Enhancing thermodynamic consistency: Clarification on the application of asymmetric activity model in multi-component chromatographic separation.

The single-component Mollerup model, with over 40 direct applications and 442 citations, is the most widely used activity model for chromatographic mechanistic modeling. Many researchers have extended this formula to multi-component systems by directly adding subscripts, a modification deemed thermodynamically inconsistent (referred to as the reference model). In this work, we rederived the asymmetric activity model for multi-component systems, using the van der Waals equation of state, and termed it the multi-component Mollerup model. In contrast to the reference model, our proposed model accounts for the contributions of all components to the activity. Three numerical experiments were performed to investigate the impact of the three different activity models on the chromatographic modeling. The results indicate that our proposed model represents a thermodynamically consistent generalization of the single-component Mollerup model to multi-component systems. This communication advocates adopting of the multi-component Mollerup model for activity modeling in multi-component chromatographic separation to enhance thermodynamic consistency.

Real-world effectiveness and safety of macitentan in patients with pulmonary artery hypertension: a multicenter, retrospective, observational study in China.

BACKGROUND: Macitentan, either as monotherapy or part of combination therapy, improved clinical outcomes in patients with pulmonary artery hypertension (PAH) in clinical trials. Evidence on the effectiveness and safety of macitentan administered in real-world clinical practice in China is limited. METHODS: This real-world, retrospective, multicenter chart review study was conducted at seven hospitals in China. Adult patients with a diagnosis of PAH who initiated macitentan and had medical assessments at 3-7 months after macitentan initiation were included. The primary outcomes were changes in the World Health Organization functional class (WHO-FC), 6-min walk distance (6MWD), and N-terminal pro-B-type natriuretic peptide (NT-proBNP)/B-type natriuretic peptide from baseline to first follow-up visit (months 3-7). Serious adverse events (SAEs) and adverse drug reactions (ADRs) of macitentan were collected. RESULTS: From 30 August 2021 to 31 March 2022, 214 eligible patients were included in the safety analysis set and 105 patients were included in the analysis of effectiveness. At the first follow-up visit compared with baseline, significant changes in WHO-FC were observed (p = .04), 93.5% patients had their WHO-FC improved (25.8%) or maintained (67.7%). 6MWD changed by a mean (standard deviation [SD]) of 45.0 (81.4) meters (p < .001), with 94.7% having their 6MWD improved (34.7%) or maintained (60.0%). The mean (SD) of NT-proBNP decreased from 1667.4 (3233.0) ng/L to 1090.0 (2230.1) ng/L (p < .001). In the safety analysis set, 24 (11.2%) patients experienced at least one ADR and/or SAE. ADRs and SAEs were reported in 11 (5.1%) and 18 (8.4%), respectively. No deaths or unexpected safety events were observed. CONCLUSION: This study provided real-world evidence on the clinical benefits and good tolerance of macitentan in Chinese patients with PAH treated in routine clinical practice.

Occurrence and emission characteristics of microplastics in agricultural surface runoff under different natural rainfall and short-term fertilizer application.

Land-based microplastics (MPs) are considered the primary source of MPs in aquatic environments, with runoff being a major pathway for their transfer from soil to surface water. However, the transportation characteristics of MPs via agricultural surface runoff remain unclear. In this study, we investigated the occurrence and emission characteristics of MPs in agricultural surface runoff under various short-term fertilizer applications and natural rainfall events using laser direct infrared imaging analysis (LDIR). MPs from fertilizers and soils co-migrated with the agricultural runoff. The abundance and concentration of MPs in runoff were 145.90 ± 22.48-2043.38 ± 89.51 items·L-1 and 39.17 ± 21.94-523.04 ± 47.85 µg·L-1, respectively. Small and low-density MPs, such as polyethylene (PE), chlorinated polyethylene (CPE), and polyurethane (PU) in film/fragment form with 20-50 µm exhibited a higher mobility. No statistical differences were observed in the distribution of runoff MPs with the application of different fertilizers. There was a significant positive relationship between runoff MP abundance and rainfall intensity. The annual emission load in this study area was 116.73 g·hm-2, indicating that the transportation of MPs via agricultural surface runoff cannot be ignored. This study is conducive to understanding the migration behavior of MPs in soil-water environments in a better manner.

