Associations of short-term ambient temperature exposure with lung function in middle-aged and elderly people: A longitudinal study in China.

The short-term associations of ambient temperature exposure with lung function in middle-aged and elderly Chinese remain obscure. The study included 19,128 participants from the Dongfeng-Tongji cohort's first (2013) and second (2018) follow-ups. The lung function for each subject was determined between April and December 2013 and re-assessed in 2018, with three parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) selected. The China Meteorological Data Sharing Service Center provided temperature data during the study period. In the two follow-ups, a total of 25,511 records (average age: first, 64.57; second, 65.80) were evaluated, including 10,604 males (41.57%). The inversely J-shaped associations between moving average temperatures (lag01-lag07) and FVC, FEV1, and PEF were observed, and the optimum temperatures at lag04 were 16.5 °C, 18.7 °C, and 16.2 °C, respectively. At lag04, every 1 °C increase in temperature was associated with 14.07 mL, 9.78 mL, and 62.72 mL/s increase in FVC, FEV1, and PEF in the low-temperature zone (

Exposure to volatile organic compounds and mortality in US adults: A population-based prospective cohort study.

Volatile organic compounds (VOCs) are ubiquitous in both indoor and outdoor environments. Evidence on the associations of individual and joint VOC exposure with all-cause and cause-specific mortality is limited. Measurements of 15 urinary VOC metabolites were available to estimate exposure to 12 VOCs in the National Health and Nutritional Examination Survey (NHANES) 2005-2006 and 2011-2018. The environment risk score (ERS) was calculated using LASSO regression to reflect joint exposure to VOCs. Follow-up data on death were obtained from the NHANES Public-Use Linked Mortality File through December 31, 2019. Cox proportional hazard models and restricted cubic spline models were applied to evaluate the associations of individual and joint VOC exposures with all-cause and cause-specific mortality. Population attributable fractions were calculated to assess the death burden attributable to VOC exposure. During a median follow-up of 6.17 years, 734 (8.34 %) deaths occurred among 8799 adults. Urinary metabolites of acrolein, acrylonitrile, 1,3-butadiene, and ethylbenzene/styrene were significantly associated with all-cause, cardiovascular disease (CVD), respiratory disease (RD), and cancer mortality in a linear dose-response manner. Linear and robust dose-response relationships were also observed between ERS and all-cause and cause-specific mortality. Each 1-unit increase in ERS was associated with a 33.6 %, 39.1 %, 109.8 %, and 67.8 % increase for all-cause, CVD, RD, and cancer mortality risk, respectively. Moreover, joint exposure to VOCs contributed to 17.95 % of all-cause deaths, 13.49 % of CVD deaths, 35.65 % of RD deaths, and 33.85 % of cancer deaths. Individual and joint exposure to VOCs may enhance the risk of all-cause and cause-specific mortality. Reducing exposure to VOCs may alleviate the all-cause and cause-specific death burden.

Pathogenomics for accurate diagnosis, treatment, prognosis of oncology: a cutting edge overview.

The capability to gather heterogeneous data, alongside the increasing power of artificial intelligence to examine it, leading a revolution in harnessing multimodal data in the life sciences. However, most approaches are limited to unimodal data, leaving integrated approaches across modalities relatively underdeveloped in computational pathology. Pathogenomics, as an invasive method to integrate advanced molecular diagnostics from genomic data, morphological information from histopathological imaging, and codified clinical data enable the discovery of new multimodal cancer biomarkers to propel the field of precision oncology in the coming decade. In this perspective, we offer our opinions on synthesizing complementary modalities of data with emerging multimodal artificial intelligence methods in pathogenomics. It includes correlation between the pathological and genomic profile of cancer, fusion of histology, and genomics profile of cancer. We also present challenges, opportunities, and avenues for future work.

Versatile CYP98A enzymes catalyse meta-hydroxylation reveals diversity of salvianolic acids biosynthesis.

