Association of plasma trans fatty acid concentrations with blood pressure and hypertension in U.S. adults.

Objective: The present study aimed to evaluate the association of plasma trans fatty acids (TFAs) biomarkers with the risk of hypertension. Methods: Using data from the National Health and Nutrition Examination Surveys (NHANES 2009-2010), we conducted a thorough analysis using both the traditional regression model and the Bayesian Kernel Machine Regression (BKMR) model to investigate the associations of individual TFAs and their mixtures with systolic blood pressure (SBP), diastolic blood pressure (DBP), and the risk of hypertension in a sample of 1,970 American adults. Results: The concentrations of TFAs were natural logarithms (ln) transformed to approximate a normal distribution. Multivariate linear regression models showed that each 1-unit increase in ln-transformed plasma concentrations of palmitelaidic, elaidic, vaccenic, and linolelaidic acids was associated with separate 2.94-, 3.60-, 2.46- and 4.78-mm Hg and 2.77-, 2.35-, 2.03-, and 3.70- mm Hg increase in SBP and DBP, respectively (P < 0.05). The BKMR model showed positive associations between the four TFAs mixtures and SBP and DBP. In addition, linolelaidic acid contributed the most to an increased blood pressure. Similar results were observed with the threshold of hypertension (≥130/80 mm Hg). Conclusion: Our findings provide preliminary evidence that plasma TFA concentrations are associated with increased blood pressure and the risk of hypertension in US adults. This study also suggests that linolelaidic acid might exhibit more deleterious effects on hypertension than other TFAs. Further studies should be conducted to validate these results.

Case Report: A developmental and epileptic encephalopathy 45 due to de novo variant of GABRB1.

Background: The gamma-aminobutyric acid (GABA) variant causes developmental and epileptic encephalopathy 45 (DEE45), an autosomal dominant disorder that results in oculocortical visual impairment, reduced muscle tone, psychomotor retardation, and epilepsy. Analysis of the clinical features and genetics of DEE45 may be helpful in complementing genotype-phenotype studies. Case presentation: We collected peripheral blood samples from the affected children and parents and extracted genomic DNA. Whole exome sequencing (WES) was utilized to identify the underlying disease-causing variant. WES showed that the prior carried a heterozygous variant c.686C > T p.(Ala229Val) in exon 7 of the GABRB1 (NM_000812.4), and no variant was detected in either parental sample. The child has DEE45. Conclusion: The variant c.686C > T of the GABRB1 is a possible cause of DEE45. Gene variant analysis of the relevant family lines using WES provides effective genetic counseling for developing and regressing such patients in the clinic. However, further studies are needed to verify the pathogenic mechanism.

Dense Amorphous Passivation Layer Formed on Aluminum Alloy Surfaces by Femtosecond Laser-Assisted Oxygen-Rich Doping.

Aluminum (Al) alloy surfaces are prone to serious corrosion in humid and salt-laden environments, which promotes the development of numerous protective approaches. Although the amorphous state is more conducive to improve corrosion resistance compared with the crystalline state, it still faces coating design problems like insufficient adhesive strength and flaking-off tendency. Here, we propose a strategy of femtosecond laser-assisted oxygen-rich doping to in situ create a dense high-quality passivation layer on Al alloy surfaces. With respect to the femtosecond laser processing in traditional air ambience, the material surface modifications within the oxygen-rich environment demonstrate some distinctiveness. For the ridge area of the laser ablation grooves, the oxidation surface is separated into two layers: the outer region presents a loose and porous appearance similar to the observations in the air ambience, while the inner region exhibits complete and homogeneous oxidation, especially associated with the continuous distribution of the amorphous substance, in sharp contrast to the nanoscale discrete amorphous formation in the air case. Simultaneously, the high degree of material oxidization with the amorphous phase is also developed on the wallside area of the groove valleys, which is much different from the incomplete oxidation in the air ambience. As a result, the measured corrosion current decreases by 49 times to a value of Icorr = 1.19 × 10-10 A/cm2 relative to the laser treatment in the air environment. Such a method offers the prospect for elevating the anticorrosion performance of metal surfaces.

