Causal relationship between air pollution and chronic obstructive pulmonary disease in European and East Asian populations: a Mendelian randomization study.

Epidemiologic studies have suggested a possible association between air pollution and chronic obstructive pulmonary disease (COPD), but it is controversial and difficult to draw causal inferences. Five methods were adopted to evaluate the causal relationship between air pollution and COPD in European and East Asian populations by using MR Analysis. A statistically significant causal relationship between PM2.5 and COPD was observed in the European population (OR: 2.34; 95% CI: 1.06-5.05; p = 0.033). Statistical significance remained after adjustment for confounding factors (adjusted OR: 2.28; 95% CI: 1.01-5.20; p = 0.048). In East Asian populations, PM2.5 absorbance, a proxy for black carbon, was statistically associated with COPD (OR: 1.41; 95% CI: 1.09-1.81; p = 0.007). We did not adjust for confounders in East Asian populations, as the association was independent of known confounders (e.g. smoking, respiratory tract infections, etc.). In conclusion, increased concentrations of PM2.5 and PM2.5 absorbance were associated with an increased risk of COPD.

Advanced cervix cancer patient with chemotherapy-induced grade IV myelosuppression achieved complete remission with cadonilimab: A case report.

BACKGROUND: The prognosis for patients with advanced metastatic cervix cancer (MCC) is poor, and this disease continues to pose a considerable therapeutic challenge. Despite the administration of first-line regimens consisting of cisplatin, paclitaxel, and bevacizumab, survival rates for patients with metastasis remain poor. The emergence of bispecific antibodies (BsAbs) offers a novel treatment option for patients diagnosed with MCC. CASE SUMMARY: In this report, we present a patient with MCC who was treated with cadonilimab monotherapy at a dose of 6 mg/kg every two weeks after chemotherapy was proven to be intolerable. The patient exhibited a sustained complete response for a duration of 6 months, demonstrating an optimistic outlook. CONCLUSION: This case illustrates the considerable efficacy of cadonilimab for treating advanced MCC. Therefore, BsAb therapy is a promising strategy for effectively treating patients with advanced MCC and should be considered as an option when patients are intolerant to standard chemotherapy.

Associated factors of undernutrition in children with congenital heart disease: a cross-sectional study.

Objective: To evaluate the prevalence and associated factors of undernutrition among children with congenital heart disease (CHD) who have not undergone surgeries in China. Methods: This cross-sectional study included 734 CHD children along with their parents. The outcome of interest was undernutrition, including underweight, wasting, and stunting, defined as Z-scores (i.e., weight-for-age, weight-for-height, and height-for-age) ≤-2, according to the World Health Organization (WHO) growth standard. Exposures of interest, containing demographics, obstetric factors, maternal dietary factors, parents' life behaviors and habits, birth-related factors, cardiac-related factors, and preoperative factors, were analyzed using a multivariate logistic regression model to test their associations with undernutrition in CHD children. Results: Overall, 36.1%, 29.7%, and 21.3% of cases were underweight, wasted, and stunted, respectively. Multivariate logistic regression indicated that underweight was associated with demographic factors (including parents' occupational status, family income, and maternal body mass index pre-pregnancy), low birth weight (OR = 4.60, 2.76-7.70), pulmonary hypertension (OR = 4.46, 3.09-6.43), and pneumonia (OR = 1.88, 1.28-2.76). Artificially-fed children were 2.34 (1.36-4.01) times more likely to be underweight. Occupied mothers (OR = 0.62, 0.44-0.88) and fathers (OR = 0.49, 0.26-0.92) served as protective factors, while mothers having gestational complications (OR = 1.56, 1.11-2.18) and exposed to noisy environment (OR = 1.64, 1.11-2.42) during this pregnancy, and pulmonary hypertension (OR = 3.21, 2.30-4.49) increased the chance of wasting in offspring. The odds of being stunted were greater in families with >2 children (OR = 1.88, 1.13-3.14), placental abruption during this pregnancy (OR = 25.15, 2.55-247.89), preterm births (OR = 1.84, 1.02-3.31), low birth weight (OR = 3.78, 2.16-6.62), pulmonary hypertension (OR = 2.35, 1.56-3.53) and pneumonia (OR = 1.93, 1.28-2.90). In subgroup analyses, the associations differed between patients with different feeding patterns (breastfeeding vs. non-breastfeeding), CHD classifications (cyanotic vs. acyanotic), and prematurity (preterm vs. non-preterm). Conclusion: Undernutrition is common in preoperative CHD children. Familial demographics, maternal factors (including having gestational complications and exposure to noisy environment during pregnancy), and patient-related factors (encompassing preterm births, low birth weight, pulmonary hypertension, pneumonia, and feeding pattern) were found to contribute to undernutrition in CHD cases. However, associated factors among the three subgroups of distinct feeding patterns, CHD categorization, and prematurity exhibited varied outcomes, suggesting the necessity for targeted interventions.