Modeling multi-component separation in hydrophobic interaction chromatography with improved parameter-by-parameter estimation method.

Mechanistic models are powerful tools for chromatographic process development and optimization. However, hydrophobic interaction chromatography (HIC) mechanistic models lack an effective and logical parameter estimation method, especially for multi-component system. In this study, a parameter-by-parameter method for multi-component system (called as mPbP-HIC) was derived based on the retention mechanism to estimate the six parameters of the Mollerup isotherm for HIC. The linear parameters (ks,i and keq,i) and nonlinear parameters (ni and qmax,i) of the isotherm can be estimated by the linear regression (LR) and the linear approximation (LA) steps, respectively. The remaining two parameters (kp,i and kkin,i) are obtained by the inverse method (IM). The proposed method was verified with a two-component model system. The results showed that the model could accurately predict the protein elution at a loading of 10 g/L. However, the elution curve fitting was unsatisfactory for high loadings (12 g/L and 14 g/L), which is mainly attributed to the demanding experimental conditions of the LA step and the potential large estimation error of the parameter qmax. Therefore, the inverse method was introduced to further calibrate the parameter qmax, thereby reducing the estimation error and improving the curve fitting. Moreover, the simplified linear approximation (SLA) was proposed by reasonable assumption, which provides the initial guess of qmax without solving any complex matrix and avoids the problem of matrix unsolvable. In the improved mPbP-HIC method, qmax would be initialized by the SLA and finally determined by the inverse method, and this strategy was named as SLA+IM. The experimental validation showed that the improved mPbP-HIC method has a better curve fitting, and the use of SLA+IM reduces the error accumulation effect. In process optimization, the parameters estimated by the improved mPbP-HIC method provided the model with excellent predictive ability and reasonable extrapolation. In conclusion, the SLA+IM strategy makes the improved mPbP-HIC method more rational and can be easily applied to the practical separation of protein mixture, which would accelerate the process development for HIC in downstream of biopharmaceuticals.

A Wearable Thin-Film Hydrogel Laser for Functional Sensing on Skin.

Flexible photonics offers the possibility of realizing wearable sensors by bridging the advantages of flexible materials and photonic sensing elements. Recently, optical resonators have emerged as a tool to improve their oversensitivity by integrating with flexible photonic sensors. However, direct monitoring of multiple psychological information on human skin remains challenging due to the subtle biological signals and complex tissue interface. To tackle the current challenges, here, we developed a functional thin film laser formed by encapsulating liquid crystal droplet lasers in a flexible hydrogel for monitoring metabolites in human sweat (lactate, glucose, and urea). The three-dimensional cross-linked hydrophilic polymer serves as the adhesive layer to allow small molecules to penetrate from human tissue to generate strong light--matter interactions on the interface of whispering gallery modes resonators. Both the hydrogel and cholesteric liquid crystal microdroplets were modified specifically to achieve high sensitivity and selectivity. As a proof of concept, wavelength-multiplexed sensing and a prototype were demonstrated on human skin to detect human metabolites from perspiration. These results present a significant advance in the fabrication and potential guidance for wearable and functional microlasers in healthcare.

Geospatial artificial intelligence for estimating daytime and nighttime nitrogen dioxide concentration variations in Taiwan: A spatial prediction model.

Nitrogen dioxide (NO2) is a major air pollutant primarily emitted from traffic and industrial activities, posing health risks. However, current air pollution models often underestimate exposure risks by neglecting the bimodal pattern of NO2 levels throughout the day. This study aimed to address this gap by developing ensemble mixed spatial models (EMSM) using geo-artificial intelligence (Geo-AI) to examine the spatial and temporal variations of NO2 concentrations at a high resolution of 50m. These EMSMs integrated spatial modelling methods, including kriging, land use regression, machine learning, and ensemble learning. The models utilized 26 years of observed NO2 measurements, meteorological parameters, geospatial layers, and social and season-dependent variables as representative of emission sources. Separate models were developed for daytime and nighttime periods, which achieved high reliability with adjusted R2 values of 0.92 and 0.93, respectively. The study revealed that mean NO2 concentrations were significantly higher at nighttime (9.60 ppb) compared to daytime (5.61 ppb). Additionally, winter exhibited the highest NO2 levels regardless of time period. The developed EMSMs were utilized to generate maps illustrating NO2 levels pre and during COVID restrictions in Taiwan. These findings could aid epidemiological research on exposure risks and support policy-making and environmental planning initiatives.

