Microdroplet-enhanced chip platform for high-throughput immunotherapy marker screening from extracellular vesicle RNAs and membrane proteins.

Extracellular vesicles (EVs) are considered as promising candidates for predicting patients who respond to immunotherapy. Nevertheless, simultaneous detection of multiple EVs markers still presents significant technical challenges. In this work, we developed a high-throughput microdroplet-enhanced chip (MEC) platform, which utilizes thousands of individual microchambers (∼pL) as reactors, accelerating the detection efficiency of the CRISPR/Cas systems and increasing the sensitivity by up to 100-fold (aM level). Ten biomarkers (including 5 RNAs and 5 proteins) from patients' EVs are successfully detected on one chip, and the comprehensive markers show increased accuracy (AUC 0.911) than the individual marker for the efficacy prediction of immunotherapy. This platform provides a high-throughput yet sensitive strategy for screening immunotherapy markers in clinical.

Efficacy and safety of recombinant human thrombopoietin for the treatment of chronic primary immune thrombocytopenia in children and adolescents: A multicentre, randomized, double-blind, placebo-controlled phase III trial.

The efficacy and safety of recombinant human thrombopoietin (rhTPO) in children and adolescent patients with chronic primary immune thrombocytopenia (ITP) remains unclear. A multicentre, randomized, double-blind, placebo-controlled phase III trial was performed. Patients aged 6-17 years, diagnosed with ITP and resistant or relapsed to corticosteroid treatment were included. For the trial, part 1 was exploratory and part 2 was the main analysis, with part 1 determining whether part 2 was stratified by age. Patients in part 1 were treated with rhTPO (the 6- to 11-/12- to 17-year-old groups; 1:1). Patients in part 2 were randomized (3:1) to receive either rhTPO treatment or placebo. Patients received rhTPO or placebo at a dose of 300 U/kg once daily for up to 14 days. A total of 68 patients were included [part 1 (12 patients), part 2 (56 patients)]. The total response rate (TRR) in part 1 was 50.0% (95% CI: 21.09%-78.91%). For part 2, the TRR was 58.5% (95% CI: 42.11%-73.68%) and 13.3% (95% CI: 1.66%-40.46%) in the rhTPO and placebo groups (FAS) respectively. The difference in TRR between the rhTPO group and placebo group was 45.2% (95% CI: 22.33%-68.08%) and 44.6% (95% CI: 21.27%-67.85%) on the FAS and per-protocol set (PPS), respectively, which indicates the superiority of rhTPO treatment.

Magnetic solid-phase extraction coupled with LC-MS/MS methods for the simple extraction and rapid determination of sugammadex in human plasma.

Sugammadex (SUG) is a novel antagonist of neuromuscular blocking agents (NMBAs). The NMBA rocuronium is usually employed to obtain better surgical conditions in kidney transplant. Nevertheless, rocuronium has several disadvantages, such as an increased risk of pulmonary complications. Thus, SUG is vital to kidney-transplant surgery. However, because SUG is excreted by the kidneys in prototypes, the pharmacokinetics (PK) may be affected in patients with renal impairment. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to monitor SUG in plasma samples to investigate the PK of SUG in kidney-transplant patients. Due to the complexity and limitation of other methods of sample preparation, magnetic solid-phase extraction (MSPE) was adopted to purify samples. Chromatographic separation was obtained using a reversed-phase Polaris® C18 column and gradient elution with 0.1% formic acid (FA) in water as phase A and in methanol (MeOH) as phase B as mobile phases. The transitions 999.7 → 963.9 (m/z) and 1055.7 → 1012.2 (m/z) were used to quantify SUG and ORG26265, respectively, under negative electrospray ionization. A linear calibration curve was achieved in concentrations varying from 100 to 10 000 ng mL-1. The acceptable accuracy varied from 95.7% to 106.4%, and intra- and inter-precision did not exceed 15% (20% at the lower limit of quantitation (LLOQ)). The matrix effect, stability, dilution integrity, and carry-over were validated. This method was applied successfully for the PK study of 13 recipients and 12 donors of kidney transplant after intravenous injection of SUG (2 mL per kg bodyweight).