Climate warming promotes collateral antibiotic resistance development in cyanobacteria.

Both cyanobacterial blooms and antibiotic resistance have aggravated worldwide and posed a great threat to public health in recent years. As a significant source and reservoir of water environmental resistome, cyanobacteria exhibit confusing discrepancy between their reduced susceptibility and their chronic exposure to antibiotic mixtures at sub-inhibitory concentrations. How the increasing temperature affects the adaptive evolution of cyanobacteria-associated antibiotic resistance in response to low-level antibiotic combinations under climate change remains unclear. Here we profiled the antibiotic interaction and collateral susceptibility networks among 33 commonly detected antibiotics in 600 cyanobacterial strains isolated from 50 sites across four eutrophicated lakes in China. Cyanobacteria-associated antibiotic resistance level was found positively correlated to antibiotic heterogeneity across all sites. Among 528 antibiotic combinations, antagonism was observed for 62 % interactions and highly conserved within cyanobacterial species. Collateral resistance was detected in 78.5 % of pairwise antibiotic interaction, leading to a widened or shifted upwards mutant selection window for increased opportunity of acquiring second-step mutations. We quantified the interactive promoting effect of collateral resistance and increasing temperature on the evolution of both phenotypic and genotypic cyanobacteria-associated resistance under chronic exposure to environmental level of antibiotic combinations. With temperature increasing from 16 °C to 36 °C, the evolvability index and genotypic resistance level increased by 1.25 - 2.5 folds and 3 - 295 folds in the collateral-resistance-informed lineages, respectively. Emergence of resistance mutation pioneered by tolerance, which was jointly driven by mutation rate and persister fraction, was found to be accelerated by increased temperature and antibiotic switching rate. Our findings provided mechanic insights into the boosting effect of climate warming on the emergence and development of cyanobacteria-associated resistance against collateral antibiotic phenotypes.

Activity refinement of aryl amino acetamides that target the P. falciparum STAR-related lipid transfer 1 protein.

Malaria is a devastating disease that causes significant morbidity worldwide. The development of new antimalarial chemotypes is urgently needed because of the emergence of resistance to frontline therapies. Independent phenotypic screening campaigns against the Plasmodium asexual parasite, including our own, identified the aryl amino acetamide hit scaffold. In a prior study, we identified the STAR-related lipid transfer protein (PfSTART1) as the molecular target of this antimalarial chemotype. In this study, we combined structural elements from the different aryl acetamide hit subtypes and explored the structure-activity relationship. It was shown that the inclusion of an endocyclic nitrogen, to generate the tool compound WJM-715, improved aqueous solubility and modestly improved metabolic stability in rat hepatocytes. Metabolic stability in human liver microsomes remains a challenge for future development of the aryl acetamide class, which was underscored by modest systemic exposure and a short half-life in mice. The optimized aryl acetamide analogs were cross resistant to parasites with mutations in PfSTART1, but not to other drug-resistant mutations, and showed potent binding to recombinant PfSTART1 by biophysical analysis, further supporting PfSTART1 as the likely molecular target. The optimized aryl acetamide analogue, WJM-715 will be a useful tool for further investigating the druggability of PfSTART1 across the lifecycle of the malaria parasite.

Demethylase FTO-Mediated m6A Modification of lncRNA MEG3 Activates Neuronal Pyroptosis via NLRP3 Signaling in Cerebral Ischemic Stroke.

Neuronal death following ischemia is the primary cause of death and disability in patients with ischemic stroke. N6-methyladenosine (m6A) modification plays essential role in various physiological and pathological conditions, but its role and mechanism in ischemic neuronal death remain unclear. In the present study, neuronal pyroptosis was an important event in brain injury caused by ischemic stroke, and the upregulation of long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) following cerebral ischemia was a key factor in activating ischemic neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling. Moreover, we first demonstrated that the demethylase fat mass and obesity-associated protein (FTO), which was decreased following ischemia, regulated MEG3 expression in an m6A-dependent manner by affecting its stability, thereby activating neuronal pyroptosis via NLRP3/caspase-1/GSDMD signaling, and ultimately leading to ischemic brain damage. Therefore, the present study provides new insights for the mechanism of ischemic stroke, and suggests that FTO may be a potential therapeutic target for ischemic stroke.

