jiangsu Province during the same period. The age-adjusted ADR report rates increased significantly from 66.20 to 96.76 per 100,000 children during the period July 2010–June 2019, with an annual increase of 4.9% (95% confidence interval 1.3–8.5%; p value 0.014). Of all ADR reports, there were 47,774 (59.8%) boys and 32,129 (40.2%) girls. Children aged 0–4 years accounted for more than half of the ADR reports (n = 47,680, 59.7%). Skin and subcutaneous tissue disorders were the most frequently reported ADRs (45,773, 57.3%). Respiratory diseases were the most commonly observed medical conditions in relation to pediatric ADRs, accounting for 68.8% (n = 54,940) of all ADR reports, and anti-infectives for systemic use consistently represented over time the most common medication group, contributing to 69.8% of all reports. A reduction in ADR report rates was observed for vaccines, with an annual decrease of 19% in children. Conclusions: ADRs remain a public health challenge among the vulnerable pediatric populations. Findings from the present study call for continuing efforts in ADR prevention and medication safety improvement in children. [ABSTRACT FROM AUTHOR]

The unfavorable outcome of acute ischemic stroke (AIS) with large vessel occlusion (LVO) is related to clinical factors at multiple time points. However, predictive models used for dynamically predicting unfavorable outcomes using clinically relevant preoperative and postoperative time point variables have not been developed. Our goal was to develop a machine learning (ML) model for the dynamic prediction of unfavorable outcomes. We retrospectively reviewed patients with AIS who underwent a consecutive mechanical thrombectomy (MT) from three centers in China between January 2014 and December 2018. Based on the eXtreme gradient boosting (XGBoost) algorithm, we used clinical characteristics on admission ("Admission" Model) and additional variables regarding intraoperative management and the postoperative National Institute of Health stroke scale (NIHSS) score ("24-Hour" Model, "3-Day" Model and "Discharge" Model). The outcome was an unfavorable outcome at the three-month mark (modified Rankin scale, mRS 3–6: unfavorable). The area under the receiver operating characteristic curve and Brier scores were the main evaluating indexes. The unfavorable outcome at the three-month mark was observed in 156 (62.0%) of 238 patients. These four models had a high accuracy in the range of 75.0% to 87.5% and had a good discrimination with AUC in the range of 0.824 to 0.945 on the testing set. The Brier scores of the four models ranged from 0.122 to 0.083 and showed a good predictive ability on the testing set. This is the first dynamic, preoperative and postoperative predictive model constructed for AIS patients who underwent MT, which is more accurate than the previous prediction model. The preoperative model could be used to predict the clinical outcome before MT and support the decision to perform MT, and the postoperative models would further improve the predictive accuracy of the clinical outcome after MT and timely adjust therapeutic strategies. [ABSTRACT FROM AUTHOR]

Biliary tract cancer (BTC) is a highly malignant tumor with limited treatment options and poor prognosis. Our study aimed to evaluate camrelizumab plus oxaliplatin‐based chemotherapy as first‐line therapy for advanced BTC. In this multicenter, open‐label, phase 2 trial conducted in China (ClinicalTrials.gov, NCT03092895), untreated patients with advanced BTC were given camrelizumab (3 mg/kg iv drip injection, every 2 weeks) plus typical FOLFOX4 (Cam‐FOLFOX4 group; infusional 5‐fluorouracil, leucovorin and oxaliplatin) or GEMOX (Cam‐GEMOX group; infusional gemcitabine and oxaliplatin). The primary endpoint was objective response rate (ORR). Ninety‐two patients were enrolled: 29 received Cam‐FOLFOX4 and 63 received Cam‐GEMOX. The confirmed ORR and disease control rate were 16.3% (95% confidence interval [CI] = 9.4‐25.5) and 75.0% (95% CI = 64.9‐83.4), respectively. Median duration of response was 8.7 months (95% CI = 5.1‐not reached). Median progression‐free survival and overall survival were 5.3 months (95% CI = 3.7‐5.7) and 12.4 months (95% CI = 8.9‐16.1), respectively. Grade ≥3 treatment‐related adverse events (TRAEs) occurred in 82.8% of patients receiving Cam‐FOLFOX4 and in 68.3% receiving Cam‐GEMOX, with no unexpected effects observed. Six (6.5%) patients discontinued treatment due to TRAE. Camrelizumab plus FOLFOX4 or GEMOX as first‐line treatment was effective and tolerable for Chinese patients with advanced BTC, warranting phase 3 trials. What's new? Biliary tract cancer is a highly malignant tumour with limited treatment options and poor prognosis. In this prospective clinical trial in Chinese patients with the intra‐hepatic cholangiocarcinoma subtype predominantly, the authors evaluated the novel PD‐1 inhibitor camrelizumab plus oxaliplatin‐based chemotherapy as first‐line treatment for advanced biliary tract cancer. Preliminary efficacy results were encouraging, with an objective response rate of 16.3%, disease control rate of 75.0%, median progression‐free survival of 5.3 months, and overall survival of 12.4 months, despite the poor baseline status of the patients. Adverse events were manageable. The combined treatment was effective and tolerable, warranting phase 3 trials. [ABSTRACT FROM AUTHOR]

Background and Purpose: The clinical use of tirofiban for patients with acute ischemic stroke (AIS) who underwent mechanical thrombectomy (MT) remains controversial. We aimed to evaluate the safety and efficacy of tirofiban combined with MT in AIS patients. Methods: Patients with AIS who underwent MT from January 2014 to December 2018 were enrolled in three stroke units in China. Subgroup analyses were performed based on stroke etiology which was classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria. Safety outcomes were in-hospital intracerebral hemorrhage (ICH), symptomatic intracerebral hemorrhage (sICH) and mortality at 3-month. Efficacy outcomes were favorable functional outcome and functional independence at 3-month and neurological improvement at 24 h, 3 d and discharge. Results: In patients with large artery atherosclerosis (LAA) stroke, multivariate analyses revealed that tirofiban significantly decreased the odds of in-hospital ICH (adjusted OR = 0.382, 95% CI 0.180–0.809) and tended to increase the odds of favorable functional outcome at 3-month (adjusted OR = 3.050, 95% CI 0.969–9.598). By contrast, in patients with cardioembolism (CE) stroke, tirofiban was not associated with higher odds of favorable functional outcome at 3-month (adjusted OR = 0.719, 95% CI 0.107–4.807), but significantly decreased the odds of neurological improvement at 24 h and 3d (adjusted OR = 0.185, 95% CI 0.047–0.726; adjusted OR = 0.268, 95% CI 0.087–0.825). Conclusions: Tirofiban combined with MT appears to be safe and effective in LAA patients, but has no beneficial effect on CE patients. [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]

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]

Millennial scale variations of terrigenous provenance in marine realm are closely related to regional environment and climate changes. Therefore, a wealth of information of past environment and climate can be constrained via fingerprinting sediment provenance. The Sea of Japan is a unique marginal sea in the North Pacific due to its high sill and distinct thermohaline circulation. The modern hydrography in the Sea of Japan is mainly affected by the East Asian Monsoon and Tsushima Warm Current, one branch of the Kuroshio Current. The Sea of Japan communicates with neighboring seas through four shallow and narrow straits, indicating great effects of global eustatic sea level change on its environment over glacial-interglacial cycles. Here we examine the terrigenous provenance in fine-grained fraction (<63 μm) of core KCES1, located near one end of the Tsushima Strait of the Sea of Japan over the last 48 ka, using radiogenic isotopes of strontium (Sr) and neodymium (Nd). Our data suggest that the terrigenous provenance in core KCES1 was mainly derived from the Yangtze River after 7 ka and a mixture of Yangtze and Yellow Rivers during the last glacial and deglacial periods. Notably, pronounced negative excursions of εNd values at HS1 were attributed to minor additions of unradiogenic Nd contribution from China-Korea cratonic hinterland. A binary mixing model further reveals that >85% terrigenous material is derived from the Yangtze and Yellow Rivers over the last 48 ka. Moreover, abrupt variations in sediment provenance occurred at ~18 ka and ~ 7 ka, which coincide with variations in oceanic surface circulation and deep ventilation recorded in the Sea of Japan. We suggest that paleo-Tsushima Warm