Circulating small extracellular vesicle RNA profiling for the detection of T1a stage colorectal cancer and precancerous advanced adenoma.

It takes more than 20 years for normal colorectal mucosa to develop into metastatic carcinoma. The long time window provides a golden opportunity for early detection to terminate the malignant progression. Here, we aim to enable liquid biopsy of T1a stage colorectal cancer (CRC) and precancerous advanced adenoma (AA) by profiling circulating small extracellular vesicle (sEV)-derived RNAs. We exhibited a full RNA landscape for the circulating sEVs isolated from 60 participants. A total of 58,333 annotated RNAs were detected from plasma sEVs, among which 1,615 and 888 sEV-RNAs were found differentially expressed in plasma from T1a stage CRC and AA compared to normal controls (NC). Then we further categorized these sEV-RNAs into six modules by a weighted gene coexpression network analysis and constructed a 60-gene t-SNE model consisting of the top 10 RNAs of each module that could well distinguish T1a stage CRC/AA from NC samples. Some sEV-RNAs were also identified as indicators of specific endoscopic and morphological features of different colorectal lesions. The top-ranked biomarkers were further verified by RT-qPCR, proving that these candidate sEV-RNAs successfully identified T1a stage CRC/AA from NC in another cohort of 124 participants. Finally, we adopted different algorithms to improve the performance of RT-qPCR-based models and successfully constructed an optimized classifier with 79.3% specificity and 99.0% sensitivity. In conclusion, circulating sEVs of T1a stage CRC and AA patients have distinct RNA profiles, which successfully enable the detection of both T1a stage CRC and AA via liquid biopsy.

Facile assembly of flexible, stretchable and attachable symmetric microsupercapacitors with wide working voltage windows and favorable durability.

With the increasing development of intelligent robots and wearable electronics, the demand for high-performance flexible energy storage devices is drastically increasing. In this study, flexible symmetric microsupercapacitors (MSCs) that could operate in a wide working voltage window were developed by combining laser-direct-writing graphene (LG) electrodes with a phosphoric acid-nonionic surfactant liquid crystal (PA-NI LC) gel electrolyte. To increase the flexibility and enhance the conformal ability of the MSC devices to anisotropic surfaces, after the interdigitated LG formed on the polyimide (PI) film surface, the devices were further transferred onto a flexible, stretchable and transparent polydimethylsiloxane (PDMS) substrate; this substrate displayed favorable flexibility and mechanical characteristics in the bending test. Furthermore, the electrochemical performances of the symmetric MSCs with various electrode widths (300, 400, 500 and 600 µm) were evaluated. The findings revealed that symmetric MSC devices could operate in a large voltage range (0-1.5 V); additionally, the device with a 300 µm electrode width (MSC-300) exhibited the largest areal capacitance of 2.3 mF cm-2 at 0.07 mA cm-2 and an areal (volumetric) energy density of 0.72 µWh cm- 2 (0.36 mWh cm- 3) at 55.07 µW cm-2 (27.54 mW cm-3), along with favorable mechanical and cycling stability. After charging for ~20 s, two MSC-300 devices connected in series could supply energy to a calculator to operate for ~130 s, showing its practical application potential as an energy storage device. Moreover, the device displayed favorable reversibility, stability and durability. After 12 months of aging in air at room temperature, its electrochemical performance was not altered, and after charging-discharging measurements for 5000 cycles at 0.07 mA cm-2, ~93.6% of the areal capacitance was still retained; these results demonstrated its practical long-term application potential as an energy storage device.

Ultrasensitive SERF atomic magnetometer with a miniaturized hybrid vapor cell.