Spatial transcriptomics reveals heterogeneity of histological subtypes between lepidic and acinar lung adenocarcinoma.

BACKGROUND: Patients who possess various histological subtypes of early-stage lung adenocarcinoma (LUAD) have considerably diverse prognoses. The simultaneous existence of several histological subtypes reduces the clinical accuracy of the diagnosis and prognosis of early-stage LUAD due to intratumour intricacy. METHODS: We included 11 postoperative LUAD patients pathologically confirmed to be stage IA. Single-cell RNA sequencing (scRNA-seq) was carried out on matched tumour and normal tissue. Three formalin-fixed and paraffin-embedded cases were randomly selected for 10× Genomics Visium analysis, one of which was analysed by digital spatial profiler (DSP). RESULTS: Using DSP and 10× Genomics Visium analysis, signature gene profiles for lepidic and acinar histological subtypes were acquired. The percentage of histological subtypes predicted for the patients from samples of 11 LUAD fresh tissues by scRNA-seq showed a degree of concordance with the clinicopathologic findings assessed by visual examination. DSP proteomics and 10× Genomics Visium transcriptomics analyses revealed that a negative correlation (Spearman correlation analysis: r = -.886; p = .033) between the expression levels of CD8 and the expression trend of programmed cell death 1(PD-L1) on tumour endothelial cells. The percentage of CD8+ T cells in the acinar region was lower than in the lepidic region. CONCLUSIONS: These findings illustrate that assessing patient histological subtypes at the single-cell level is feasible. Additionally, tumour endothelial cells that express PD-L1 in stage IA LUAD suppress immune-responsive CD8+ T cells.

Maternal anaemia during early pregnancy and the risk of neonatal outcomes: a prospective cohort study in Central China.

BACKGROUND: The purpose of this study was to explore the association between anaemia during early pregnancy and the risk of neonatal outcomes. METHODS: We collected clinical data from pregnant women (≥18 years) who received their first antenatal care between 8 and 14 weeks of gestation in Hunan Provincial Maternal and Child Health Care Hospital. Multiple logistic regression models and restricted cubic spline regression models were used to analyse the association between anaemia during early pregnancy and the risk of neonatal outcomes. In addition, sensitivity analysis was further performed to assess the robustness of the results. RESULTS: The prospective cohort study ultimately included 34 087 singleton pregnancies. In this study, the rate of anaemia during early pregnancy was 16.3%. Our data showed that there was a positive relationship between the rate of preterm birth, low birth weight as well as small for gestational age (SGA) and the severity of maternal anaemia (Ptrend<0.05). After adjustment, the association of early pregnancy anaemia and haemoglobin (Hb) levels with the risk of preterm birth (mild anaemia adjusted OR (aOR) 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 4.03 (95% CI 2.67 to 6.08), respectively), low birth weight (mild anaemia aOR 1.61 (95% CI 1.44 to 1.79), moderate anaemia aOR 2.01 (95% CI 1.75 to 2.30) and severe anaemia aOR 6.11 (95% CI 3.99 to 9.36), respectively) and SGA (mild anaemia aOR 1.37 (95% CI 1.25 to 1.52), moderate anaemia aOR 1.54 (95% CI 1.35 to 1.76) and severe anaemia aOR 2.61 (95% CI 1.74 to 4.50), respectively; Pnon-linear<0.05) was observed. However, no association was found between early pregnancy anaemia or Hb levels and the risk of congenital malformations. Sensitivity analysis verified the stability of the results. CONCLUSIONS: Maternal anaemia during early pregnancy was associated with an increased risk of preterm birth, low birth weight and SGA and their rates may increase with the severity of maternal anaemia. TRIAL REGISTRATION NUMBER: ChiCTR1800016635.