Salvianolic acids (SA), such as rosmarinic acid (RA), danshensu (DSS), and their derivative salvianolic acid B (SAB), etc. widely existed in Lamiaceae and Boraginaceae families, are of interest due to medicinal properties in the pharmaceutical industries. Hundreds of studies in past decades described that 4-coumaroyl-CoA and 4-hydroxyphenyllactic acid (4-HPL) are common substrates to biosynthesize SA with participation of rosmarinic acid synthase (RAS) and cytochrome P450 98A (CYP98A) subfamily enzymes in different plants. However, in our recent study, several acyl donors and acceptors included DSS as well as their ester-forming products all were determined in SA-rich plants, which indicated that previous recognition to SA biosynthesis is insufficient. Here, we used Salvia miltiorrhiza, a representative important medicinal plant rich in SA, to elucidate the diversity of SA biosynthesis. Various acyl donors as well as acceptors are catalysed by SmRAS to form precursors of RA and two SmCYP98A family members, SmCYP98A14 and SmCYP98A75, are responsible for different positions' meta-hydroxylation of these precursors. SmCYP98A75 preferentially catalyses C-3' hydroxylation, and SmCYP98A14 preferentially catalyses C-3 hydroxylation in RA generation. In addition, relative to C-3' hydroxylation of the acyl acceptor moiety in RA biosynthesis, SmCYP98A75 has been verified as the first enzyme that participates in DSS formation. Furthermore, SmCYP98A enzymes knockout resulted in the decrease and overexpression leaded to dramatic increase of SA accumlation. Our study provides new insights into SA biosynthesis diversity in SA-abundant species and versatility of CYP98A enzymes catalytic preference in meta-hydroxylation reactions. Moreover, CYP98A enzymes are ideal metabolic engineering targets to elevate SA content.

Association of shift work with oxidative stress and alteration of fasting plasma glucose level in Chinese adults.

OBJECTIVE: This study aimed to assess the association of shift work with blood glucose and the mediating role of oxidative stress. METHODS: Fasting plasma glucose (FPG) and urinary concentrations of oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine [8-OHdG], 4-hydroxy-2-nonenal-mercapturic acid, and 8-iso-prostaglandin F2α [8-isoPGF2α ]) were measured among 831 participants. RESULTS: Positive dose-response relationships among shift work duration,  FPG (ptrend < 0.001), and abnormal glucose regulation (AGR; ptrend = 0.035) were found. Compared with participants without shift work, three-shift work was associated with a higher level of FPG (percentage change: 6.49%, 95% CI: 4.21%-8.83%) and a higher prevalence of impaired fasting glucose (odds ratio: 1.886, 95% CI: 1.114-3.192) and AGR (odds ratio: 1.929, 95% CI: 1.197-3.111). A dose-response relationship was found between shift work duration and 8-OHdG (ptrend = 0.002) and 8-isoPGF2α (ptrend = 0.019). Urinary 8-OHdG and 8-isoPGF2α partially mediated the association between shift work duration and FPG levels and the prevalence of impaired fasting glucose and AGR, with mediating proportions ranging from 4.77% to 20.76%. CONCLUSIONS: These findings suggest that shift work is positively associated with blood glucose, and the association is partially mediated by oxidative stress.

Corrigendum: OpenCL-accelerated first-principles calculations of all-electron quantum perturbations on HPC resources.

[This corrects the article DOI: 10.3389/fchem.2023.1156891.].

Ambient temperature exposure causes lung function impairment: The evidence from Controlled Temperature Study in Healthy Subjects (CTSHS).