The chip-scale hybrid optical pumping spin-exchange relaxation-free (SERF) atomic magnetometer with a single-beam arrangement has prominent applications in biomagnetic measurements because of its outstanding features, including ultrahigh sensitivity, an enhanced signal-to-noise ratio, homogeneous spin polarization and a much simpler optical configuration than other devices. In this work, a miniaturized single-beam hybrid optical pumping SERF atomic magnetometer based on a microfabricated atomic vapor cell is demonstrated. Although the optically thin Cs atoms are spin-polarized, the dense Rb atoms determine the experimental results. The enhanced signal strength and narrowed resonance linewidth are experimentally proven, which shows the superiority of the proposed magnetometer scheme. By using a differential detection scheme, we effectively suppress optical noise with an approximate five-fold improvement. Moreover, the cell temperature markedly affects the performance of the magnetometer. We systematically investigate the effects of temperature on the magnetometer parameters. The theoretical basis for these effects is explained in detail. The developed miniaturized magnetometer has an optimal magnetic sensitivity of 20 fT/Hz1/2. The presented work provides a foundation for the chip-scale integration of ultrahighly sensitive quantum magnetometers that can be used for forward-looking magnetocardiography (MCG) and magnetoencephalography (MEG) applications.

An integrated micromachined flexible ultrasonic-inductive sensor for pipe contaminant multiparameter detection.

Pipe contaminant detection holds considerable importance within various industries, such as the aviation, maritime, medicine, and other pertinent fields. This capability is beneficial for forecasting equipment potential failures, ascertaining operational situations, timely maintenance, and lifespan prediction. However, the majority of existing methods operate offline, and the detectable parameters online are relatively singular. This constraint hampers real-time on-site detection and comprehensive assessments of equipment status. To address these challenges, this paper proposes a sensing method that integrates an ultrasonic unit and an electromagnetic inductive unit for the real-time detection of diverse contaminants and flow rates within a pipeline. The ultrasonic unit comprises a flexible transducer patch fabricated through micromachining technology, which can not only make installation easier but also focus the sound field. Moreover, the sensing unit incorporates three symmetrical solenoid coils. Through a comprehensive analysis of ultrasonic and induction signals, the proposed method can be used to effectively discriminate magnetic metal particles (e.g., iron), nonmagnetic metal particles (e.g., copper), nonmetallic particles (e.g., ceramics), and bubbles. This inclusive categorization encompasses nearly all types of contaminants that may be present in a pipeline. Furthermore, the fluid velocity can be determined through the ultrasonic Doppler frequency shift. The efficacy of the proposed detection principle has been validated by mathematical models and finite element simulations. Various contaminants with diverse velocities were systematically tested within a 14 mm diameter pipe. The experimental results demonstrate that the proposed sensor can effectively detect contaminants within the 0.5-3 mm range, accurately distinguish contaminant types, and measure flow velocity.

Piezoelectric Hinged Beam with Arc Mass Stopper for Vibration and Human Motion Energy Harvesting.

Compact reliable structure and strong electromechanical coupling are hot pursuits in piezoelectric vibration energy harvester (PVEH) design. PVEH with a static arc stopper makes piezoelectric stress uniformly distributed and widens the frequency band by collision but wastes space. This Article proposes a hinged PVEH with two arc mass stoppers (AS-H-PVEH). Two arc stoppers as movable masses increase the vibration energy and the effective electromechanical coupling coefficient to achieve strong electromechanical coupling. AS-H-PVEH generates a 4.1 mW power output at 11.6-12.0 Hz and 0.2 g. AS-H-PVEH sustains 4 g acceleration vibration for 10 min without attenuation. To offset the resonance frequency increase caused by arc contact, we discuss the magnetic coupling, and axial force effects are discussed. The design of the arc stopper radius, nonlinear electromechanical coupling model, and system parameter identification method are presented. The displacement varied mechanical quality factor and effective electromechanical coupling coefficient are considered in the modified model for the first time. The model obtained good agreement under experiments. The power generation and driven wireless sensor performance of AS-H-PVEH was verified. This research has important theoretical and application value for the performance optimization of PVEH with an arc stopper.

Improved high-performance liquid chromatography tandem mass spectrometry method for quantification of infliximab in pediatric plasma and its application in therapeutic drug monitoring.

