3D printing processes in precise drug delivery for personalized medicine.

With the advent of personalized medicine, the drug delivery system will be changed significantly. The development of personalized medicine needs the support of many technologies, among which three-dimensional printing (3DP) technology is a novel formulation-preparing process that creates 3D objects by depositing printing materials layer-by-layer based on the computer-aided design method. Compared with traditional pharmaceutical processes, 3DP produces complex drug combinations, personalized dosage, and flexible shape and structure of dosage forms (DFs) on demand. In the future, personalized 3DP drugs may supplement and even replace their traditional counterpart. We systematically introduce the applications of 3DP technologies in the pharmaceutical industry and summarize the virtues and shortcomings of each technique. The release behaviors and control mechanisms of the pharmaceutical DFs with desired structures are also analyzed. Finally, the benefits, challenges, and prospects of 3DP technology to the pharmaceutical industry are discussed.

Twenty-four-hour blood pressure trajectories and clinical outcomes in patients who had an acute ischaemic stroke.

OBJECTIVE: The management of blood pressure (BP) in acute ischaemic stroke remains a subject of controversy. This investigation aimed to explore the relationship between 24-hour BP patterns following ischaemic stroke and clinical outcomes. METHODS: A cohort of 4069 patients who had an acute ischaemic stroke from 26 hospitals was examined. Five systolic BP trajectories were identified by using latent mixture modelling: trajectory category 5 (190-170 mm Hg), trajectory category 4 (180-140 mm Hg), trajectory category 3 (170-160 mm Hg), trajectory category 2 (155-145 mm Hg) and trajectory category 1 (150-130 mm Hg). The primary outcome was a composite outcome of death and major disability at 3 months poststroke. RESULTS: Patients with trajectory category 5 exhibited the highest risk, while those with trajectory category 1 had the lowest risk of adverse outcomes at 3-month follow-up. Compared with the patients in the trajectory category 5, adjusted ORs (95% CIs) for the primary outcome were 0.79 (0.58 to 1.10), 0.70 (0.53 to 0.93), 0.64 (0.47 to 0.86) and 0.47 (0.33 to 0.66) among patients in trajectory category 4, trajectory category 3, trajectory category 2 and trajectory category 1, respectively. Similar trends were observed for death, vascular events and the composite outcome of death and vascular events. CONCLUSION: Patients with persistently high BP at 180 mm Hg within 24 hours of ischaemic stroke onset had the highest risk, while those maintaining stable BP at a moderate-low level (150 mm Hg) or even a low level (137 mm Hg) had more favourable outcomes.

Characterization of VOC emissions and health risk assessment in the plastic manufacturing industry.

Volatile organic compounds (VOCs) significantly contribute to ozone pollution formation, and many VOCs are known to be harmful to human health. Plastic has become an indispensable material in various industries and daily use scenarios, yet the VOC emissions and associated health risks in the plastic manufacturing industry have received limited attention. In this study, we conducted sampling in three typical plastic manufacturing factories to analyze the emission characteristics of VOCs, ozone formation potential (OFP), and health risks for workers. Isopropanol was detected at relatively high concentrations in all three factories, with concentrations in organized emissions reaching 322.3 µg/m3, 344.8 µg/m3, and 22.6 µg/m3, respectively. Alkanes are the most emitted category of VOCs in plastic factories. However, alkenes and oxygenated volatile organic compounds (OVOCs) exhibit higher OFP. In organized emissions of different types of VOCs in the three factories, alkenes and OVOCs contributed 22.8%, 67%, and 37.8% to the OFP, respectively, highlighting the necessity of controlling them. The hazard index (HI) for all three factories was less than 1, indicating a low non-carcinogenic toxic risk; however, there is still a possibility of non-cancerous health risks in two of the factories, and a potential lifetime cancer risk in all of the three factories. For workers with job tenures exceeding 5 years, there may be potential health risks, hence wearing masks with protective capabilities is necessary. This study provides evidence for reducing VOC emissions and improving management measures to ensure the health protection of workers in the plastic manufacturing industry.

One-Year Disability Trajectories and Long-Term Cardiovascular Events, Recurrent Stroke, and Mortality After Ischemic Stroke.