Dihydrophenanthropyrans derived from the pseudobulbs of Pholidota chinensis alleviates neutrophilic inflammation by inhibiting MAPKs and calcium.

Five dihydrophenanthropyrans (1-5) were isolated from the pseudobulbs of Pholidota chinensis, among which 1,3-di(4'-hydroxybenzy)-imbricatin (3) was isolated from the nature for the first time. Their structures were elucidated and established through various spectroscopic methods. These compounds exhibited a potent inhibition effect on both N-formyl-methionyl-leucyl-phenylalanine (fMLF)-induced superoxide anion generation and elastase release with IC50 values ranging from 0.23 to 7.63 µM. Furthermore, dihydrophenanthropyrans (1-3) also demonstrated a dose-dependent reactive oxygen species (ROS) scavenging effect. In addition, dihydrophenanthropyrans (2-3) exhibited a dose-dependent reduction in the intracellular Ca2+ concentration ([Ca2+]i) in fMLF-activated human neutrophils. Moreover, dihydrophenanthropyrans (1-3) selectively inhibited the phosphorylation of c-Jun N-terminal kinases (JNKs) and p38, while only dihydrophenanthropyran (1) inhibited the phosphorylation of extracellular signal-regulated kinases (ERKs) in fMLF-activated human neutrophils. Notably, dihydrophenanthropyrans (1-3) did not affect protein kinase B (AKT) activity in these cells. These findings highlight the potent anti-inflammatory capabilities of dihydrophenanthropyrans, manifested through their ability to inhibit superoxide anion generation, suppress elastase release, and selectively modulate key signaling pathways in human neutrophils. This suggests that dihydrophenanthropyrans hold significant promise as therapeutic agents for conditions associated with neutrophil-mediated inflammation.

The Prognostic Value of Left Ventricular Entropy From T1 Mapping in Patients With Hypertrophic Cardiomyopathy.

Background: The prognostic value of left ventricular (LV) entropy in hypertrophic cardiomyopathy (HCM) is unclear. Objectives: This study aimed to assess the prognostic value of LV entropy from T1 mapping in HCM. Methods: A total of 748 participants with HCM, who underwent cardiovascular magnetic resonance (CMR), were consecutively enrolled. LV entropy was quantified by native T1 mapping. A competing risk analysis and a Cox proportional hazards regression analysis were performed to identify potential associations of LV entropy with sudden cardiac death (SCD) and cardiovascular death (CVD), respectively. Results: A total of 40 patients with HCM experienced SCD, and 65 experienced CVD during a median follow-up of 43 months. Participants with increased LV entropy (≥4.06) were more likely to experience SCD and CVD (all P < 0.05) in the entire study cohort or the subgroup with low late gadolinium enhancement (LGE) extent (<15%). After adjustment for the European Society of Cardiology predictors and the presence of high LGE extent (≥15%), LV mean entropy was an independent predictor for SCD (HR: 1.03; all P < 0.05) by the multivariable competing risk analysis and CVD (HR: 1.06; 95% CI: 1.03-1.09; P < 0.001) by multivariable Cox regression analysis. Conclusions: LV mean entropy derived from native T1 mapping, reflecting myocardial tissue heterogeneity, was an independent predictor of SCD and CVD in participants with HCM. (Cardiac Magnetic Resonance Imaging Clinical Application Registration Study; ChiCTR1900024094).

Therapeutic value of patent foramen ovale closure for drug-resistant epilepsy: A case series report.