RATIONALE: The application of infliximab (IFX) to immune-mediated disease is limited by the significant individual variability and associated clinical nonresponse, emphasizing the importance of therapeutic drug monitoring (TDM). Because of the cross-reactivity, limited linear range, and high costs, the clinical application of the previous reported methods was limited. Here, an improved high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method was developed to address the issues. METHODS: This study developed an improved bioanalytical HPLC-MS/MS method coupling nanosurface and molecular-orientation limited proteolysis technology. The commercially available compound P14R was selected as the internal standard. This method was developed with fewer volume of reagents and was thoroughly validated. The validated method was applied to TDM in pediatric inflammatory bowel disease (IBD). RESULTS: Chromatography was performed using a Shim-pack GISS-HP C18 metal-free column (3 µm, 2.1 × 100 mm) with a gradient elution of 0.1% formic acid in water and acetonitrile at 0.4 mL/min. Detection and quantitation were performed using electrospray ionization (ESI) and multiple reaction monitoring in the positive ion mode. The method was validated to demonstrate its selectivity, linearity, accuracy, precision, recovery, matrix effect, and stability. The method exhibited a linear dynamic range of 0.3-100 µg/mL, with intra- and inter-day precision and relative errors below 15%. The recovery and matrix effect were measured as 87.28%-89.72% and 41.98%-67.17%, respectively, which were effectively compensated by the internal standard. A total of 32 samples collected from 24 pediatric patients with IBD were analyzed using the validated method, and only 46.9% achieved the reported targeted trough level. CONCLUSION: This study developed an improved HPLC-MS/MS method for the quantitative determination of IFX concentration in human plasma. The accurate, reliable, and cost-effective method was validated and utilized in the analysis of clinical samples. The results confirmed the importance of TDM on IFX and the clinical application prospects of the improved method.

Cell dehydration enables massive production of engineered membrane vesicles with therapeutic functions.

Extracellular vesicles (EVs) have emerged as promising biomaterials for the treatment of different disease. However, only handful types of EVs with clinical transformation potential have been reported to date, and their preparation on a large scale under biosafety-controlled conditions is limited. In this study, we characterize a novel type of EV with promising clinical application potential: dehydration-induced extracellular vesicles (DIMVs). DIMV is a type of micron-diameter cell vesicle that contains more bioactive molecules, such as proteins and RNA, but not DNA, than previously reported cell vesicles. The preparation of DIMV is extraordinarily straightforward, which possesses a high level of biosafety, and the protein utilization ratio is roughly 600 times greater than that of naturally secreted EVs. Additional experiments demonstrate the viability of pre- or post-isolation DIMV modification, including gene editing, nucleic acid encapsulation or surface anchoring, size adjustment. Finally, on animal models, we directly show the biosafety and immunogenicity of DIMV, and investigate its potential application as tumour vaccine or drug carrier in cancer treatment.

Small-size temperature/high-pressure integrated sensor via flip-chip method.

Hydraulic technology with smaller sizes and higher reliability trends, including fault prediction and intelligent control, requires high-performance temperature and pressure-integrated sensors. Current designs rely on planar wafer- or chip-level integration, which is limited by pressure range, chip size, and low reliability. We propose a small-size temperature/high-pressure integrated sensor via the flip-chip technique. The pressure and temperature units are arranged vertically, and the sensing signals of the two units are integrated into one plane through silicon vias and gold-gold bonding, reducing the lateral size and improving the efficiency of signal transmission. The flip-chip technique ensures a reliable electrical connection. A square diaphragm with rounded corners is designed and optimised with simulation to sense high pressure based on the piezoresistive effect. The temperature sensing unit with a thin-film platinum resistor measures temperature and provides back-end high-precision compensation, which will improve the precision of the pressure unit. The integrated chip is fabricated by MEMS technology and packaged to fabricate the extremely small integrated sensor. The integrated sensor is characterised, and the pressure sensor exhibits a sensitivity and sensitivity drift of 7.97 mV/MPa and -0.19% FS in the range of 0-20 MPa and -40 to 120 °C. The linearity, hysteresis, repeatability, accuracy, basic error, and zero-time drift are 0.16% FS, 0.04% FS, 0.06% FS, 0.18% FS, ±0.23% FS and 0.04% FS, respectively. The measurement error of the temperature sensor and temperature coefficient of resistance is less than ±1 °C and 3142.997 ppm/°C, respectively. The integrated sensor has broad applicability in fault diagnosis and safety monitoring of high-end equipment such as automobile detection, industrial equipment, and oil drilling platforms.