BACKGROUND: Patients with stroke are often affected by varying degrees of functional disability and have different evolution patterns in functional disability. However, little is known about the predictive usefulness of disability changes after stroke. We aimed to describe 1-year disability trajectories and to assess the associations of longitudinal disability trajectories with 24-month clinical outcomes after ischemic stroke. METHODS AND RESULTS: A total of 3533 patients with ischemic stroke from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) were studied. Distinct trajectories of disability were identified by the group-based trajectory model, as measured by modified Rankin Scale score within 12 months. Cox proportional hazards regression models were used to examine the associations of disability trajectories with 24-month cardiovascular events and all-cause mortality. We identified 4 distinct disability trajectories: no significant disability (562 participants [15.9%]), slight disability to recovery (1575 participants [44.6%]), severe to moderate disability (1087 participants [30.8%]), and persistent severe disability (309 participants [8.7%]). Compared with no significant disability trajectory, the multivariable adjusted hazard ratios (95% CIs) of patients within the persistent heavy-severe trajectory were 2.63 (1.20-5.76) for cardiovascular events, 2.55 (1.12-5.79) for recurrent stroke, and 6.10 (2.22-16.72) for all-cause mortality; notably, the hazard ratios (95% CIs) for patients within the severe to moderate disability trajectory were 1.99 (1.01-3.94) for cardiovascular events and 1.85 (1.03-3.33) for the composite outcome of cardiovascular events and all-cause mortality. CONCLUSIONS: Functional disability trajectories within 12 months after stroke onset were associated with the risk of 24-month adverse outcomes. Patients with persistent severe disability or severe to moderate disability had higher risk of cardiovascular events and all-cause mortality. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Efficacy of Immediate Antihypertensive Treatment in Patients With Acute Ischemic Stroke With Different Blood Pressure Genetic Variants.

BACKGROUND: It remains unclear whether blood pressure (BP) genetic variants could modify the efficacy of immediate antihypertensive treatment after acute ischemic stroke. We conducted a secondary analysis of the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) to investigate the effect of early antihypertensive treatment on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. METHODS: The CATIS randomized 4071 patients with acute ischemic stroke with elevated systolic BP to receive antihypertensive treatment or discontinue all antihypertensive agents during hospitalization. Randomization was conducted centrally and was stratified by participating hospitals and use of antihypertensive medications. Five BP-associated single nucleotide polymorphisms (rs16849225, rs17030613, rs1173766, rs6825911, and rs35444 in FIGN-GRB14, ST7L-CAPZA1, NPR3, ENPEP, and near TBX3, respectively) were genotyped among 2590 patients. The primary outcome was a combination of death and major disability at 14 days or hospital discharge. A weighted BP genetic risk score was constructed by the 5 single nucleotide polymorphisms. RESULTS: At 14 days or hospital discharge, the primary outcome was not significantly different between antihypertensive treatment and control groups based on genotype subgroups for all 5 single nucleotide polymorphisms (all P>0.05 for interaction). In addition, the BP genetic risk score did not modify the effect of antihypertensive treatment. The odds ratios (95% CIs) for the primary outcome were 0.95 (0.71-1.26), 1.08 (0.80-1.44), and 0.91 (0.69-1.22) in patients with low, intermediate, and high BP genetic risk score, respectively (P=0.88 for interaction). CONCLUSIONS: Early antihypertensive treatment had a neutral effect on clinical outcomes among patients with acute ischemic stroke according to 5 BP-associated genetic variants. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.

BACKGROUND: BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). METHODS: We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. RESULTS: In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE ɛ4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.

Association of Pulse Pressure Fluctuation During Hospitalization With Adverse Outcomes Within 3 Months After Ischemic Stroke.

BACKGROUND: Pulse pressure (PP) depends on heart function and arterial wall elasticity, which is closely related to the incidence of ischemic stroke. However, the association of PP fluctuation during hospitalization with adverse outcomes after ischemic stroke remains unclear. METHODS: The present study included 3,971 patients with ischemic stroke. The primary outcome was the composite outcome of death or vascular events within 3 months after ischemic stroke. PP fluctuation was reflected by successive variation of PP (PP-SV). RESULTS: The cumulative incidence rates of the primary outcome were the highest in the patients in the highest quartiles of PP-SV (P < 0.05). The multivariable-adjusted hazard ratios (95% confidence intervals) of the primary outcome in the highest quartiles were 1.86 (1.03-3.38) for death or vascular events, and 2.15 (1.06-4.37) for vascular events (all Ptrend < 0.05). Multivariable-adjusted restricted cubic spline analyses showed linear associations of PP-SV during hospitalization with the primary outcome (P for linearity <0.05). CONCLUSIONS: Large PP fluctuation during hospitalization was associated with increased risks of adverse outcomes within 3 months after ischemic stroke, which provided valuable new insight for blood pressure management in the acute phase of ischemic stroke. Controlling PP fluctuation may be contributing to improving prognosis after ischemic stroke.