BACKGROUND: The effect of non-optimal ambient temperatures (low and high temperatures) on lung function and the underlying mechanisms remains unclear. METHODS: Forty-three (20 males, 23 females) healthy non-obese volunteers with an average of 23.9 years participated in the controlled temperature study. All volunteers underwent three temperature exposures in a sequence (moderate [18 °C], low [6 °C], and high [30 °C] temperatures) lasting 12 h with air pollutants controlled. lung function parameters (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], and peak expiratory flow [PEF]) were determined in each exposure. Blood and urine samples were collected after each exposure and assayed for inflammatory markers [C-reactive protein (CRP), procalcitonin (PCT), platelet-lymphocyte ratio (PLR), and neutrophil-lymphocyte ratio (NLR)] and oxidative damage markers [protein carbonylation (PCO), 4-hydroxy-2-nominal-mercapturic acid (HNE-MA), 8-iso-prostaglandin-F2α (8-isoPGF2α), and 8-hydroxy-2-deoxyguanosine (8-OHdG)]. Mixed-effects models were constructed to assess the changes of the above indexes under low or high temperatures relative to moderate temperature, and then the repeated measures correlation analyses were performed. RESULTS: Compared with moderate temperature, a 2.20% and 2.59% net decrease in FVC, FEV1, and a 5.68% net increase for PEF were observed under low-temperature exposure, while a 1.59% net decrease in FVC and a 7.29% net increase in PEF under high-temperature exposure were found (all P < 0.05). In addition, low temperature elevated inflammatory markers (PCT, PLR, and NLR) and oxidative damage markers (8-isoPGF2α, 8-OHdG), and high temperature elevated HNE-MA. Repeated measures correlation analyses revealed that PCT (r = -0.33) and NLR (r = -0.31) were negatively correlated with FVC and HNE-MA (r = -0.35) and 8-OHdG (r = -0.31) were negatively correlated with the FEV1 under low-temperature exposure (all P < 0.05). CONCLUSION: Non-optimal ambient temperatures exposure alters lung function, inflammation, and oxidative damage. Inflammation and oxidative damage might be involved in low temperature-related lung function reduction.

OpenCL-accelerated first-principles calculations of all-electron quantum perturbations on HPC resources.

We have proposed, for the first time, an OpenCL implementation for the all-electron density-functional perturbation theory (DFPT) calculations in FHI-aims, which can effectively compute all its time-consuming simulation stages, i.e., the real-space integration of the response density, the Poisson solver for the calculation of the electrostatic potential, and the response Hamiltonian matrix, by utilizing various heterogeneous accelerators. Furthermore, to fully exploit the massively parallel computing capabilities, we have performed a series of general-purpose graphics processing unit (GPGPU)-targeted optimizations that significantly improved the execution efficiency by reducing register requirements, branch divergence, and memory transactions. Evaluations on the Sugon supercomputer have shown that notable speedups can be achieved across various materials.

Obesity modifies the association of environmental pyrethroid exposure with glucose homeostasis in the US general adults.

Environmental pyrethroids are concerning due to their widespread residues and potential implications on human health. We aimed to assess the association of pyrethroid exposure with glucose homeostasis and examine the interaction between obesity and pyrethroid exposure. A total of 4233 US general adults from the National Health and Nutrition Examination Survey with measured urinary pyrethroid metabolites, fasting plasma glucose (FPG), fasting insulin (FINS), and glycated hemoglobin A1c (HbA1c) were included in the study. The homeostasis model assessment (HOMA2) calculator was utilized to assess insulin resistance (HOMA2-IR), insulin sensitivity (HOMA2-IS), and beta-cell function (HOMA2-ß). We estimated the associations of pyrethroid metabolites with glucose homeostasis parameters (FPG, FINS, HbA1c, HOMA2-IR, HOMA2-IS, and HOMA2-ß) using multivariate linear regression models and restricted cubic spline models and further assessed the interaction between obesity and pyrethroid metabolites on glucose dyshomeostasis. Urinary 3-phenoxybenzoic acid (3-PBA) was the most detected pyrethroid metabolite (81%) with a median concentration of 0.43 (interquartile range 0.20-1.01) µg/g urinary creatinine. Compared with the participants in the lowest quartile, those in the highest quartile of 3-PBA had a 1.93% (95% confidence interval: 0.46%, 3.42%), 6.69% (1.96%, 11.64%), 1.60% (0.64%, 2.57%), 7.06% (2.33%, 12.01%), -6.59% (-10.72%, -2.28%), and 1.10% (-2.69%, 5.04%) alteration in FPG, FINS, HbA1c, HOMA2-IR, HOMA2-IS, and HOMA2-ß, respectively. The restricted cubic spline model displayed a linear positive association between 3-PBA and FPG, FINS, HbA1c, and HOMA2-IR, and a negative association with HOMA2-IS (all P for overall <0.05 and P for non-linear >0.05). Additionally, the association between urinary 3-PBA and FPG was modified by general obesity (P for interaction <0.05), with a more pronounced association observed in obese participants than in non-obese participants. Our findings suggested that pyrethroid exposure was associated with glucose dyshomeostasis. General obesity significantly heightened the association between pyrethroid exposure and increased FPG level.