Effects of combined morbid insomnia and sleep apnea on long-term cardiovascular risk and all-cause mortality in elderly patients: a prospective cohort study.

PURPOSE: It is reported that insomnia and obstructive sleep apnea (OSA) increase the incidence of adverse cardiovascular events. The aim of this study was to analyze the risk of cardiovascular disease and mortality in elderly patients with comorbid insomnia and obstructive sleep apnea (COMISA). METHODS: We included 868 elderly patients with OSA who underwent sleep monitoring at a multicenter sleep room from January 2015 to October 2017. We collected demographic data, clinical features, medical history, sleep parameters, and laboratory findings. Cox proportional hazards analysis was used to identify the relationship between COMISA and adverse cardiovascular events and all-cause mortality. RESULTS: There were 181 elderly patients with COMISA. The median follow-up was 43 months, during which we observed major adverse cardiac events (MACE) in 90 patients. The Kaplan-Meier survival curve indicated a significant relationship between COMISA and MACE (Plog Rank < 0.001). Multivariate Cox regression analysis showed that COMISA increased the incidence of MACE (HR = 2.328, 95% CI: 1.349-4.018, P = 0.002), hospitalization for unstable angina (HR = 2.915, 95% CI: 1.397-6.081, P = 0.004), and the combination of all events (HR = 2.301, 95% CI: 1.393-3.803, P = 0.001). However, there were no significant differences in cardiovascular death, all-cause mortality, myocardial infarction, or hospitalized heart failure in patients with COMISA (P > 0.05). Subgroup analyses showed that among COMISA patients, male sex (HR = 2.800, 95% CI: 1.458-5.377, P = 0.002), age < 70 years (HR = 4.050, 95% CI: 2.022-8.115, P < 0.001), and overweight and obesity (HR = 2.482, 95% CI: 1.383-4.453, P = 0.002) were associated with a higher risk of MACE. CONCLUSIONS: Our results showed that COMISA increased the risk of MACE, unstable angina, and the compound occurrence of all events. Male, overweight or obese COMISA patients under 70 years of age have an increased risk of MACE.

Fabrication and characterization of high-sensitivity, wide-range, and flexible MEMS thermal flow velocity sensors.

With the rapid development of various fields, including aerospace, industrial measurement and control, and medical monitoring, the need to quantify flow velocity measurements is increasing. It is difficult for traditional flow velocity sensors to fulfill accuracy requirements for velocity measurements due to their small ranges, susceptibility to environmental impacts, and instability. Herein, to optimize sensor performance, a flexible microelectromechanical system (MEMS) thermal flow sensor is proposed that combines the working principles of thermal loss and thermal temperature difference and utilizes a flexible cavity substrate made of a low-thermal-conductivity polyimide/SiO2 (PI/SiO2) composite porous film to broaden the measurement range and improve the sensitivity. The measurement results show that the maximum measurable flow velocity can reach 30 m/s with a resolution of 5.4 mm/s. The average sensitivities of the sensor are 59.49 mV/(m s-1) in the medium-to-low wind velocity range of 0-2 m/s and 467.31 mV/(m s-1) in the wind velocity range of 2-30 m/s. The sensor proposed in this work can enable new applications of flexible flow sensors and wearable devices.

Patchy profile sign in RAPID software: a specific marker for intracranial atherosclerotic stenosis in acute ischemic stroke.