The risk of attention-deficit hyperactivity disorder among children with congenital heart disease: A systematic review and meta-analysis.

BACKGROUND: Although current treatments are effective in dealing with congenital heart disease (CHD), non-cardiac comorbidities such as attention-deficit hyperactivity disorder (ADHD) have received widespread attention. The purpose of this systematic review and meta-analysis is to assess the risk of ADHD associated with CHD. METHODS: The literature search was carried out systematically through eight different databases by the end of September 2022. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. The heterogeneity of the studies was assessed by the Cochran Q test and the I2 statistic. Subgroup and sensitivity analyses were used to explore the potential sources of heterogeneity. RESULTS: Eleven studies were included in this study, which involved a total of 296 741 participants. Our study showed that the children with CHD were at a significantly increased risk of ADHD compared with the reference group (OR = 2.98, 95% CI: 2.18-4.08). The results were moderately heterogeneous. These factors including study design, geographic region and study quality were identified as the first three of the most relevant heterogeneity moderators by subgroup analyses. Sensitivity analysis yielded consistent results. There was no evidence of publication bias. CONCLUSIONS: The present study suggests that CHD children have a significantly higher risk of ADHD when compared with those without CHD. Early identification and intervention of ADHD is important to reduce its symptoms and adverse effects; therefore, clinicians should increase screening for ADHD in children with CHD and intervene promptly to reduce its effects whenever possible.

Associations between maternal syphilis infection during pregnancy and low birth weight and preterm birth: a prospective cohort study.

BACKGROUND: In recent years, syphilis is still the most common sexually transmitted disease worldwide. Pregnant women infected with syphilis can transmit it to the fetus in utero through mother-to-child transmission, which can directly lead to adverse pregnancy outcomes. The aim of this study was to investigate the associations between maternal syphilis infection and low birth weight and preterm birth in offspring. METHODS: Multinomial logistic regression model was used to analyze the associations between maternal syphilis infection and low birth weight and preterm birth, and to explore its stability through subgroup analysis. RESULTS: A total of 34,074 subjects were included in the study. After adjusting for potential confounders, maternal syphilis infection during pregnancy was associated with a 2.60-fold (95% CI 1.83-3.69) increased risk of low birth weight and a 1.91-fold (95% CI 1.35-2.69) increased risk of preterm birth. Subgroup analysis showed that the association was stable. CONCLUSION: We found that maternal syphilis infection during pregnancy was significantly associated with an increased risk of low birth weight and preterm birth. The implementation of reasonable syphilis screening and standardized treatment and follow-up of pregnant syphilis may have important practical significance in reducing the low birth weight and preterm birth rate in offspring.

Carboxyl-Alkyl Functionalized Conjugated Polyelectrolytes for High Performance Organic Electrochemical Transistors.

Contemporary design principles for organic mixed ionic electronic conductors (OMIECs) are mostly based on the ethylene glycol moiety, which may not be representative of the OMIEC class as a whole. Furthermore, glycolated polymers can be difficult to synthesize and process effectively. As an emerging alternative, we present a series of polythiophenes functionalized with a hybrid carboxyl-alkyl side chain. By variation of the alkyl spacer length, a comprehensive evaluation of both the impact of carboxylic acid functionalization and alkyl spacer length was conducted. COOH-functionalization endows the polymer with preferential intrinsic low-swelling behavior and water processability to yield solvent-resistant conjugated polyelectrolytes while retaining substantial electroactivity in aqueous environments. Advanced in situ techniques, including time-resolved spectroelectrochemistry and Raman spectroscopy, are used to interrogate the materials' microstructure, ionic-electronic coupling, and operational stability in devices. To compare these materials' performance to state-of-the-art technology for the design of OMIECs, we benchmarked the materials and demonstrated significant application potential in both planar and interdigitated organic electrochemical transistors (OECTs). The polythiophene bearing carboxyl-butyl side chains exhibits greater electrochemical performance and faster doping kinetics within the polymer series, with a record-high OECT performance among conjugated polyelectrolytes ([µC*]pOECT = 107 ± 4 F cm-1 V-1 s-1). The results provide an enhanced understanding of structure-property relationships for conjugated polyelectrolytes operating in aqueous media and expand the materials options for future OMIEC development. Further, this work demonstrates the potential for conjugated polymers bearing alkyl-COOH side chains as a path toward robust OMIEC designs that may facilitate further facile (bio)chemical functionalization for a range of (bio)sensing applications.