Associations of urinary 1,3-butadiene metabolite with glucose homeostasis, prediabetes, and diabetes in the US general population: Role of alkaline phosphatase.

The chemical - 1,3-butadiene (BD) is a volatile organic compound ubiquitous in the environment. However, the relationships and underlying mechanisms between BD exposure and glucose dyshomeostasis and diabetes in the general population remain unclear. We sought to explore the associations of BD exposure with glucose homeostasis, prediabetes, and diabetes, as well as the role of serum alkaline phosphatase (ALP) in these associations. This study included 5092 US general residents from the National Health and Nutrition Examination Survey with measurements of urinary BD metabolite (N-Acetyl-S-(3,4-dihydroxybutyl)-L-cysteine, DHBMA) and serum ALP. Glucose homeostasis was evaluated by fasting plasma glucose (FPG), fasting serum insulin (FINS), glycohemoglobin (HbA1c), and homeostasis model assessment of insulin resistance (HOMA-IR). HOMA-IR>2.6 was considered as insulin resistance (IR). Prediabetes and diabetes were determined according to the recommendations of the American Diabetes Association. The associations of DHBMA with glucose homeostasis, prediabetes, and diabetes were assessed by linear regression models and logistic regression models. The mediating role of ALP was evaluated by mediation analysis. We observed positive dose-response relationships of DHBMA level with glucose homeostasis indices and ALP levels, as well as with the risks of prediabetes and diabetes (all P < 0.05 and/or P for trend <0.05). Each 2-fold increase in DHBMA was associated with a 1.32%, 9.20%, 0.72%, and 10.64% increase in FPG, FINS, HbA1c, and HOMA-IR, respectively (all P < 0.05). And the corresponding odds ratios (ORs) and 95% confidence intervals (CIs) for IR, prediabetes, and diabetes were 1.36 (1.14, 1.61), 1.51 (1.26, 1.83), and 1.20 (0.90, 1.61), respectively. Furthermore, increased ALP significantly mediated 15.29%-41.12% of the associations of DHBMA with glucose dyshomeostasis and increased risks of prediabetes and diabetes. Our findings indicated that BD exposure was associated with glucose dyshomeostasis and increased risks of prediabetes and diabetes. The upregulation of ALP might play a significant role in these associations.

MIST: multiple instance learning network based on Swin Transformer for whole slide image classification of colorectal adenomas.

Colorectal adenoma is a recognized precancerous lesion of colorectal cancer (CRC), and at least 80% of colorectal cancers are malignantly transformed from it. Therefore, it is essential to distinguish benign from malignant adenomas in the early screening of colorectal cancer. Many deep learning computational pathology studies based on whole slide images (WSIs) have been proposed. Most approaches require manual annotation of lesion regions on WSIs, which is time-consuming and labor-intensive. This study proposes a new approach, MIST - Multiple Instance learning network based on the Swin Transformer, which can accurately classify colorectal adenoma WSIs only with slide-level labels. MIST uses the Swin Transformer as the backbone to extract features of images through self-supervised contrastive learning and uses a dual-stream multiple instance learning network to predict the class of slides. We trained and validated MIST on 666 WSIs collected from 480 colorectal adenoma patients in the Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School. These slides contained six common types of colorectal adenomas. The accuracy of external validation on 273 newly collected WSIs from Nanjing First Hospital was 0.784, which was superior to the existing methods and reached a level comparable to that of the local pathologist's accuracy of 0.806. Finally, we analyzed the interpretability of MIST and observed that the lesion areas of interest in MIST were generally consistent with those of interest to local pathologists. In conclusion, MIST is a low-burden, interpretable, and effective approach that can be used in colorectal cancer screening and may lead to a potential reduction in the mortality of CRC patients by assisting clinicians in the decision-making process. © 2022 The Pathological Society of Great Britain and Ireland.