Blood pressure control and antihypertensive medication use after discharge and prognosis of ischemic stroke.

OBJECTIVE: To investigate the effect of consistently blood pressure (BP) control status after discharge on adverse clinical outcomes among ischemic stroke (IS) patients. METHODS: Three thousand, four hundred and six acute IS patients were included and followed up at 3 months, 12 months, and 24 months after stroke. Study outcomes were defined as death, vascular events and composite of death or vascular events. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confident interval (CI) of death and the composite outcome of death or vascular events associated with BP control and antihypertensive medication use. RESULTS: The multivariable adjusted HRs were 0.22 [95% confidence interval (CI): 0.09-0.57] for death and 0.60 (95% CI: 0.39-0.97) for the composite outcome of death or vascular events among participants with consistently controlled BP compared with those with consistently uncontrolled BP. The participants with both consistently controlled BP and regular use of antihypertensive medication had the lowest risks of death [hazard ratio (HR): 0.18, 95% CI: 0.04-0.75] and composite outcome of death or vascular events (HR: 0.54, 95% CI: 0.29-0.98) in comparison with those with both uncontrolled BP and irregular use of antihypertensive medication. DISCUSSION: Continuous BP control and regular use of antihypertensive medications after discharge can decrease the risks of death and composite outcome of death or vascular events among IS patients, suggesting the importance of continuous BP control and regular use of antihypertensive medications after discharge for improving prognosis of IS.

Magnitude of Systolic Blood Pressure Reduction and Early Achieved Blood Pressure and Clinical Outcomes After Acute Ischemic Stroke.

Background We aimed to evaluate the relationships between the magnitude of systolic blood pressure (SBP) reduction and achieved SBP in the acute phase of ischemic stroke onset and subsequent clinical outcomes. Methods and Results This study was a secondary analysis of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), a multicenter randomized controlled trial of 4071 patients with acute ischemic stroke. SBP reduction was defined as the proportional SBP changes from baseline to 24 hours after randomization, and achieved SBP was the mean of SBP measurements at day 7. The study outcomes included functional outcome of death or major disability (modified Rankin Scale score ≥3), death, and cardiovascular events at 3 months after recruitment. Compared with the reference group of increase or no change in SBP within the first 24 hours, the odds ratios (95% CIs) of functional outcome of death or major disability were 0.62 (0.47-0.83) and 0.61 (0.42-0.87) for the reduction of 11% to 20% and >20%, respectively. Compared with participants in highest achieved SBP group (≥160 mm Hg) at day 7, odds ratios or hazard ratios of lower achieved SBP (<130 mm Hg) were 0.54 (95% CI, 0.37-0.80) for functional outcome, and 0.36 (95% CI, 0.17-0.80) for death or cardiovascular events. Conclusions A moderate magnitude of SBP reduction and a lower early achieved SBP were associated with a decreased risk of poor functional outcome, death, and cardiovascular events after acute ischemic stroke. Further studies are warranted to confirm these findings. REGISTRATION: URL: ClinicalTrials.gov; Unique identifier: NCT01840072.

Characteristics of secondary inorganic aerosols and contributions to PM2.5 pollution based on machine learning approach in Shandong Province.

