[Pharmacokinetics, pharmacodynamics, and tissue distribution of oral co-loaded puerarin/daidzein mixed micelles in rats].

This study investigated the drug delivery performance of oral co-loaded puerarin(PUE) and daidzein(DAZ) mixed micelles(PUE/DAZ-FS/PMMs) from the perspectives of pharmacokinetics, pharmacodynamics, and tissue distribution. The changes in PUE plasma concentration in rats were evaluated based on PUE suspension, single drug-loaded micelles(PUE-FS/PMMs), and co-loaded micelles(PUE/DAZ-FS/PMMs). Spontaneously hypertensive rats(SHR) were used to monitor systolic blood pressure, diastolic blood pressure, and mean arterial pressure for 10 weeks after administration by tail volume manometry. The content of PUE in the heart, liver, spleen, lung, kidney, brain, and testes was determined using LC-MS/MS. The results showed that compared with PUE suspension and PUE-FS/PMMs, PUE/DAZ-FS/PMMs significantly increased C_(max) in rats(P<0.01) and had a relative bioavailability of 122%. The C_(max), AUC_(0-t), AUC_(0-∞), t_(1/2), and MRT of PUE/DAZ-FS/PMMs were 1.77, 1.22, 1.22, 1.17, and 1.13 times higher than those of PUE suspension, and 1.76, 1.16, 1.08, 0.84, and 0.78 times higher than those of PUE-FS/PMMs, respectively. Compared with the model control group, PUE/DAZ-FS/PMMs significantly reduced systolic blood pressure, diastolic blood pressure, and mean arterial pressure in SHR rats(P<0.05). The antihypertensive effect of PUE/DAZ-FS/PMMs was greater than that of PUE suspension, and even greater than that of PUE-FS/PMMs at high doses. Additionally, the distribution of PMMs in various tissues showed dose dependency. The distribution of PMMs in the kidney and liver, which are metabolically related tissues, was lower than that in the suspension group, while the distribution in the brain was higher than that in the conventional dose group. In conclusion, PUE/DAZ-FS/PMMs not only improved the bioavailability of PUE and synergistically enhanced its therapeutic effect but also prolonged the elimination of the drug to some extent. Furthermore, the micelles facilitated drug penetration through the blood-brain barrier. This study provides a foundation for the development of co-loaded mixed micelles containing homologous components.

Developing an Interpretable Machine Learning Model to Predict in-Hospital Mortality in Sepsis Patients: A Retrospective Temporal Validation Study.

BACKGROUND: Risk stratification plays an essential role in the decision making for sepsis management, as existing approaches can hardly satisfy the need to assess this heterogeneous population. We aimed to develop and validate a machine learning model to predict in-hospital mortality in critically ill patients with sepsis. METHODS: Adult patients fulfilling the definition of Sepsis-3 were included at a large tertiary medical center. Relevant clinical features were extracted within the first 24 h in ICU, re-classified into different genres, and utilized for model development under three strategies: "Basic + Lab", "Basic + Intervention", and "Whole" feature sets. Extreme gradient boosting (XGBoost) was compared with logistic regression (LR) and established severity scores. Temporal validation was conducted using admissions from 2017 to 2019. RESULTS: The final cohort included 24,272 patients, of which 4013 patients formed the test cohort for temporal validation. The trained and fine-tuned XGBoost model with the whole feature set showed the best discriminatory ability in the test cohort with AUROC as 0.85, significantly higher than the XGBoost "Basic + Lab" model (0.83), the LR "Whole" model (0.82), SOFA (0.63), SAPS-II (0.73), and LODS score (0.74). The performance in varying subgroups remained robust, and predictors, such as increased urine output and supplemental oxygen therapy, were crucially correlated with improved survival when interpretability was explored. CONCLUSIONS: We developed and validated a novel XGBoost-based model and demonstrated significantly improved performance to LR and other scores in predicting the mortality risks of sepsis patients in the hospital using features in the first 24 h.

The Impact of Manufacturing Imperfections on the Performance of Metalenses and a Manufacturing-Tolerant Design Method.