Associations of bifenthrin exposure with glucose homeostasis and type 2 diabetes mellitus in a general Chinese population: Roles of protein carbonylation.

The adverse health effects of pyrethroids exposure have attracted wide concern. We aimed to assess the associations of bifenthrin, a widely used pyrethroid, with glucose homeostasis and risk of type 2 diabetes mellitus (T2DM) and to explore the underlying mechanism. Serum bifenthrin, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and plasma protein carbonyl (PCO) were determined among 3822 participants from the Wuhan-Zhuhai cohort. Glucose homeostasis was evaluated by FPG, FPI, homeostasis model assessment of insulin resistance (HOMA-IR), impaired fasting glucose (IFG), and abnormal glucose regulation (AGR). The associations of serum bifenthrin with glucose homeostasis and risk of T2DM were assessed by generalized linear models and logistic regression models. The role of PCO in the above associations was evaluated by mediation analyses. After adjusting for covariates, each 2-fold increase in serum bifenthrin was associated with a 0.21 mmol/L increase in FPG and a 5.19%, 10.49%, and 12.18% increase in FPI, HOMA-IR, and PCO levels, respectively. Monotonically elevated ORs of IFG and AGR (all P and P for trend <0.05), but not T2DM (P > 0.05) were detected to be associated with increased bifenthrin. Compared with the participants with low bifenthrin and low PCO, participants with high bifenthrin exposure and high PCO showed a 0.40 mmol/L, 11.07%, and 22.50% increase in FPG, FPI, and HOMA-IR, as well as a 119.97% and 48.88% increase in risks of IFG and AGR, respectively (P for trend <0.05). Moreover, PCO mediated 13.61%-24.98% of the serum bifenthrin-associated glucose dyshomeostasis. The study suggested that bifenthrin exposure was dose-dependently associated with glucose dyshomeostasis in the general Chinese urban adults, and these associations were exacerbated and partly mediated by PCO. Given that other pollutants were not included in this study, the effect of co-exposure of pyrethroids with multiple pollutants is necessary to be considered in future studies.

Association of noise exposure, plasma microRNAs with arterial stiffness among Chinese workers.

Long-term noise exposure is reported to damage cardiovascular system, but the relationship between occupational noise exposure and arterial stiffness (AS) and the underlying mechanism is still unclear. We aimed to investigate the association of occupational noise exposure with arterial stiffness (AS), and further explore the mediation roles of microRNAs (miRNAs). A total of 838 workers were recruited from two companies in Wuhan, Hubei, China. Cumulative occupational noise exposure (CNE) was assessed through noise level of job title and work years in occupational noise. The AS for the participants were evaluated using brachial-ankle pulse wave velocity (baPWV) measured by an oscillometric device. Each 1-unit increase in CNE levels was significantly associated with a 0.002 (95% confidence interval (CI) = 0.001-0.003) unit increase in ln-transformed values of baPWV. In the sex-specific analysis, the association was significant in males (ß = 0.002, 95%CI = 0.001-0.003). Meanwhile, the risk of bilateral hearing loss at high frequency was significantly higher in the high-exposed group than non-exposed group (OR = 1.895, 95%CI = 1.024-3.508), and participants with bilateral hearing loss at high frequency had a significantly higher level of ln-transformed baPWV (ß = 0.032, 95%CI = 0.003-0.061). Occupational noise exposure and AS were both negatively associated with plasma miR-92a-3p and miR-21-5p, and the two miRNAs mediated 15.0% and 16.8% of the association of occupational noise with AS (P < 0.05). Our findings suggest that occupational noise exposure is positively associated with AS, and plasma miR-92a-3p and miR-21-5p may partly mediate such association.