OBJECTIVE: Closure surgery of patent foramen ovale (PFO) has been found to effectively control cryptogenic stroke and migraine, but it is uncertain whether PFO closure could also alleviate epileptic seizures. This study aims to observe the therapeutic effect of PFO closure on epileptic seizures. METHODS: Since July 11th, 2017, in the neurology department of West China Hospital, Sichuan University, Chengdu, we have been regularly monitoring patients with epilepsy who have undergone PFO closure. The patient's clinical information, such as frequency, duration, and severity of seizures, before and after surgery was recorded in detail as well as postoperative safety events. RESULTS: Of the 31 epilepsy patients who confirmed PFO observed (27 cases were drug-resistant epilepsy, 87.10%), average age of surgery was 23.74 years, and 12 cases were female (38.71%). After one-year follow-up, 26 patients (83.87%) achieved remission of seizure frequency, and 22 of whom (70.97%) experienced a remission of more than 50%. Additionally, compared to before surgery, 22 cases (70.97%) reported a decrease in the average seizure duration, and 20 cases (64.52%) reported a reduction in seizure severity. In the seizure indicators of frequency, average duration and severity, significant differences were identified between preoperative and postoperative comparisons with all test p values were <0.05. Furthermore, no serious safety events were reported except for one patient who briefly reported chest pain, and all patients expressed effective PFO closure. SIGNIFICANCE: The PFO closure has been shown for the first time to result in a significant reduction in the frequency, duration, and severity of seizures. Patients with drug-resistant epilepsy and PFO with a large shunt are ideal candidates for undergoing PFO closure. PLAIN LANGUAGE SUMMARY: Since PFO closure was found to have a good therapeutic effect on cryptogenic stroke and migraine, it has become a credible complementary therapy for the treatment of neurological diseases, and drug-resistant epilepsy with PFO is expected to become the next target disease that PFO closure could significantly improve.

Cytotoxicity and Multi-Enzyme Inhibition of Nepenthes miranda Stem Extract on H838 Human Non-Small Cell Lung Cancer Cells and RPA32, Elastase, Tyrosinase, and Hyaluronidase Proteins.

The carnivorous pitcher plants of the genus Nepenthes have long been known for their ethnobotanical applications. In this study, we prepared various extracts from the pitcher, stem, and leaf of Nepenthes miranda using 100% ethanol and assessed their inhibitory effects on key enzymes related to skin aging, including elastase, tyrosinase, and hyaluronidase. The cytotoxicity of the stem extract of N. miranda on H838 human lung carcinoma cells were also characterized by effects on cell survival, migration, proliferation, apoptosis induction, and DNA damage. The cytotoxic efficacy of the extract was enhanced when combined with the chemotherapeutic agent 5-fluorouracil (5-FU), indicating a synergistic effect. Flow cytometry analysis suggested that the stem extract might suppress H838 cell proliferation by inducing G2 cell cycle arrest, thereby inhibiting carcinoma cell proliferation. Gas chromatography-mass spectrometry (GC-MS) enabled the tentative identification of the 15 most abundant compounds in the stem extract of N. miranda. Notably, the extract showed a potent inhibition of the human RPA32 protein (huRPA32), critical for DNA replication, suggesting a novel mechanism for its anticancer action. Molecular docking studies further substantiated the interaction between the extract and huRPA32, highlighting bioactive compounds, especially the two most abundant constituents, stigmast-5-en-3-ol and plumbagin, as potential inhibitors of huRPA32's DNA-binding activity, offering promising avenues for cancer therapy. Overall, our findings position the stem extract of N. miranda as a promising source of natural compounds for anticancer therapeutics and anti-skin-aging treatments, warranting further investigation into its molecular mechanisms and potential clinical applications.

Novel Cervical Endoscopic Unilateral Laminoforaminotomy for Bilateral Decompression in Cervical Spondylosis Myeloradiculopathy: A Technical Note and Clinical Results.

Background: This study investigates the efficacy of the Cervical Endoscopic Unilateral Laminoforaminotomy for Bilateral Decompression (CE-ULFBD) technique in treating cervical myeloradiculopathy, primarily caused by degenerative spondylosis. Traditionally managed through multisegmental anterior cervical discectomy and fusion (ACDF) or laminoplasty combined with foraminotomy, this condition has recently experienced a promising shift towards minimally invasive approaches, particularly endoscopic spinal decompression. While empirical evidence is still emerging, these techniques show potential for effective treatment. Method: The objective was to evaluate the outcomes of CE-ULFBD in achieving single or multilevel bilateral foraminal and central decompression, emphasizing the reduction of injury to posterior cervical muscles and the associated postoperative neck soreness common in conventional procedures. This paper delineates the surgical procedures involved in CE-ULFBD and presents the clinical outcomes of nine patients diagnosed with myeloradiculopathy due to severe cervical stenosis. Result: Assessments were conducted using the Visual Analogue Scale (VAS) for neck and arm pain and the Modified Japanese Orthopaedic Association scale (mJOA) for the activity measurement of daily living. Results indicated a considerable decrease in pain levels according to the VAS, coupled with significant improvements in functional capacities as measured by the mJOA scale. Additionally, no major postoperative complications were noted during the follow-up period. Conclusion: The study concludes that CE-ULFBD is a safe and effective approach for the treatment of cervical myeloradiculopathy resulting from severe cervical stenosis, offering a viable and less invasive alternative to traditional decompressive surgeries.