The effectiveness of home rehabilitation based on BPMpathway exercise rehabilitation system for patients after total knee arthroplasty in China.

BACKGROUND: There is significant interest in the use of web-based technologies for rehabilitation of patients after total knee arthroplasty (TKA). BPMpathway is a combination of a wireless BPMpro sensor and mobile app to provide a personalized post-operative support programme for TKA patients. OBJECTIVE: To investigate the impact of the BPMpathway exercise rehabilitation system on home rehabilitation for TKA patients. METHODS: This study had a quasi-experimental design and was conducted with 42 inpatients after TKA. Patients were divided into a control group (n = 21) and an intervention group (n = 21) according to sequence of hospitalization. After discharge, patients in the control group received routine follow-up outside the hospital, while the intervention group, underwent out-of-hospital transitional care utilizing the BPMpathway exercise rehabilitation system. Knee function scores (HSS), quality of life scores (SF-36), and functional exercise compliance scores were compared between the two groups at 1, 3, and 6 months after TKA. RESULTS: The between-group differences in knee function were statistically significant at 1, 3, and 6 months post-operation (t = 6.299, 10.021, 13.064, all P < 0.05). There were between-group significant differences observed in functional exercise compliance and quality of life at 1 and 3 months (t = 7.166, 2.435, both P < 0.05; t = 2.879, 3.117, both P < 0.05). However, there were no significant differences at 6 months in these two respects (t = 0.167, 0.901, both P > 0.05). CONCLUSIONS: The BPMpathway exercise rehabilitation system seems to be potential effective in improving knee function, early compliance with functional exercise and quality of life in TKA patients.

Relationships between Maternal Folic Acid Supplementation and GATA4 Gene Polymorphisms in Patients with Non-Chromosomal Congenital Heart Disease: A Hospital-Based Case-Control Study in China.

This study aimed to investigate the relationships between maternal FA supplementation and nine single-nucleotide variants of the GATA4 gene in non-chromosomal CHD and further explore the gene-environment interactions associated with CHD. A total of 585 CHD patients and 600 controls were recruited in the case-control study. Maternal FA (FA-containing multivitamin) supplementation information and nine polymorphisms of the GATA4 gene were collected in this study. Adjusted ORs (aOR) and their 95% confidence intervals (CIs) were calculated using proper statistical methods to analyze the relationships between the two main exposures of interest with respect to CHD. After adjusting the suspicious confounding factors, a significantly increased risk for CHD in offspring was found with non-FA supplementation before/during the pregnancy to CHD in offspring (aOR = 1.58, 95% CI: 1.01-2.48). We suggested taking FA supplementation before/during the pregnancy to prevent CHD in offspring, especially in the preconception period (aOR = 0.53, 95% CI: 0.32-0.90). The genetic results showed that the polymorphisms of rs4841588, rs12458, and rs904018 under specific genotypes and genetic models were significantly related to CHD. The gene-environment interaction between rs10108052 and FA supplementation before/during pregnancy could increase the risk of CHD (aOR = 5.38, 95% CI: 1.67-17.09, Pinteraction = 0.004). Relationships between maternal FA supplementation and specific polymorphisms of the GATA4 gene, as well as the gene-environment interaction, were significantly associated with CHD in offspring.

Predictive value of machine learning algorithm of coronary artery calcium score and clinical factors for obstructive coronary artery disease in hypertensive patients.