Purpose: Identifying the etiology of acute ischemic stroke (AIS) before endovascular treatment (EVT) is important but challenging. In CT perfusion imaging processed by perfusion software, we observed a phenomenon called patchy profile sign (PPS), that is, the hypoperfusion morphology in RAPID software is a discontinuous sheet pattern. This phenomenon is predominantly observed in patients diagnosed with intracranial atherosclerotic stenosis (ICAS). The study intends to assess whether the PPS can be used to differentiate ICAS from intracranial embolism. Method: Patients with AIS due to M1 segment occlusion of the MCA who underwent mechanical thrombectomy were retrospectively enrolled. The receiver operating characteristic (ROC) curve analysis was performed to assess the value of PPS in predicting ICAS. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the PPS for prediction of ICAS were calculated. Results: A total of 51 patients were included in the study. The PPS was observed in 10 of 19 (52.6%) patients with ICAS, and in 2 of 32 (6.3%) patients with intracranial embolism (p < 0.001). Interobserver agreement for identifying PPS was excellent (κ = 0.944). The sensitivity, specificity, PPV, NPV, and accuracy of the PPS for predicting ICAS were 52.6, 93.8, 83.3, 76.9, and 78.4%, respectively. Conclusion: The PPS on RAPID software is an imaging marker with high specificity for ICAS. Larger sample sizes are imperative to validate the findings.

Split ring hole metamaterial-enhanced pyroelectric detector for efficient multi-narrowband terahertz detection.

Derived from infrared pyroelectric detection, typical terahertz (THz) pyroelectric detectors have low sensitivity at low-frequency THz bands. Based on the high-efficiency absorption of the metamaterial perfect absorber (MPA), a novel split ring hole metamaterial-enhanced pyroelectric detector is proposed to achieve efficient multi-narrowband THz detection. Using high frequency simulation software (HFSS), the dimensional parameters including ring radius, ring width, connection beam width, array period, and thickness, are optimized to enhance efficient multi-narrowband absorption. The as-optimized metamaterial-enhanced detectors are fabricated via micro-nano manufacturing technology. The voltage responsiveness and noise equivalent power of the metamaterial-enhanced detector are tested by THz focused optical path and compared with those of the typical pyroelectric detector and the simulated MPA absorptivity. The results indicate that the metamaterial-enhanced detector has a multi-narrowband detection capability at 0.245 THz, 0.295 THz, and 0.38 THz, which is close to the simulated MPA absorptivity. Compared to the typical pyroelectric detector, the split ring hole metamaterial-enhanced detector can simultaneously achieve thermal absorption, thermal conduction, and pyroelectricity in the same MPA structure, providing faster response speed above 100 Hz chopper frequency and two times higher detection sensitivity at multi-narrowband THz frequencies. This research can be used for THz sensing, absorption filtering, biological macromolecule detection, and other applications.

Quantitative evaluation of the time-course and efficacy of targeted agents for ulcerative colitis.

Background: Targeted agents are widely utilized in the treatment of ulcerative colitis (UC). Hence, a comprehensive understanding of comparative drug efficacy in UC is of great importance for drug development and clinical practice. Our objective was the quantitative evaluation of the comparative efficacy of targeted agents for UC. Methods: Three mathematical models were developed based on data from randomized controlled trials in patients with moderate-to-severe UC to describe the time-course and dose-response of efficacy defined as clinical remission, clinical response, and endoscopic improvement, as well as the placebo effect. The covariate effects were further evaluated. Model simulation was performed in a hypothetical population to compare the efficacies across different drugs. Results: The analysis dataset was composed of data from 35 trials of 12 drugs in UC. Time-response relationships were evaluated that indicated a gradual onset of drug efficacy in adalimumab, ozanimod, and Janus kinase (JAK) inhibitors. The dose-response relationships were estimated for each drug respectively. Patient age, disease duration, baseline weight, prior tumor necrosis factor (TNF) inhibitor exposure, and current treatment with corticosteroid showed an impact on efficacy, suggesting that younger patients with shorter UC duration without prior anti-TNF treatment and current corticosteroids therapy tend to display greater treatment effects. Conclusion: This study developed three longitudinal models for UC to quantitatively describe the efficacy of targeted agents, as well as the influencing factors of efficacy. Infliximab and upadacitinib were determined to be the most effective biological and small targeted molecules, respectively. These findings may provide valuable implications for guiding future decision-making in clinical practice and drug development for UC.