Light-Chain Cardiac Amyloidosis: Cardiac Magnetic Resonance for Assessing Response to Chemotherapy.

OBJECTIVE: Cardiac magnetic resonance (CMR) is a diagnostic tool that provides precise and reproducible information about cardiac structure, function, and tissue characterization, aiding in the monitoring of chemotherapy response in patients with light-chain cardiac amyloidosis (AL-CA). This study aimed to evaluate the feasibility of CMR in monitoring responses to chemotherapy in patients with AL-CA. MATERIALS AND METHODS: In this prospective study, we enrolled 111 patients with AL-CA (50.5% male; median age, 54 [interquartile range, 49-63] years). Patients underwent longitudinal monitoring using biomarkers and CMR imaging. At follow-up after chemotherapy, patients were categorized into superior and inferior response groups based on their hematological and cardiac laboratory responses to chemotherapy. Changes in CMR findings across therapies and differences between response groups were analyzed. RESULTS: Following chemotherapy (before vs. after), there were significant increases in myocardial T2 (43.6 ± 3.5 ms vs. 44.6 ± 4.1 ms; P = 0.008), recovery in right ventricular (RV) longitudinal strain (median of -9.6% vs. -11.7%; P = 0.031), and decrease in RV extracellular volume fraction (ECV) (median of 53.9% vs. 51.6%; P = 0.048). These changes were more pronounced in the superior-response group. Patients with superior cardiac laboratory response showed significantly greater reductions in RV ECV (-2.9% [interquartile range, -8.7%-1.1%] vs. 1.7% [-5.5%-7.1%]; P = 0.017) and left ventricular ECV (-2.0% [-6.0%-1.3%] vs. 2.0% [-3.0%-5.0%]; P = 0.01) compared with those with inferior response. CONCLUSION: Cardiac amyloid deposition can regress following chemotherapy in patients with AL-CA, particularly showing more prominent regression, possibly earlier, in the RV. CMR emerges as an effective tool for monitoring associated tissue characteristics and ventricular functional recovery in patients with AL-CA undergoing chemotherapy, thereby supporting its utility in treatment response assessment.

A comprehensive examination of temporal-seasonal variations of PM1.0 and PM2.5 in taiwan before and during the COVID-19 lockdown.

COVID-19 has been a significant global concern due to its contagious nature. In May 2021, Taiwan experienced a severe outbreak, leading the government to enforce strict Pandemic Alert Level 3 restrictions in order to curtail its spread. Although previous studies in Taiwan have examined the effects of these measures on air quality, further research is required to compare different time periods and assess the health implications of reducing particulate matter during the Level 3 lockdown. Herein, we analyzed the mass concentrations, chemical compositions, seasonal variations, sources, and potential health risks of PM1.0 and PM2.5 in Central Taiwan before and during the Level 3 lockdown. As a result, coal-fired boilers (47%) and traffic emissions (53%) were identified as the predominant sources of polycyclic aromatic hydrocarbons (PAHs) in PM1.0, while in PM2.5, the dominant sources of PAHs were coal-fired boilers (28%), traffic emissions (50%), and iron and steel sinter plants (22.1%). Before the pandemic, a greater value of 20.9 ± 6.92 µg/m3 was observed for PM2.5, which decreased to 15.3 ± 2.51 µg/m3 during the pandemic due to a reduction in industrial and anthropogenic emissions. Additionally, prior to the pandemic, PM1.0 had a contribution rate of 79% to PM2.5, which changed to 89% during the pandemic. Similarly, BaPeq values in PM2.5 exhibited a comparable trend, with PM1.0 contributing 86% and 65% respectively. In both periods, the OC/EC ratios for PM1.0 and PM2.5 were above 2, due to secondary organic compounds. The incremental lifetime cancer risk (ILCR) of PAHs in PM2.5 decreased by 4.03 × 10-5 during the pandemic, with PM1.0 contributing 73% due to reduced anthropogenic activities.