BACKGROUND: The addition of coronary artery calcium score (CACS) to prediction models has been verified to improve performance. Machine learning (ML) algorithms become important medical tools in an era of precision medicine, However, combined utility by CACS and ML algorithms in hypertensive patients to forecast obstructive coronary artery disease (CAD) on coronary computed tomography angiography (CCTA) is rare. METHODS: This retrospective study was composed of 1,273 individuals with hypertension and without a history of CAD, who underwent dual-source computed tomography evaluation. We applied five ML algorithms, coupled with clinical factors, imaging parameters, and CACS to construct predictive models. Moreover, 80% individuals were randomly taken as a training set on which 5-fold cross-validation was done and the remaining 20% were regarded as a validation set. RESULTS: 16.7% (212 out of 1,273) of hypertensive patients had obstructive CAD. Extreme Gradient Boosting (XGBoost) posted the biggest area under the receiver operator characteristic curve (AUC) of 0.83 in five ML algorithms. Continuous net reclassification improvement (NRI) was 0.55 (95% CI (0.39-0.71), p < 0.001), and integrated discrimination improvement (IDI) was 0.04 (95% CI (0.01-0. 07), p = 0.0048) when the XGBoost model was compared with traditional Models. In the subgroup analysis stratified by hypertension levels, XGBoost still had excellent performance. CONCLUSION: The ML model incorporating clinical features and CACS may accurately forecast the presence of obstructive CAD on CCTA among hypertensive patients. XGBoost is superior to other ML algorithms.

Toxic vascular effects of polystyrene microplastic exposure.

Polystyrene microplastics (PSMPs) are some of the most common microplastic components, and the resulting pollution has become a global problem. Extensive studies have been conducted on the toxic effects of PSMPs on the heart, lungs, liver, kidneys, nerves, intestines and other tissues. However, the impact of PSMPs on vascular toxicity is poorly understood at present. The aim of this study was to reveal the vascular toxicity of microplastics (MPs). Patients were assigned to a calcification group (25 patients) or a non-calcification group (22 patients) based on the presence or absence of calcification in the thoracic aorta wall. We detected 7 polymer types in human feces. Patients with vascular calcification (VC) had higher levels of total MPs, polypropylene (PP) and polystyrene (PS) in feces than patients without VC. The thoracic aortic calcification score was significantly positively correlated with the total MP abundance (Spearman r = 0.8109, p < 0.0001), PP (Spearman r = 0.7211, p = 0.0160) and PS (Spearman r = 0.6523, p = 0.0471) in feces. We then explored the effects of PSMP exposure on normal and vitamin D3 + nicotine (VDN)-treated rats. PSMP exposure induced mild VC in normal rats and aggravated VC in VDN-treated rats. PSMP exposure disturbed the gut microbiota, causing Proteobacteria and Escherichia_Shigella to be the dominant phylum and genus, respectively. It also induced intestinal inflammatory responses in normal rats, aggravated intestinal inflammation in VDN-treated rats, impaired the intestinal mucosal barrier, and increased intestinal permeability. This study provides a theoretical basis for the risk assessment of MP-induced cardiovascular disease.

Association between air pollution and primary liver cancer in European and east Asian populations: a Mendelian randomization study.

Purpose: The incidence of primary liver cancer is increasing year by year, with environmental factors playing a non-negligible role. At present, many studies are still disputing whether air pollution is associated with primary liver cancer incidence, and it is difficult to draw causal inferences. Therefore, in this study, we used two-sample Mendelian randomization (MR) to assess the causal relationship between air pollution (including PM2.5, PM2.5-10, PM10, nitrogen dioxide and nitrogen oxides) and primary liver cancer risk and its related biomarkers (Alpha-fetoprotein, Osteopontin, Glypican-3 and Arginase-1). Patients and methods: We used large-scale publicly available genome-wide association studies (GWAS) summary data to conduct MR analyses of European and East Asian populations. Inverse variance weighted (IVW) method was used as the main analysis method, and weighted median model, MR-Egger, simple model and weighted model methods were selected for quality control. Heterogeneity was checked by the Cochran's Q test. The MR-Egger regression and the MR-PRESSO global test detect pleiotropy. The sensitivity analysis was performed using the leave-one-out method. Results: Between air pollution and primary liver cancer in either European (PM2.5: p = 0.993; PM2.5-10: p = 0.833; PM10: p = 0.257; nitrogen dioxide: p = 0.215; nitrogen oxides: p = 0.614) or East Asian (PM2.5: p = 0.718; PM2.5-10: p = 0.362; PM10: p = 0.720; nitrogen dioxide: p = 0.101; nitrogen oxides: p = 0.760) populations were found no statistical association. Notably, there was a causal relationship between nitrogen oxides and Arginase-1, a biomarker associated with hepatocellular differentiation, statistically significant associations remained after deletion for single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency, Body mass index (BMI) and cancers (Beta: 4.46; 95%CI: 0.83-8.08; p = 0.015). There was no heterogeneity or pleiotropy in the results. Conclusion: This MR study found no evidence to support a causality between air pollution and primary liver cancer in European and East Asian populations, but nitrogen oxides may affect hepatocellular differentiation.