The global burden of disease attributable to high fasting plasma glucose in 204 countries and territories, 1990-2019: An updated analysis for the Global Burden of Disease Study 2019.

AIMS: High fasting plasma glucose (HFPG) is an independent risk factor for several adverse health outcomes and has become a serious public health problem. We aimed to evaluate the spatial pattern and temporal trend of disease burden attributed to HFPG from 1990 to 2019 using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. MATERIALS AND METHODS: Using data from GBD 2019, we estimated the numbers and age-standardized rates of deaths and disability-adjusted life years (DALYs) attributed to HFPG by calendar year, age, gender, country, region, Socio-demographic Index (SDI), and specific causes. The joinpoint regression analysis was used to assess the temporal trends of deaths and DALYs from 1990 to 2019. RESULTS: In 2019, globally, the numbers of deaths and DALYs attributable to HFPG were approximately 6.50 million and 172.07 million, respectively, with age-standardized rates of 83.00 per 100,000 people and 2104.26 per 100,000 people, respectively. From 1990 to 2019, the global numbers of deaths and DALYs attributed to HFPG have over doubled. The age-standardized rate of DALYs showed an increasing trend, particularly in males and in regions with middle SDI or below. The leading causes of the global disease burden attributable to HFPG in 2019 were diabetes mellitus, ischaemic heart disease, stroke, and chronic kidney disease. CONCLUSIONS: HFPG is an important contributor to increasing the global and regional disease burden. Necessary measures should be taken to curb the growing burden attributed to HFPG, particularly in males and in regions with middle SDI or below.

Urinary polycyclic aromatic hydrocarbon metabolites and depression: a cross-sectional study of the National Health and Nutrition Examination Survey 2005-2016.

BACKGROUND: The adverse effects of polycyclic aromatic hydrocarbon (PAHs), a group of common environmental pollutants, on mental health are unclear. This study is developed to evaluate the potential association of urinary PAH metabolites with depression in US adults. METHODS: Measurement of 8 urinary PAH metabolites and assessment of depression were available for 9625 adults in the National Health and Nutritional Examination Survey 2005-2016. Multiple logistic regression models and weighted quantile sum (WQS) regression models were applied to evaluate the association between urinary PAH metabolites and depression. RESULTS: Among 9625 individuals with a weighted geometric mean age of 42.63 years, 801 participants suffered from depression. Significant positive dose-response relationships were observed between specific urinary PAH metabolites and the risk of depression after adjusting for potential confounders. Urinary 1-hydroxynaphthalene was positively and dose-dependently associated with the risk of depression among total participants (odds ratio: 1.188; 95% confidence interval: 1.096-1.288). In addition, each 1-unit increase of ln-transformed urinary 1-hydroxynaphthalene, 2-hydroxynaphthalene, 3-hydroxyfluorene, 2-hydroxyfluorene, 1-hydroxyphenanthrene, 2&3-hydroxyphenanthrene, 1-hydroxypyrene, and total PAH metabolites was associated with a 23.3%, 32.6%, 23.3%, 29.4%, 30.8%, 22.8%, 29.4%, and 31.7% increment in the risk of depression in smokers, respectively (all P and P trend < 0.05). Of note, the positive WQS index was also significantly associated with the increased risk of depression in smokers (1.122, 1.059-1.188). CONCLUSION: Exposure to PAHs may elevate the risk of depression among US adults. More studies are warranted to investigate the underlying mechanism by which PAHs induce the development of depression.

Urinary acrolein metabolites, systemic inflammation, and blood lipids: Results from the National Health and Nutrition Examination Survey.