Primary emissions of particulate matter and gaseous pollutants, such as SO2 and NOx have decreased in China following the implementation of a series of policies by the Chinese government to address air pollution. However, controlling secondary inorganic aerosol pollution requires attention. This study examined the characteristics of the secondary conversion of nitrate (NO3-) and sulfate (SO42-) in three coastal cities of Shandong Province, namely Binzhou (BZ), Dongying (DY), and Weifang (WF), and an inland city, Jinan (JN), during December 2021. Furthermore, the Shapley Additive Explanation (SHAP), an interpretable attribution technique, was adopted to accurately calculate the contributions of secondary formations to PM2.5. The nitrogen oxidation rate exhibited a significant dependence on the concentration of O3. High humidity facilitates sulfur oxidation. Compared to BZ, DY, and WF, the secondary conversion of NO3- and SO42- was more intense in JN. The light-gradient boosting model outperformed the random forest and extreme-gradient boosting models, achieving a mean R2 value of 0.92. PM2.5 pollution events in BZ, DY, and WF were primarily attributable to biomass burning, whereas pollution in Jinan was contributed by the secondary formation of NO3- and vehicle emissions. Machine learning and the SHAP interpretable attribution technique offer a precise analysis of the causes of air pollution, showing high potential for addressing environmental concerns.

Plasma homeostatic chemokines CCL19 and CCL21 and the prognosis of ischemic stroke in two Chinese prospective cohorts.

BACKGROUND: The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post-ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke. METHODS: Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined. RESULTS: In CATIS, multivariable-adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes. CONCLUSIONS: Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.

HS-CRP Modifies the Prognostic Value of Platelet Count for Clinical Outcomes After Ischemic Stroke.

Background We examined whether the relationship between baseline platelet count and clinical outcomes is modulated by HS-CRP (high-sensitivity C-reactive protein) in patients with ischemic stroke. Methods and Results A total of 3267 patients with ischemic stroke were included in the analysis. The primary outcome was a combination of death and major disability at 1 year after ischemic stroke. Secondary outcomes included major disability, death, vascular events, composite outcome of vascular events or death, and an ordered 7-level categorical score of the modified Rankin Scale at 1 year. Multivariate logistic regression and Cox proportional hazards regression models were used to assess the association between the baseline platelet count and clinical outcomes stratified by HS-CRP levels when appropriate. There was an interaction effect of platelet count and HS-CRP on the adverse clinical outcomes after ischemic stroke (all Pinteraction<0.05). The elevated platelet count was significantly associated with the primary outcome (odds ratio [OR], 3.14 [95% CI, 1.77-5.58]), major disability (OR, 2.07 [95% CI, 1.15-3.71]), death (hazard ratio [HR], 2.75 [95% CI, 1.31-5.79]), and composite outcome of vascular events or death (HR, 2.57 [95% CI, 1.38-4.87]) among patients with high HS-CRP levels (all Ptrend<0.05). Conclusions The HS-CRP levels had a modifying effect on the association between platelet count and clinical outcomes in patients with ischemic stroke. Elevated platelet count was significantly associated with adverse clinical outcomes in patients with ischemic stroke with high HS-CRP levels, but not in those with low HS-CRP levels. These findings suggest that strategies for anti-inflammatory and antiplatelet therapy should be developed according to the results of both platelet and HS-CRP testing.

Challenges and opportunities in delivering oral peptides and proteins.

INTRODUCTION: Rapid advances in bioengineering enable the use of complex proteins as therapeutic agents to treat diseases. Compared with conventional small molecule drugs, proteins have multiple advantages, including high bioactivity and specificity with low toxicity. Developing oral dosage forms with active proteins is a route to improve patient compliance and significantly reduce production costs. However, the gastrointestinal environment remains a challenge to this delivery path due to enzymatic degradation, low permeability, and weak absorption, leading to reduced delivery efficiency and poor clinical outcomes. AREAS COVERED: This review describes the barriers to oral delivery of peptides and complex proteins, current oral delivery strategies utilized and the opportunities and challenges ahead to try and circumvent these barriers. Oral protein drugs on the market and clinical trials provide insights and approaches for advancing delivery strategies. EXPERT OPINION: Although most current studies on oral protein delivery rely on in vitro and in vivo animal data, the safety and limitations of the approach in humans remain uncertain. The shortage of clinical data limits the development of new or alternative strategies. Therefore, designing appropriate oral delivery strategies remains a significant challenge and requires new ideas, innovative design strategies and novel model systems.

High Serum Brain-Derived Neurotrophic Factor Is Associated With Decreased Risks of Poor Prognosis After Ischemic Stroke.