Fertility intentions to have a second or third child among the childbearing-age population in Central China under China's three-child policy: A cross-sectional study.

Background: On May 31, 2021, the Chinese authorities announced that couples can have up to three children, aiming to stimulate a rise in fertility levels. However, there is limited research on second and third birth intentions of the childbearing-age population under China's three-child policy, and the existing results are inconsistent. Methods: A cross-sectional survey was performed in Central China from June to August 2022. A total of 13 479 respondents aged 20-49 were enrolled in the study through a multi-stage sampling method. Data on the intentions to have a second or third child were collected using anonymized questionnaires. Descriptive statistics were performed to assess fertility intentions. Multivariate logistic regression analyses were used to assess the associations between fertility intentions and the related factors. Results: Among families with a single child, 29.7% (1444 / 4859) of the respondents intended to have a second child, while among two-child families, 10.6% (750 / 7056) respondents intended to have a third child. Overall, participants indicated that the ideal number of children was 1.85 ± 0.52. The age-specific fertility intentions of the one-child families were always higher than those of two-child families; however, based on couples' age groups, the number of ideal children reported by two-child families was always higher than that of one-child families. Fertility intentions were influenced by the respondents' gender, age, residence, marital status, educational level, average working time, childcare support, marital satisfaction, accessibility of educational resources, health condition of both spouses, loan situation, size of living house and the gender of the first child or second child. Conclusions: The general prevalence of the second and third birth intention of the childbearing-age population in Central China is not high. To increase the birth rate, it is necessary to create a favourable fertility context and offer supportive measures.

Association of MTR gene polymorphisms with the occurrence of non-syndromic congenital heart disease: a case-control study.

To exhaustively explore the association of infant genetic polymorphisms of methionine synthase (MTR) gene with the risk of non-syndromic congenital heart disease (CHD). A hospital-based case-control study involving 620 CHD cases and 620 health controls was conducted from November 2017 to March 2020. Eighteen SNPs were detected and analyzed. Our date suggested that the genetic polymorphisms of MTR gene at rs1805087 (GG vs. AA: aOR = 6.85, 95% CI 2.94-15.96; the dominant model: aOR = 1.77, 95% CI 1.35-2.32; the recessive model: aOR = 6.26, 95% CI 2.69-14.54; the addictive model: aOR = 1.81, 95% CI 1.44-2.29) and rs2275565 (GT vs. GG: aOR = 1.52, 95% CI 1.15-1.20; TT vs. GG: aOR = 4.93, 95% CI 1.93-12.58; the dominant model: aOR = 1.66, 95% CI 1.27-2.17; the recessive model: aOR = 4.41, 95% CI 1.73-11.22; the addictive model: aOR = 1.68, 95% CI 1.32-2.13) were significantly associated with the higher risk of CHD. And three haplotypes of G-A-T (involving rs4659724, rs95516 and rs4077829; OR = 5.48, 95% CI 2.58-11.66), G-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 0.78, 95% CI 0.63-0.97) and T-C-A-T-T-G (involving rs2275565, rs1266164, rs2229276, rs4659743, rs3820571 and rs1050993; OR = 1.60, 95% CI 1.26-2.04) were observed to be significantly associated with risk of CHD. Our study found that genetic polymorphisms of MTR gene at rs1805087 and rs2275565 were significantly associated with higher risk of CHD. Additionally, our study revealed a significant association of three haplotypes with risk of CHD. However, the limitations in this study should be carefully taken into account. In the future, more specific studies in different ethnic populations are required to refine and confirm our findings.Trial registration: Registration number: ChiCTR1800016635; Date of first registration: 14/06/2018.