Exposure to acrolein was reported to be related with adverse health effects. However, the associations between acrolein exposure and blood lipids remain largely unknown. We assessed the associations of urinary acrolein metabolites with blood lipids using data from the National Health and Nutrition Examination Survey (NHANES) and further investigated the existence of mediation by systemic inflammation in the associations. Urinary acrolein metabolites, N-acetyl-S-(carboxyethyl)-l-cysteine (CEMA) and N-acetyl-S-(3-hydroxypropyl)-l-cysteine (3-HPMA), blood lipids, and serum high sensitivity C-reactive protein (hs-CRP) were measured in the NHANES. The associations of urinary acrolein metabolites with blood lipids and dyslipidemia and hs-CRP were estimated by multiple linear and logistic regression models. Mediation analysis was conducted to evaluate the mediating effects of hs-CRP on the associations between urinary acrolein metabolites and blood lipids. We found urinary CEMA+3-HPMA (∑acrolein) was significantly associated with higher levels of serum triglycerides (TG), hs-CRP, and lower levels of high-density lipoprotein cholesterol (HDL-C). Each 1-unit increment in ln-transformed level of ∑acrolein was associated with a 0.06 mmol/L increment in TG and 0.02 mmol/L decrement in HDL-C (all P <0.05). A positive dose-response relationship was observed between urinary ∑acrolein and dyslipidemia risk. In addition, hs-CRP significantly mediated the associations of urinary ∑acrolein with serum TG and HDL-C, with mediated proportions of 22.12% and 41.41%, respectively. In conclusion, acrolein exposure is associated with the levels of serum TG, HDL-C, and hs-CRP. Hs-CRP may mediate acrolein-associated alterations of blood lipids. Our results indicated that decreased exposure to acrolein may reduce systemic inflammation and dyslipidemia risk.

Intelligible Models for HealthCare: Predicting the Probability of 6-Month Unfavorable Outcome in Patients with Ischemic Stroke.

Early prediction of unfavorable outcome after ischemic stroke is significant for clinical management. Machine learning as a novel computational modeling technique could help clinicians to address the challenge. We aim to investigate the applicability of machine learning models for individualized prediction in ischemic stroke patients and demonstrate the utility of various model-agnostic explanation techniques for machine learning predictions. A total of 499 consecutive patients with Unfavorable [modified Rankin Scale (mRS) score 3-6, n = 140] and favorable (mRS score 0-2, n = 359) outcome after 6-month from ischemic stroke were enrolled in this study. Four machine learning models, including Random Forest [RF], eXtreme Gradient Boosting [XGBoost], Adaptive Boosting [Adaboost] and Support Vector Machine [SVM] were performed with the area-under-the-curve (AUC): (90.20 ± 0.22)%, (86.91 ± 1.05)%, (86.49 ± 2.35)%, (81.89 ± 2.40)%, respectively. Three global interpretability techniques (Feature Importance shows the contribution of selected features, Partial Dependence Plot aims to visualize the average effect of a feature on the predicted probability of unfavorable outcome, Feature Interaction detects the change in the prediction that occurs by varying the features after considering the individual feature effects) and one local interpretability technique (Shapley Value indicates the probability of unfavorable outcome of different instances) have been applied to present the interpretability techniques via visualization. Thereby, the current study is important for better understanding intelligible healthcare analytics via explanations for the prediction of local and global levels, and potentially reduction of the mortality of patients with ischemic stroke by assisting clinicians in the decision-making process.

Association of hearing loss with total and cause-specific mortality in US adults.