Metalenses play an important role in optoelectronic integrated devices, given their advantages in miniaturization and integration. Due to its high aspect ratio subwavelength structure, fabricating metalenses requires a high-level dry etching technology. Consequently, structure deformation of the metalens will exist if the etching process of the material is not mature enough, which will impair the metalens' performance. In this paper, a polarization-independent InP dielectric metalens is designed to focus the incident light from air into the substrate, which is used for monolithically integrating with the InGaAs/InP photodetector in the future. Subsequently, with the simulation method, we investigated the impact of the structure deformation on the metalens' performance, which was found in our InP dry etching process development. We have found that the sidewall slope and aspect ratio-dependent etching effect greatly impaired the focusing efficiency because of the phase modulation deviation. To solve this problem, we proposed a manufacturing-tolerant design method, which effectively improved the performance of the device with structural deformation. Our work is instructive for developing metalenses and can accelerate their integration application.

Association of Sex With Clinical Outcome in Critically Ill Sepsis Patients: A Retrospective Analysis of the Large Clinical Database MIMIC-III.

INTRODUCTION: The objective of our study was to explore the association between sex and clinical outcome in sepsis patients in a large, diverse population. MATERIALS AND METHODS: We analyzed 6,134 adult patients with sepsis from the critical care units of Beth Israel Deaconess Medical Center between 2001 and 2012. Study data were retrospectively extracted from Medical Information Mart for Intensive Care-III, a multiparameter intensive care database. RESULTS: There were 2,677 (43.6%) female and 3,457 (56.4%) male patients. Compared with female patients, male patients with sepsis had a higher 1-year mortality rate (55.6% vs. 51.4%, P = 0.001), and so did the 90-day mortality rate (45.1% vs. 42.1%, P = 0.018). 33.8% of male and 31.3% of female patients with sepsis died during hospitalization (P = 0.041). The median length of hospitalization and intensive care unit (ICU) stay for male patients was 19.54 and 7.54 days, while that for female patients was 16.49 and 6.75 days (P < 0.001, P = 0.002, respectively). Male patients were more likely to require dialysis therapy (P = 0.109), ventilation support (P = 0.012) and more vasoactive agents (dopamine P = 0.113, norepinephrine P = 0.016, and epinephrine P = 0.093) during the ICU period than female patients. Our Cox proportional hazard regression model confirmed that the risk of death within 1 year of ICU admission in male patients is 1.083 times that in female. CONCLUSION: Female patients with sepsis have better clinical outcomes than male patients in terms of mortality and length of hospitalization and ICU stay.

Increased body mass index linked to greater short- and long-term survival in sepsis patients: A retrospective analysis of a large clinical database.

OBJECTIVES: We investigated the impact of obesity (proxied as body mass index (BMI)), on short- and long-term mortality in sepsis patients. METHODS: We conducted a retrospective analysis with adult sepsis ICU patients in a US medical institution from 2001 to 2012 in the MIMIC-III database. The WHO BMI categories were used. Multivariate logistic regression assessed the relationships between BMI and 30-day and 1-year mortality. RESULTS: In total, 5563 patients were enrolled. Obese patients tended to be younger (P<0.001), to be female (P<0.001), to acquire worse SOFA scores (P<0.001), and to receive more aggressive treatment compared with their normal weight counterparts. Obese patients had notably longer mechanical ventilation periods and ICU and hospital lengths of stay (LOSs). In the final model, overweight and obese patients had lower 30-day (OR 0.77, 95% CI 0.66-0.91; OR 0.65, 95% CI 0.56-0.77, respectively) and 1-year (OR 0.83, 95% CI 0.71-0.96; OR 0.70, 95% CI 0.60-0.81, respectively) mortality risks than normal weight patients. In contrast, underweight patients had worse 30-day and 1-year outcomes compared with normal weight patients (P=0.01, P<0.001, respectively). In morbidly obese, severe sepsis and septic shock patients, obesity remained protective. CONCLUSIONS: Obesity was correlated with short- and long-term survival advantages in sepsis patients.