Current invaded into the Sea of Japan with reopening of the Tsushima Strait at HS1 and the Tsushima Warm Current substantially entered the Sea of Japan after 7 ka due to intensified Kuroshio Current and rising eustatic sea level. The inflow of Tsushima Warm Current gives rise to a range of changes in surface hydrography, deep ventilation, ecological communities and productivity and sediment texture. The combination of fluxes of paleo-rivers and the intensity of Kuroshio Current, which are closely tied to the eustatic sea level and the East Asian Monsoon, plays a key role in controlling the variations in sediment provenance in the Ulleung Basin. Our study provides unique insight into the tight coupling between changes in sediment provenance and oceanic environment over the last 48 ka in the Sea of Japan. • Radiogenic Sr and Nd isotopes reveal the main provenance of terrigenous materials in the Ulleung Basin over the last 48 ka • Abrupt shift in terrigenous provenance at ~18 ka and ~ 7 ka indicates intrusions of Tsushima Current into the Sea of Japan • Main mechanisms controlling variations in terrigenous provenance in the Ulleung Basin are revealed [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]

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]

Intracerebral hemorrhage (ICH) is a devastating disease, and there is currently no specific pharmacological treatment that can improve clinical outcomes. Y-2 sublingual tablets, each containing 30 mg edaravone and 6 mg (+) - borneol, is undergoing a phase III clinical trial for treatment of ischemic stroke in China. The purpose of the present study is to investigate the efficacy and potential mechanism of Y-2 in a rat model of collagenase IV injection induced ICH. Sublingual administration of Y-2 at the dose of 1, 3 and 6 mg/kg improved ICH-induced sensorimotor dysfunction, alleviated cell death and histopathological change, restored the hippocampal long-term potentiation (LTP), reduced brain edema and maintained blood-brain barrier (BBB) integrality in ICH rats. Further study demonstrated that Y-2 could reduce inflammatory response and oxidative stress by decreasing the levels of myeloperoxidase (MPO), ionized calcium-binding adaptor protein-1 (Iba-1), inflammatory cytokines and oxidative products, inhibit transcription factor nuclear factor-κB (NF-κB) activation, cyclooxygenase-2 (COX-2) and matrix metallopeptidase 9 (MMP-9) expression in brain tissue around in the core regions of hematoma. Importantly, the protective efficacy of Y-2 from ICH-induced injury was superior to edaravone. In conclusion, Y-2 sublingual tablets might be a promising therapeutic agent for the treatment of ICH. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy combined with chemotherapy has been shown to be efficacious as treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations; however, there is scarce evidence of the effectiveness of the combinations in the Asian population. We evaluated camrelizumab plus chemotherapy against non-squamous NSCLC in China., Methods: We did a randomised, open-label, multicentre, phase 3 trial (CameL) in 52 hospitals in China for patients with non-squamous NSCLC without EGFR and ALK alteration. Eligible patients were aged 18-70 years and had no previous systemic chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients were randomly assigned (1:1) to receive 4-6 cycles of carboplatin (area under curve 5 mg/mL per min) plus pemetrexed (500 mg/m 2 ) with or without camrelizumab (200 mg) every 3 weeks, followed by maintenance therapy with camrelizumab plus pemetrexed or pemetrexed alone. Medication was administered intravenously on day 1 of each 3-week treatment cycle. Randomisation was done using a centralised interactive web-response system with the block size randomly generated as four or six and stratified by sex and smoking history. The two primary endpoints were progression-free survival per blinded independent central review, in all patients and in patients who were PD-L1 positive. Primary analysis was done in the full analysis set that included all randomly assigned patients who received at least one dose of the study treatment. Herein, due to the primary endpoint being met at the interim analysis, we reported the findings of prespecified interim analysis, which only included confirmatory statistical testing for progression-free survival in all patients. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT03134872 (follow-up is ongoing)., Findings: Between May 12, 2017, and June 6, 2018, of the 419 patients who were randomly assigned, seven did not receive assigned treatment and 412 received either camrelizumab plus chemotherapy (n=205) or chemotherapy alone (n=207). At interim analysis, median follow-up duration was 11·9 months (IQR 9·0-14·9). Progression-free survival in this interim analysis was significantly prolonged with camrelizumab plus chemotherapy than with chemotherapy alone (median 11·3 months [95% CI 9·6-15·4] vs 8·3 months [6·0-9·7]; hazard ratio 0·60 [0·45-0·79]; one-sided p=0·0001). Most common grade 3 or worse treatment-related adverse events were decreased neutrophil count (78 [38%] patients in the camrelizumab plus chemotherapy group vs 63 [30%] patients in the chemotherapy alone group), decreased white blood cell count (40 [20%] vs 30 [14%]), anaemia (38 [19%] vs 23 [11%]), and decreased platelet count (34 [17%] vs 24 [12%]). Serious treatment-related adverse events occurred in 74 (36%) patients in the camrelizumab plus chemotherapy group and 27 (13%) patients in the chemotherapy alone group., Interpretation: The primary endpoint was met at the interim analysis, showing a statistically significant and clinically meaningful improvement in progression-free survival with camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in all patients, supporting camrelizumab plus carboplatin and pemetrexed as a first-line treatment option for Chinese patients with advanced non-squamous NSCLC without EGFR and ALK alterations. The trial is being continued to collect long-term outcomes in all patients and carry out confirmatory statistical testing for progression-free survival in the PD-L1-positive population., Funding: Jiangsu Hengrui Medicine., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Patients with advanced or metastatic oesophageal squamous cell carcinoma have poor prognosis and few treatment options after first-line therapy. We aimed to assess efficacy and safety of the anti-PD-1 antibody camrelizumab versus investigator's choice of chemotherapy in previously treated patients., Methods: ESCORT is a randomised, open-label, phase 3 study of patients aged 18 to 75 years with a histological or cytological diagnosis of advanced or metastatic oesophageal squamous cell carcinoma done at 43 hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had progressed on, or were intolerant to, first-line standard therapy. Patients were randomly assigned (1:1) to camrelizumab (200 mg every 2 weeks) or chemotherapy with docetaxel (75 mg/m 2 every 3 weeks) or irinotecan (180 mg/m 2 every 2 weeks), all given intravenously. Central randomisation was done using the Randomization and Trial Supply Management system with block size randomly generated as four or six and stratified by disease and ECOG performance status. The primary endpoint was overall survival, assessed in randomised patients who had received at least one dose of treatment. Safety was assessed in all treated patients. The trial is registered with ClinicalTrials.gov, NCT03099382, and is closed to new participants., Findings: From May 10, 2017, to July 24, 2018, 457 (75%) of 607 screened patients were randomly assigned to treatment, of whom 228 received camrelizumab treatment and 220 received chemotherapy. As of data cutoff on May 6, 2019, with a median follow-up time of 8·3 months (IQR 4·1-12·8) in the camrelizumab group and 6·2 months (3·6-10·1) in the chemotherapy group, median overall survival was 8·3 months (95% CI 6·8-9·7) in the camrelizumab group and 6·2 months (5·7-6·9) in the chemotherapy group (hazard ratio 0·71 [95% CI 0·57-0·87]; two-sided p=0·0010). The most common treatment-related adverse events of grade 3 or worse were anaemia (camrelizumab vs chemotherapy: six [3%] vs 11 [5%]), abnormal hepatic function (four [2%] vs one [<1%]), and diarrhoea (three [1%] vs nine [4%]). Serious treatment-related adverse events occurred in 37 (16%) of 228 patients in the camrelizumab group, and in 32 (15%) of 220 patients in the chemotherapy group. Ten treatment-related deaths occurred, seven (3%) in the camrelizumab group (three deaths from unknown causes, one enterocolitis, one hepatic function abnormal, one pneumonitis, and one myocarditis) and three (1%) in the chemotherapy group (two deaths from unknown causes, and one gastrointestinal haemorrhage)., Interpretation: Second-line camrelizumab significantly improved overall survival in patients with advanced or metastatic oesophageal squamous cell carcinoma compared with chemotherapy, with a manageable safety profile. It might represent a potential option of standard second-line treatment for patients with oesophageal squamous cell carcinoma in China., Funding: Jiangsu Hengrui Medicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Association of immune-related adverse events with tumor response has been reported. Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common adverse event related to camrelizumab, an immune checkpoint inhibitor, but lack of comprehensive analyses. In this study, we conducted comprehensive analyses on RCCEP in advanced hepatocellular carcinoma (HCC) patients treated with camrelizumab monotherapy., Methods: Data were derived from a Chinese nationwide, multicenter phase 2 trial of camrelizumab in pre-treated advanced HCC. The occurrence, clinicopathological characteristics, and prognostic value of RCCEP were analyzed., Results: With a median follow-up of 12.5 months, 145 of the 217 camrelizumab-treated patients (66.8%) experienced RCCEP (all grade 1 or 2). RCCEP occurred on the skin surface, mainly on the skin surface of head, face, and trunk. RCCEP could be divided into 5 types including "red-nevus-like," "pearl-like," "mulberry-like," "patch-like," and "tumor-like," according to the morphological features. RCCEP biopsy and pathology showed capillary endothelial hyperplasia and capillary hyperplasia in dermis. Significant association between RCCEP occurrence with higher objective response rate was observed (19.3% vs. 5.6%; one-sided p = 0.0044). Compared with those without RCCEP, patients with RCCEP had prolonged progression-free survival (median PFS; 3.2 months vs. 1.9 months; one-sided p < 0.0001) and overall survival (median OS; 17.0 months vs. 5.8 months; one-sided p < 0.0001). In multivariable analyses, the development of RCCEP was significantly associated with prolonged PFS and OS after adjusting for baseline covariates. In addition, the landmark analyses of PFS and OS were consistent with the unadjusted analysis., Conclusions: RCCEP occurred on the skin surface and was an immune response of skin capillary endothelial cells. RCCEP occurrence positively associated with outcomes of camrelizumab in advanced HCC.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Accurate prognostication of unfavorable outcome made at the early onset of stroke is important to both the clinician and the patient management. This study was aimed to develop a nomogram based on the integration of parameters to predict the probability of 3-month unfavorable functional outcome in Chinese acute ischemic stroke patients., Methods: We retrospectively collected patients who underwent acute ischemic stroke at Stroke Center of the Nanjing First Hospital (China) between May 2013 and May 2018. After exclusion, the study population includes 1,025 patients for nomogram development. The main outcome measure was 3-month unfavorable outcome (modified Rankin Scale > 2). Multivariable logistic regression analysis was used to develop the predicting model, and stepwise logistic regression with the Akaike information criterion was utilized to find best-fit nomogram model. We incorporated the creatinine, fast blood glucose, age, previous cerebral hemorrhage, previous valvular heart disease, and NHISS score (COACHS), and these factors were presented with a nomogram. We assessed the discriminative performance by using the area under curve (AUC) of receiver-operating characteristic (ROC) and calibration of risk prediction model by using the Hosmer-Lemeshow test., Results: Multivariate analysis of the 1,025 patients for logistic regression helped identify the independent factors as National Institutes of Health Stroke Scale score on admission, age, previous valvular heart disease, fasting blood glucose, creatinine, and previous cerebral hemorrhage, which were included in the COACHS nomogram. The AUC-ROC of nomogram was 0.799. Calibration was good (p = 0.1376 for the Hosmer-Lemeshow test)., Conclusions: The COACHS nomogram may be used to predict unfavorable outcome at 3 months after acute ischemic stroke in Chinese population. It may be also a reliable tool that is effective in its clinical utilization to risk-stratify acute stroke patients., (© 2019 S. Karger AG, Basel.)