BACKGROUND: BDNF (brain-derived neurotrophic factor) has been implicated in cardiovascular homeostasis and ischemic stroke pathogenesis. We aimed to prospectively investigate the associations between serum BDNF levels and the prognosis of ischemic stroke in a multicenter cohort study. METHODS: This prospective study follows the STROBE reporting guideline. Serum BDNF concentrations were measured in 3319 ischemic stroke patients from the China Antihypertensive Trial in Acute Ischemic Stroke between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was the composite outcome of death and major disability (modified Rankin Scale score ≥3) at 3 months after stroke onset. Multivariate logistic regression or Cox proportional hazards regression analysis was used to assess the associations between serum BDNF levels and adverse clinical outcomes. RESULTS: During the 3-month follow-up period, 827 (24.92%) patients experienced a primary outcome, including 734 major disabilities and 93 deaths. After adjusting for age, sex, and other important prognostic factors, elevated serum BDNF levels were associated with decreased risks of primary outcome (odds ratio, 0.73 [95% CI, 0.58-0.93]), major disability (odds ratio, 0.78 [95% CI, 0.62-0.99]), death (hazard ratio, 0.55 [95% CI, 0.32-0.97]), and the composite outcome of death and vascular events (hazard ratio, 0.61 [95% CI, 0.40-0.93]) when 2 extreme tertiles were compared. Multivariable-adjusted spline regression analyses showed a linear association between serum BDNF levels and the primary outcome (P value for linearity=0.005). The addition of BDNF to conventional risk factors slightly improved reclassification for the primary outcome (net reclassification improvement: 19.33%; P<0.001; integrated discrimination index: 0.24%; P=0.011). CONCLUSIONS: Elevated serum BDNF concentrations were independently associated with decreased risks of adverse outcomes after ischemic stroke, suggesting that serum BDNF may be a potential biomarker for prognosis after ischemic stroke. Further studies are warranted to investigate the potential therapeutic benefit of BDNF for ischemic stroke.

The relationship between neurological function trajectory, assessed by repeated NIHSS measurement, and long-term cardiovascular events, recurrent stroke, and mortality after ischemic stroke.

BACKGROUND: Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury or neurological improvement. However, the National Institutes of Health Stroke Scale (NIHSS) score is only evaluated once in most studies, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. METHODS: A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3-24 months after ischemic stroke onset. Cox proportional hazards models were used to examine the associations of neurological function trajectories with outcomes. RESULTS: We identified three distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% confidence intervals) = 1.77 (1.10-2.86)), recurrent stroke (1.82 (1.10-3.00)), and all-cause mortality (5.64 (3.37-9.43)). Those with moderate trajectory had an intermediate risk: 1.45 (1.03-2.04) for cardiovascular events and 1.52 (1.06-2.19) for recurrent stroke. CONCLUSION: Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.

Mechanistic understanding of rapid H2SO4-HNO3-NH3 nucleation in the upper troposphere.

The upper troposphere (UT) nucleation is thought to be responsible for at least one-third of the global cloud condensation nuclei. Although NH3 was considered to be extremely rare in the UT, recent studies show that NH3 is convected aloft, promoting H2SO4-HNO3-NH3 rapid nucleation in the UT during the Asian monsoon. In this study, the roles of HNO3, H2SO4 (SA), and NH3 in the nucleation of SA-HNO3-NH3 were investigated by quantum chemical calculation and molecular dynamic (MD) simulations at the level of M06-2×/6-31 + G (d, p). The nucleation ability of SA-HNO3-NH3 is suppressed as the temperature increases in the UT. The results indicated that bisulfate (HSO4-), nitrate (NO3-), and ammonium (NH4+) ionized from SA, HNO3, and NH3, respectively, can significantly enhance the nucleation ability of SA-HNO3-NH3. In addition, hydrated hydrogen ion (H3O+) as well as sulfate ions (SO42-) ionized by SA can also actively participate in the process of ion-induced nucleation. The results reveal that the enhancement effect of five ions on the SA-HNO3-NH3 nucleation can be ordered as follows: SO42- > H3O+ > HSO4- > NO3- > NH4+. Many ion-induced nucleation pathways of SA-HNO3-NH3 with the Gibbs free energies of formation (ΔG) lower than -100 kcal mol-1 were energetically favorable. HNO3 and NH3 can promote the nucleation of SA-HNO3-NH3 and water (W) molecules are also beneficial to promote the new particle formation (NPF) of SA-HNO3-NH3. Under the action of H-bonds and electrostatic interaction, ion-induced nucleation could lead to the rapid nucleation of H2SO4-HNO3-NH3 in the UT.