We expected to explore the associations of hearing loss and hearing thresholds at different frequencies with total and cause-specific mortality. In this study, 11,732 individuals derived from the National Health and Nutrition Examination Survey (NHANES) 1999-2012 were included. Data of death was extracted from the NHANES Public-Use Linked Mortality File through December 31, 2015. Cox proportional hazards models were used to explore the associations between hearing loss, hearing thresholds at different frequencies, and total or cause-specific mortality. A total of 1,253 deaths occurred with a median follow-up of 12.15 years. A significant positive dose-response relationship between hearing loss in speech frequency and total mortality was observed, and the HRs and 95% CIs were 1.16 (0.91, 1.47), 1.54 (1.19, 2.00), and 1.85 (1.36, 2.50), respectively, for mild, moderate, and severe speech-frequency hearing loss (SFHL) with a P trend of 0.0003. In addition, moderate (HR: 1.90, 95% CI: 1.20-3.00) and greater (3.50, 1.38-8.86) SFHL significantly elevated risk of heart disease mortality. Moreover, hearing thresholds of >25 dB at 500, 1000, or 2000 Hz were significantly associated with elevated mortality from all causes (1.40, 1.17-1.68; 1.44, 1.20-1.73; and 1.33, 1.10-1.62, respectively) and heart disease (1.89, 1.08-3.34; 1.95, 1.21-3.16; and 1.89, 1.16-3.09, respectively). Hearing loss is associated with increased risks of total mortality and heart disease mortality, especially for hearing loss at speech frequency. Preventing or inhibiting the pathogenic factors of hearing loss is important for reducing the risk of death.

Dynamics of Acquired Resistance to Nivolumab Therapies Varies From Administration Strategies.

PURPOSE: The identification of optimal drug administration schedules to overcome the emergence of resistance that causes treatment failure is a major challenge in cancer research. We report the outcomes of a computational strategy to assess the dynamics of tumor progression as a function of time under different treatment regimens. METHODS: We developed an evolutionary game theory model that combined Lotka-Volterra equations and pharmacokinetic properties with 2 competing cancer species: nivolumab-response cells and Janus kinase (JAK1/2) mutation cells. We selected 3 therapeutic schemes that have been tested in the clinical trials: 3 mg/kg Q2w, 10 mg/kg Q2w, and 480 mg Q4w. The simulation was performed under the intervals of 75, 125, and 175 days, respectively, for each regimen. The data sources of the pharmacokinetic parameters used in this study were collected from previous published clinical trials. Other parameters in the evolutionary model come from the existing references. FINDINGS: Predictions under various dose schedules indicated a strong selection for nivolumab-independent cells. Under the 3 mg/kg dose strategy, the reproduction rate of JAK mutation cells was highest, with strongest tumor elimination ability at a 75-day interval between treatments. Prolonged drug intervals to 125 or 175 days delayed tumor evolution but accelerated tumor recurrence. Although 10 mg/kg Q2w had an obvious clinical effect in a short time, it further promotes the progress of resistant population compared with the 3 mg/kg dose. Our model suggests that 480 mg Q4w would be more valuable in terms of clinical efficacy, but complete resistant occurs earlier regardless the interval. IMPLICATIONS: The results of this study emphasize that increasing the dose or shortening the interval between doses accelerates the evolution of heterogeneous populations, although the short-term effect is significant. In practice, the therapeutic regimen should be balanced according to the evolutionary principle.

Highly individual- and tissue-specific expression of glycoprotein group A and B blood antigens in the human kidney and liver.

BACKGROUND: Currently, research on the quantitative distribution of ABO antigens in different organs and tissues remains limited. We aimed to examine the individual characteristics of blood group glycoprotein A and B antigen expression in human kidneys and livers. METHODS: We obtained human samples, including the renal artery, renal vein, renal tissue, hepatic artery, hepatic vein, portal vein, and hepatic tissue, from 24 deceased organ transplant donors. The expression of the blood group antigens glycoprotein A and B was analysed and compared by Western blotting. RESULTS: There was no significant difference in the expression between blood group glycoprotein A and B antigens at any of the seven sites (p > 0.05). The expression of both A and B antigens was highest in renal tissue and the portal vein and was lowest in the renal artery. A large difference in glycoprotein antigen expression was observed among various donors or different regions of the same individual. Univariate analysis revealed that glycoprotein A/B antigens were affected by the age and sex of donors and were significantly higher in males and in young people. CONCLUSIONS: Our study found that blood group glycoprotein antigen expression showed certain trends and distinct distribution in the kidney, liver, and vessels among individuals and in different regions of the same individual, which may explain the different clinical outcomes of patients who received ABO-incompatible transplantation.