Background: Ondansetron oral soluble film is designed to be applied on top of the tongue without requiring water to aid dissolution or swallowing, which is especially fitting for nausea and vomiting patients., Purpose: This study was conducted to compare the bioavailability of two 8 mg ondansetron oral soluble film formulations., Patients and Methods: This randomized, open-label, two-period crossover study was performed under fasting conditions. A total of ten eligible subjects were randomly assigned at a 1:1 ratio to receive a single 8 mg dose of the test and reference ondansetron oral soluble film formulations, followed by a 1-week washout period and administration of the alternate formulation. The concentrations of ondansetron were assayed using an liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) method. For analysis of pharmacokinetic properties, including the peak concentration of T max (C max), AUC from time 0 (baseline) to t hours (AUC0- t ), and AUC from baseline to infinity (AUC0-∞), blood samples were obtained at intervals over the 24-hour period after studying drug administration. 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 mean (standard derivation [SD]) relative bioavailability was 96.5 (23.7%). The 90% confidence intervals (CIs) for the log-transformed ratios of C max and AUC0- t were 84.71%-103.28% and 91.38%-108.60%, respectively (P>0.05). Similar results were found for the data without log-transformation. No statistically significant differences were found based on analysis of variance. No significant adverse events occurred or were reported during the study., Conclusion: As the 90% CIs based on the differences between the test and reference formulation were within the 80%-125% range for both the C max and AUC0- t , we concluded that the two formulations were bioequivalent with respect to the rate or the extent of absorption. Both formulations are well tolerated.

A selective and sensitive high-performance liquid chromatography-electrospray-tandem mass spectrometry method (HPLC-ESI-MS-MS) has been developed for the determination of adefovir in human plasma using adenine (PMPA) as an internal standard. After protein precipitation with methanol, the plasma sample was separated by HPLC on a reversed-phase XTerra MS/MS C(18) column (100 mm x 2.1 mm i.d., 3.5 mm) with a mobile phase of methanol-water (20:80, v/v). Standard curves were linear (r(2) = 0.9962) over the concentration range of 0.20-100 ng/mL and had acceptable accuracy and precision. The intra- and inter-batch precisions were within 11.30%. The lower limit of quantification (LLOQ) was 0.20 ng/mL. The validated HPLC-ESI-MS-MS method has been used successfully to study the pharmacokinetics of adefovir in healthy Chinese volunteers. The following pharmacokinetic parameters were elucidated after administering a single dose of 10 mg, 20 mg, and 30 mg of adefovir dipivoxil. Peak plasma concentrations (C(max)) were (26.6 +/- 6.1), (55.7 +/- 16.2), and (70.2 +/- 11.8) ng/mL, respectively; time to C(max) (T(max)) were (1.5 +/- 0.6), (1.6 +/- 0.7), and (1.8 +/- 0.6) h, respectively; the area under the plasma concentration versus time curve from time 0 h to 36 h (AUC(0-36)) were (184.5 +/- 25.2), (379.3 +/- 61.8) and (556.5 +/- 86.7) ng/mL, respectively; mean residence times (MRT) were (8.9 +/- 0.9), (9.0 +/- 1.0), and (8.9 +/- 1.0) h, respectively; and the elimination half-life (t(1/2)) were (8.0 +/- 0.9), (7.5 +/- 0.8), and (7.5 +/- 0.9) h, respectively. The pharmacokinetic parameters can provide some information for clinical medication.

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 C(max), AUC from time 0 (baseline) to 6 hours (AUC(0-6)), and AUC from baseline to infinity (AUC(0-infinity)), 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 C(max) 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 C(max), AUC(0-6;), and AUC(0-infinity) 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.