Identification of eight genomic protective alleles for mitochondrial diabetes by Kinship-graph convolutional network.

AIMS: Nearly 85% of maternally inherited diabetes and deafness (MIDD) are caused by the m.3243A>G mutation in the mitochondrial DNA. However, the clinical phenotypes of MIDD may also be influenced by the nuclear genome, this study aimed to investigate nuclear genome variants that influence clinical phenotypes associated with m.3243A>G mutation in MIDD based on whole-genome sequencing of the patients belonging to pedigrees. MATERIALS AND METHODS: We analyzed a whole-genome sequencing (WGS) dataset from blood samples of 38 MIDD patients with the m.3243A > G mutation belonging to 10 pedigrees, by developing a Kinship-graph convolutional network approach, called Ki-GCN, integrated with the conventional genome-wide association study (GWAS) methods. RESULTS: We identified eight protective alleles in the nuclear genome that have protective effects against the onset of MIDD, related deafness, and also type 2 diabetes. Based on these eight protective alleles, we constructed an effective logistic regression model to predict the early or late onset of MIDD patients. CONCLUSIONS: There are protective alleles in the nuclear genome that are associated with the onset-age of MIDD patients and might also provide protective effects on the deafness derived from MIDD patients.

A novel nomogram for predicting the prolonged length of stay in post-anesthesia care unit after elective operation.

BACKGROUND: Prolonged length of stay in post-anesthesia care unit (PLOS in PACU) is a combination of risk factors and complications that can compromise quality of care and operating room efficiency. Our study aimed to develop a nomogram to predict PLOS in PACU of patients undergoing elective surgery. METHODS: Data from 24017 patients were collected. Least absolute shrinkage and selection operator (LASSO) was used to screen variables. A logistic regression model was built on variables determined by a combined method of forward selection and backward elimination. Nomogram was designed with the model. The nomogram performance was evaluated with the area under the receiver operating characteristic curve (AUC) for discrimination, calibration plot for consistency between predictions and actuality, and decision curve analysis (DCA) for clinical application value. RESULTS: A nomogram was established based on the selected ten variables, including age, BMI < 21 kg/m2, American society of Anesthesiologists Physical Status (ASA), surgery type, chill, delirium, pain, naloxone, operation duration and blood transfusion. The C-index value was 0.773 [95% confidence interval (CI) = 0.765 - 0.781] in the development set and 0.757 (95% CI = 0.744-0.770) in the validation set. The AUC was > 0.75 for the prediction of PLOS in PACU. The calibration curves revealed high consistencies between the predicted and actual probability. The DCA showed that if the threshold probability is over 10% , using the models to predict PLOS in PACU and implement intervention adds more benefit. CONCLUSIONS: This study presented a nomogram to facilitate individualized prediction of PLOS in PACU for patients undergoing elective surgery.

Effect of General Anesthetic Agents on Microglia.

The effects of general anesthetic agents (GAAs) on microglia and their potential neurotoxicity have attracted the attention of neuroscientists. Microglia play important roles in the inflammatory process and in neuromodulation of the central nervous system. Microglia-mediated neuroinflammation is a key mechanism of neurocognitive dysfunction during the perioperative period. Microglial activation by GAAs induces anti-inflammatory and pro-inflammatory effects in microglia, suggesting that GAAs play a dual role in the mechanism of postoperative cognitive dysfunction. Understanding of the mechanisms by which GAAs regulate microglia may help to reduce the incidence of postoperative adverse effects. Here, we review the actions of GAAs on microglia and the consequent changes in microglial function. We summarize clinical and animal studies associating microglia with general anesthesia and describe how GAAs interact with neurons via microglia to further explore the mechanisms of action of GAAs in the nervous system.