Standardized approach for accurate and reliable model development of ion-exchange chromatography based on parameter-by-parameter method and consideration of extra-column effects.

Developing an accurate and reliable model for chromatographic separation that meets regulatory requirements and ensures consistency in model development remains challenging. In order to address this challenge, a standardized approach was proposed in this study with ion-exchange chromatography (IEC). The approach includes the following steps: liquid flow identification, system and column-specific parameters determination and validation, multi-component system identification, protein amount validation, steric mass action parameters determination and evaluation, and validation of the calibrated model's generalization ability. The parameter-by-parameter (PbP) calibration method and the consideration of extra-column effects were integrated to enhance the accuracy of the developed models. The experiments designed for implementing the PbP method (five gradient experiments for model calibration and one stepwise experiment for model validation) not only streamline the experimental workload but also ensure the extrapolation abilities of the model. The effectiveness of the standardized approach is successfully validated through an application about the IEC separation of industrial antibody variants, and satisfactory results were observed with R2 ≈ 0.9 for the majority of calibration and validation experiments. The standardized approach proposed in this work contributes significantly to improve the accuracy and reliability of the developed IEC models. Models developed using this standardized approach are ready to be applied to a broader range of industrial separation systems, and are likely find further applications in model-assisted decision-making of process development.

Residence time distribution in continuous virus filtration.

Regulatory authorities recommend using residence time distribution (RTD) to address material traceability in continuous manufacturing. Continuous virus filtration is an essential but poorly understood step in biologics manufacturing in respect to fluid dynamics and scale-up. Here we describe a model that considers nonideal mixing and film resistance for RTD prediction in continuous virus filtration, and its experimental validation using the inert tracer NaNO3. The model was successfully calibrated through pulse injection experiments, yielding good agreement between model prediction and experiment ( R 2 > ${R}^{2}\gt $ 0.90). The model enabled the prediction of RTD with variations-for example, in injection volumes, flow rates, tracer concentrations, and filter surface areas-and was validated using stepwise experiments and combined stepwise and pulse injection experiments. All validation experiments achieved R 2 > ${R}^{2}\gt $ 0.97. Notably, if the process includes a porous material-such as a porous chromatography material, ultrafilter, or virus filter-it must be considered whether the molecule size affects the RTD, as tracers with different sizes may penetrate the pore space differently. Calibration of the model with NaNO3 enabled extrapolation to RTD of recombinant antibodies, which will promote significant savings in antibody consumption. This RTD model is ready for further application in end-to-end integrated continuous downstream processes, such as addressing material traceability during continuous virus filtration processes.

The impact of type 2 diabetes mellitus on the clinical profile, myocardial fibrosis, and prognosis in non-ischemic dilated cardiomyopathy: a prospective cohort study.