Contributions of various driving factors to air pollution events: Interpretability analysis from Machine learning perspective.

The air quality in China has been improved substantially, however fine particulate matter (PM2.5) still remain at a high level in many areas. PM2.5 pollution is a complex process that is attributed to gaseous precursors, chemical, and meteorological factors. Quantifying the contribution of each variable to air pollution can facilitate the formulation of effective policies to precisely eliminate air pollution. In this study, we first used decision plot to map out the decision process of the Random Forest (RF) model for a single hourly data set and constructed a framework for analyzing the causes of air pollution using multiple interpretable methods. Permutation importance was used to qualitatively analyze the effect of each variable on PM2.5 concentrations. The sensitivity of secondary inorganic aerosols (SIA): SO42-, NO3- and NH4+ to PM2.5 was verified by Partial dependence plot (PDP). Shapley Additive Explanation (Shapley) was used to quantify the contribution of drivers behind the ten air pollution events. The RF model can accurately predict PM2.5 concentrations, with determination coefficient (R2) of 0.94, root mean square error (RMSE) and mean absolute error (MAE) of 9.4 µg/m3 and 5.7 µg/m3, respectively. This study revealed that the order of sensitivity of SIA to PM2.5 was NH4+＞NO3-＞SO42-. Fossil fuel and biomass combustion may be contributing factors to air pollution events in Zibo in 2021 autumn-winter. NH4+ contributed 19.9-65.4 µg/m3 among ten air pollution events (APs). K, NO3-, EC and OC were the other main drivers, contributing 8.7 ± 2.7 µg/m3, 6.8 ± 7.5 µg/m3, 3.6 ± 5.8 µg/m3 and 2.5 ± 2.0 µg/m3, respectively. Lower temperature and higher humidity were vital factors that promoted the formation of NO3-. Our study may provide a methodological framework for precise air pollution management.

Osteoprotegerin and Ischemic Stroke Prognosis: A Prospective Multicenter Study and Mendelian Randomization Analysis.

BACKGROUND: Osteoprotegerin was implicated in vascular injury and inflammatory responses, but its prognostic value in ischemic stroke remained unclear. We aimed to prospectively investigate the association between plasma osteoprotegerin and ischemic stroke prognosis combined with a Mendelian randomization analysis. METHODS: Our prospective study follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting guideline. We measured baseline plasma osteoprotegerin levels for 3490 ischemic stroke patients recruited between August 2009 and May 2013 in 26 hospitals across China. The primary outcome was a composite outcome of death and major disability at 3 months after ischemic stroke. RESULTS: After adjustment for age, sex, admission National Institutes of Health Stroke Scale score, and other important covariates, elevated osteoprotegerin levels were associated with increased risks of primary outcome (odds ratio, 1.40 [95% CI, 1.05-1.88]), death (hazard ratio, 2.05 [95% CI, 1.04-4.08]), and composite outcome of death and vascular events (hazard ratio, 2.00 [95% CI, 1.15-3.48]) when 2 extreme quartiles were compared. Each 1-SD higher log-osteoprotegerin was associated with a 18% (95% CI, 6%-32%) increased risk of primary outcome, 69% (95% CI, 31%-118%) increased risk of death, and 53% (95% CI, 24%-89%) increased risk of composite outcome of death and vascular events, respectively. Multiple-adjusted spline regression model showed a linear association of osteoprotegerin with primary outcome (P for linearity <0.001). Adding osteoprotegerin to conventional risk factors did not significantly improve discriminatory power (C statistics, 0.817 versus 0.818; P=0.232) but did slightly improve the risk reclassification of primary outcome (net reclassification improvement: 13.68%, P<0.001; integrated discrimination improvement: 0.23%, P=0.039). In Mendelian randomization analysis, genetically determined high plasma osteoprotegerin was associated with increased risk of primary outcome (odds ratio, 5.74 [95% CI, 1.12-29.44]; P=0.036). CONCLUSIONS: Elevated plasma osteoprotegerin was associated with poor prognosis of ischemic stroke, and genetically determined high plasma osteoprotegerin was associated with an increased risk of primary outcome in Mendelian randomization analysis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01840072.