Gut microbiota and type 1 diabetes: a two-sample bidirectional Mendelian randomization study.

Objective: The real causal relationship between human gut microbiota and T1D remains unclear and difficult to establish. Herein, we adopted a two-sample bidirectional mendelian randomization (MR) study to evaluate the causality between gut microbiota and T1D. Methods: We leveraged publicly available genome-wide association study (GWAS) summary data to perform MR analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen were used. The summary statistic data for T1D (n = 264,137) were obtained from the latest release from the FinnGen consortium as the outcome of interest. The selection of instrumental variables conformed strictly to a series of preset inclusion and exclusion criteria. MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods were used to assess the causal association. The Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy. Results: At the phylum level, only Bacteroidetes was indicated to have causality on T1D (OR = 1.24, 95% CI = 1.01-1.53, P = 0.044) in the IVW analysis. When it comes to their subcategories, Bacteroidia class (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P FDR = 0.085), Bacteroidales order (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P FDR = 0.085), and Eubacterium eligens group genus (OR = 0.64, 95% CI = 0.50-0.81, P = 2.84×10-4, P FDR = 0.031) were observed to have a causal relationship with T1D in the IVW analysis. No heterogeneity and pleiotropy were detected. Conclusions: The present study reports that Bacteroidetes phylum, Bacteroidia class, and Bacteroidales order causally increase T1D risk, whereas Eubacterium eligens group genus, which belongs to the Firmicutes phylum, causally decreases T1D risk. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa's role in the pathophysiology of T1D.

Association of maternal methionine synthase reductase gene polymorphisms with the risk of congenital heart disease in offspring: a hospital-based case-control study.

BACKGROUND: Evidence suggests that periconceptional folic acid supplementation may prevent congenital heart disease (CHD). Methionine synthase reductase (MTRR) is one of the key regulatory enzymes in the folate metabolic pathway. This study aimed to comprehensively evaluate the association of single nucleotide polymorphisms (SNPs) in the maternal MTRR gene with CHD risk in offspring. METHODS: A hospital-based case-control study involving 740 mothers of CHD cases and 683 health controls was conducted. RESULTS: The study showed that maternal MTRR gene polymorphisms at rs1532268 (C/T vs. C/C: aOR = 1.524; T/T vs. C/C: aOR = 3.178), rs1802059 (G/A vs. G/G: aOR = 1.410; A/A vs. G/G: aOR = 3.953), rs2287779 (G/A vs. G/G: aOR = 0.540), rs16879334 (C/G vs. C/C: aOR = 0.454), and rs2303080 (T/A vs. T/T: aOR = 0.546) were associated with the risk of CHD. And seven haplotypes were observed to be associated with the risk of CHD, T-G-A haplotype (OR = 1.298), C-A-C-C (OR = 4.824) and A-G haplotype (OR = 1.751) were associated with increased risk of CHD in offspring; A-A-A (OR = 0.773), T-A-A (OR = 0.557), G-A-C-C (OR = 0.598) and G-C (OR = 0.740) were associated with decreased risk of CHD in offspring. CONCLUSIONS: Maternal MTRR gene polymorphisms were associated with CHD in offspring, and its haplotypes have affected the occurrence of CHD. Furthermore, given the complexity and heterogeneity of CHD, the mechanisms by which these factors influence offspring cardiac development remain unknown, and studies in larger samples in an ethnically diverse population are needed.

E2EFP-MIL: End-to-end and high-generalizability weakly supervised deep convolutional network for lung cancer classification from whole slide image.

Efficient and accurate distinction of histopathological subtype of lung cancer is quite critical for the individualized treatment. So far, artificial intelligence techniques have been developed, whose performance yet remained debatable on more heterogenous data, hindering their clinical deployment. Here, we propose an end-to-end, well-generalized and data-efficient weakly supervised deep learning-based method. The method, end-to-end feature pyramid deep multi-instance learning model (E2EFP-MIL), contains an iterative sampling module, a trainable feature pyramid module and a robust feature aggregation module. E2EFP-MIL uses end-to-end learning to extract generalized morphological features automatically and identify discriminative histomorphological patterns. This method is trained with 1007 whole slide images (WSIs) of lung cancer from TCGA, with AUCs of 0.95-0.97 in test sets. We validated E2EFP-MIL in 5 real-world external heterogenous cohorts including nearly 1600 WSIs from both United States and China with AUCs of 0.94-0.97, and found that 100-200 training images are enough to achieve an AUC of >0.9. E2EFP-MIL overperforms multiple state-of-the-art MIL-based methods with high accuracy and low hardware requirements. Excellent and robust results prove generalizability and effectiveness of E2EFP-MIL in clinical practice. Our code is available at https://github.com/raycaohmu/E2EFP-MIL.