BACKGROUND: The impact of the coexistence of type 2 diabetes mellitus (T2DM) in patients with non-ischemic dilated cardiomyopathy (DCM) on clinical profiles, myocardial fibrosis, and outcomes remain incompletely understood. METHOD: A total of 1152 patients diagnosed with non-ischemic DCM were prospectively enrolled from June 2012 to October 2021 and categorized into T2DM and non-T2DM groups. Clinical characteristics, cardiac function, and myocardial fibrosis evaluated by CMR were compared between the two groups. The primary endpoint included both all-cause mortality and heart transplantation. Cause of mortality was classified into heart failure death, sudden cardiac death, and non-cardiac death. Cox regression analysis and Kaplan-Meier analysis were performed to identify the association between T2DM and clinical outcomes. Propensity score matching (PSM) cohort including 438 patients was analyzed to reduce the bias from confounding covariates. RESULTS: Among the 1152 included DCM patients, 155 (13%) patients had T2DM. Patients with T2DM were older (55 ± 12 vs. 47 ± 14 years, P < 0.001), had higher New York Heart Association (NYHA) functional class (P = 0.003), higher prevalence of hypertension (37% vs. 21%, P < 0.001), atrial fibrillation (31% vs. 16%, P < 0.001), lower left ventricular (LV) ejection fraction (EF) (23 ± 9% vs. 27 ± 12%, P < 0.001), higher late gadolinium enhancement (LGE) presence (55% vs. 45%, P = 0.02), and significantly elevated native T1 (1323 ± 81ms vs. 1305 ± 73ms, P = 0.01) and extracellular volume fraction (ECV) (32.7 ± 6.3% vs. 31.3 ± 5.9%, P = 0.01) values. After a median follow-up of 38 months (interquartile range: 20-57 months), 239 patients reached primary endpoint. Kaplan-Meier analysis showed that patients with T2DM had worse clinical outcomes compared with those without T2DM in the overall cohort (annual events rate: 10.2% vs. 5.7%, P < 0.001). T2DM was independently associated with an increased risk of primary endpoint in the overall (Hazard ratio [HR]: 1.61, 95% CI: 1.13-2.33, P = 0.01) and PSM (HR: 1.54, 95% CI: 1.05-2.24, P = 0.02) cohorts. Furthermore, T2DM was associated with a higher risk of heart failure death (P = 0.006) and non-cardiac death (P = 0.02), but not sudden cardiac death (P = 0.16). CONCLUSIONS: Patients with T2DM represented a more severe clinical profile and experienced more adverse outcomes compared to those without T2DM in a large DCM cohort. TRIAL REGISTRATION: Trial registration number: ChiCTR1800017058; URL: https://www. CLINICALTRIALS: gov .

Properties of biochar colloids and behaviors in the soil environment: Influencing the migration of heavy metals.

Biochar pyrolyzed by biomass shows excellent application prospects for heavy metal (HM) remediation, but a part of biochar can be inevitably broken into micro- and nano-sized biochar colloids (BCs) under biological and physicochemical actions in soil. BCs derived in the process of remediation have rough surface, rich elemental species and contents, and multiple functional groups, which are similar to biochar. However, BCs have some unique colloidal properties because of their micro and nano scale size. Due to these properties, BCs exhibit strong mobilities in the soil environment, and the mobilities may be influenced by a combination of colloidal properties of BCs and environmental factors including soil colloids and other soil environmental conditions. In addition, BCs may have affinity effects on HMs through electrostatic adsorption, ion exchange, surface complexation, precipitation/co-precipitation, and redox because of the properties such as large specific surface area, and rich oxygen-containing functional groups and minerals on the surface. This review summarizes the physicochemical and migratory properties of BCs, and the internal and external factors affecting the migration of BCs in the soil environment, and the possible effects of BCs on HMs are high-lighted. This review provides a theoretical basis for the optimization of soil contaminated with HMs after remediation using biochar. Notably, the innovative idea that BCs may influence the presence of HMs in soil needs to be further confirmed by more targeted detection and analysis methods in future studies to prevent the possible environmental toxicities of the lateral and vertical diffusion of HM caused by BCs in soil.

Quantitative determination of potential genotoxic impurities in metformin hydrochloride and empagliflozin tablets through ultra-performance liquid chromatographymass spectrometry.

An increasing number of drug research institutions consider genotoxic impurity research a core task in drug research and development. Peroxides in drugs may directly or indirectly attack and damage cell DNA, posing a potential carcinogenic risk to the human body. Currently, the literature only studies hydroperoxide impurities, and benzyl peroxide has not been studied yet. In this study, an effective method for ultra-performance liquid chromatographymass spectrometry (UPLCMS/MS) was established and verified to detect and quantify the potential genotoxic impurity (PGI), empagliflozin benzyl peroxide, in metformin-empagliflozin combination formulations, which has not been reported thus far. A Waters ACQUITY UPLC HSS T3 (3.0 ×100 mm, 1.8 µm) column was used to achieve chromatographic separation with gradient elution. The mass spectrometry conditions were optimized using electrospray ionization in the negative mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology can quantify PGIs at 1.35 ng/mL (5.4 ppm) in samples. This validated method exhibited good linearity over a concentration range of 5.4 to 36 ppm, and the accuracy of this method was in the range of 83.2-95.0% for empagliflozin benzyl peroxide. This approach fills the gap in the detection method for benzyl peroxide impurities in metformin hydrochloride and empagliflozin tablets, providing technical support for the quality control of the drug.