Modulation of mercaptopurine intestinal toxicity and pharmacokinetics by gut microbiota.

The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.

Advances in biosensors for major depressive disorder diagnostic biomarkers.

Depression is one of the most common mental disorders and is mainly characterized by low mood or lack of interest and pleasure. It can be accompanied by varying degrees of cognitive and behavioral changes and may lead to suicide risk in severe cases. Due to the subjectivity of diagnostic methods and the complexity of patients' conditions, the diagnosis of major depressive disorder (MDD) has always been a difficult problem in psychiatry. With the discovery of more diagnostic biomarkers associated with MDD in recent years, especially emerging non-coding RNAs (ncRNAs), it is possible to quantify the condition of patients with mental illness based on biomarker levels. Point-of-care biosensors have emerged due to their advantages of convenient sampling, rapid detection, miniaturization, and portability. After summarizing the pathogenesis of MDD, representative biomarkers, including proteins, hormones, and RNAs, are discussed. Furthermore, we analyzed recent advances in biosensors for detecting various types of biomarkers of MDD, highlighting representative electrochemical sensors. Future trends in terms of new biomarkers, new sample processing methods, and new detection modalities are expected to provide a complete reference for psychiatrists and biomedical engineers.

Population pharmacokinetics of nirmatrelvir in Chinese patients with COVID-19: Therapeutic drug monitoring and dosing regimen selection in clinical practice.

OBJECTIVES: To establish a population pharmacokinetics (PopPK) model of nirmatrelvir in Chinese COVID-19 patients and provide reference for refining the dosing strategy of nirmatrelvir in patients confirmed to be infected with SARS-CoV-2. METHODS: A total of 80 blood samples were obtained from 35 mild to moderate COVID-19 patients who were orally administered nirmatrelvir/ritonavir tablets. The PopPK model of nirmatrelvir was developed using a nonlinear mixed effects modelling approach. The stability and prediction of the final model were assessed through a combination of goodness-of-fit and bootstrap method. The exposure of nirmatrelvir across various clinical scenarios was simulated using Monte Carlo simulations. RESULTS: The pharmacokinetics of nirmatrelvir was well characterised by a one-compartment model with first-order absorption, and with creatinine clearance (Ccr) as the significant covariate. Typical population parameter estimates of apparent clearance and distribution volume for a patient with a Ccr of 95.5 mL·min-1were 3.45 L·h-1 and 48.71 L, respectively. The bootstrap and visual predictive check procedures demonstrated satisfactory predictive performance and robustness of the final model. CONCLUSION: The final model was capable of offering an early prediction of drug concentration ranges for different nirmatrelvir dosing regimens and optimise the dose regimen of nirmatrelvir in individuals with confirmed SARS-CoV-2 infection.

Advances in heart failure monitoring: Biosensors targeting molecular markers in peripheral bio-fluids.

Cardiovascular diseases (CVDs), especially chronic heart failure, threaten many patients' lives worldwide. Because of its slow course and complex causes, its clinical screening, diagnosis, and prognosis are essential challenges. Clinical biomarkers and biosensor technologies can rapidly screen and diagnose. Multiple types of biomarkers are employed for screening purposes, precise diagnosis, and treatment follow-up. This article provides an up-to-date overview of the biomarkers associated with the six main heart failure etiology pathways. Plasma natriuretic peptides (BNP and NT-proBNP) and cardiac troponins (cTnT, cTnl) are still analyzed as gold-standard markers for heart failure. Other complementary biomarkers include growth differentiation factor 15 (GDF-15), circulating Galactose Lectin 3 (Gal-3), soluble interleukin (sST2), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). For these biomarkers, the electrochemical biosensors have exhibited sufficient sensitivity, detection limit, and specificity. This review systematically summarizes the latest molecular biomarkers and sensors for heart failure, which will provide comprehensive and cutting-edge authoritative scientific information for biomedical and electronic-sensing researchers in the field of heart failure, as well as patients. In addition, our proposed future outlook may provide new research ideas for researchers.