Effect of the interaction between advanced maternal age and pre-pregnancy BMI on pre-eclampsia and GDM in Central China.

INTRODUCTION: To investigate the independent and combined effects of advanced maternal age and pre-pregnancy body mass index (BMI) on the risk of pre-eclampsia and gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: Logistic regression models were used to estimate the OR and 95% CIs of pre-eclampsia and GDM with advanced maternal age and pre-pregnancy BMI, respectively, and the interaction between advanced maternal age and pre-pregnancy BMI. We also used causal mediation analysis to assess the mediating role of pre-pregnancy BMI on maternal age-pre-eclampsia/GDM associations. RESULTS: In this study, 788 cases (2.31%) were diagnosed with pre-eclampsia and 5430 cases (15.92%) were diagnosed with GDM. We found that advanced maternal age was associated with a higher risk for pre-eclampsia and GDM, with adjusted ORs (aORs) of 1.74 (95% CI 1.49-2.05) and 1.76 (95% CI 1.65-1.89) after adjusting for potential confounders, respectively. In addition, maternal pre-pregnancy overweight/obesity was associated with the risk of pre-eclampsia and GDM, with the corresponding aORs of 3.64 (95% CI 3.12-4.24) and 1.71 (95% CI 1.60-1.85), respectively. We also observed the interaction between maternal age and pre-pregnancy BMI for the risk of pre-eclampsia/GDM (all p for interaction <0.001). In the mediating effect analysis, we found that maternal pre-pregnancy BMI mediated the associations between maternal age and the development of pre-eclampsia and GDM. CONCLUSIONS: Advanced maternal age and pre-pregnancy BMI were respectively associated with the risk of pre-eclampsia/GDM, and there was an interaction between the two risk factors. In addition, we found that pre-pregnancy BMI served as a mediator of the association between advanced maternal age and the risk of pre-eclampsia/GDM, providing an essential target for the prevention of maternal overweight/obesity.

WRKY29 transcription factor regulates ethylene biosynthesis and response in arabidopsis.

The gaseous phytohormone ethylene participates in a lot of physiological processes in plants. 1-aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS, EC 4.4.1.14) and the ACC oxidase (ACO, EC 1.14.17.4) are key enzymes in ethylene biosynthesis. However, how ACSs and ACOs are regulated at the transcriptional level is largely unknown. In the present study, we showed that an Arabidopsis (Arabidopsis thaliana) WRKY-type transcription factor (TF), WRKY29 positively regulated the expression of ACS5, ACS6, ACS8, ACS11 and ACO5 genes and thus promoted basal ethylene production. WRKY29 protein was localized in nuclei and was a transcriptional activator. Overexpression of WRKY29 caused pleiotropic effect on plant growth, development and showed obvious response even without ACC treatment. Inducible overexpression of WRKY29 also reduced primary root elongation and lateral root growth. A triple response assay of overexpression and mutant seedlings of WRKY29 showed that overexpression seedlings had shorter hypocotyls than the transgenic GFP (Green Fluorescence Protein) control, while mutants had no difference from wild-type. A qRT-PCR assay demonstrated that expression of multiple ACSs and ACO5 was up-regulated in WRKY29 overexpression plants. A transactivation assay through dual luciferase reporter system confirmed the regulation of promoters of ACS5, ACS6, ACS8, ACS11 and ACO5 by WRKY29. Both in vivo chromatin immunoprecipitation (ChIP)- quantitative PCR and in vitro electrophoretic mobility shift assay (EMSA) revealed that WRKY29 directly bound to the promoter regions of its target genes. Taken together, these results suggest that WRKY29 is a novel TF positively regulating ethylene production by modulating the expression of ACS and ACO genes.