Research on forming method of additive manufacturing of frozen sand mold.

In order to promote the green and sustainable development of the foundry industry, it is necessary to further explore new methods and technologies for green foundry. This paper innovatively proposes a method of additive manufacturing of frozen sand mold, using water as the binder instead of resin binders for additive manufacturing in low-temperature environments, which effectively solves the problems of harmful gas emissions during the pouring process and the difficulty of direct recycling of molding sand, and realizes high-performance green casting of complex castings. In this paper, the liquid-solid phase transition mechanism of the binder for additive manufacturing of frozen sand mold and the change law of the normal temperature field and phase transition field of the pre-cooled powder bed porous medium at different temperatures are studied, and the process window of additive manufacturing of frozen sand mold is obtained, which provides a new green casting method for the foundry field.

Platycoside E alleviates allergic airway inflammation in obesity-related asthma mouse model.

BACKGROUND: Overweight and obesity are related to an increased risk of asthma. The effect of platycoside E (PE) on obesity-related asthma remains unknown. METHODS: To mimic obesity-related asthma conditions in vivo, C57BL/6 mice were exposed to a high-fat diet (HFD) and challenged with ovalbumin (OVA). PE was administrated intraperitoneally during the OVA treatment. Body weight was measured at 8th week before PE treatment and after sacrificing the mice. Airway inflammation and airway hyperresponsiveness (AHR) were evaluated. Immunohistochemistry staining was performed to evaluate eosinophils. Histopathological changes were determined by HE staining. Cellular model of asthma was established using IL-13 in BEAS-2B cells. Levels of proinflammatory cytokines and oxidative stress indicators were measured by ELISA kits and commercial kits, respectively. Cell viability was detected by CCK-8 assays. RESULTS: IL-13 treatment led to inflammatory and oxidative damage in bronchial epithelial cells, which was relieved by PE. PE administration significantly reduced HFD-induced obesity and relieved AHR and airway inflammation in obese asthmatic mice. The expression of proinflammatory cytokines in BALF and lung tissues in obese asthmatic mice were reduced by PE. PE administration also reduced infiltration of eosinophils and inflammation scores in obese asthmatic mice. CONCLUSION: PE suppresses airway inflammation and AHR in obese asthmatic mice and serves as an effective option for treating obesity-related asthma.

Targeted gene panel provides advantages over whole-exome sequencing for diagnosing obesity and diabetes mellitus.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

Genetic variants in epoxyeicosatrienoic acid processing and degradation pathways are associated with gestational diabetes mellitus.

AIM: To explore the genetic effects of CYP2C8, CYP2C9, CYP2J2, and EPHX2, the key genes involved in epoxyeicosatrienoic acid processing and degradation pathways in gestational diabetes mellitus (GDM) and metabolic traits in Chinese pregnant women. METHODS: A total of 2548 unrelated pregnant women were included, of which 938 had GDM and 1610 were considered as controls. Common variants were genotyped using the Infinium Asian Screening Array. Association studies of single nucleotide polymorphisms (SNPs) with GDM and related traits were performed using logistic regression and multivariable linear regression analyses. A genetic risk score (GRS) model based on 12 independent target SNPs associated with GDM was constructed. Logistic regression was used to estimate odds ratios and 95% confidence intervals, adjusting for potential confounders including age, pre-pregnancy body mass index, history of polycystic ovarian syndrome, history of GDM, and family history of diabetes, with GRS entered both as a continuous variable and categorized groups. The relationship between GRS and quantitative traits was also evaluated. RESULTS: The 12 SNPs in CYP2C8, CYP2C9, CYP2J2, and EPHX2 were significantly associated with GDM after adjusting for covariates (all P < 0.05). The GRS generated from these SNPs significantly correlated with GDM. Furthermore, a significant interaction between CYP2J2 and CYP2C8 in GDM (PInteraction = 0.014, ORInteraction= 0.61, 95%CI 0.41-0.90) was observed. CONCLUSION: We found significant associations between GDM susceptibility and 12 SNPs of the four genes involved in epoxyeicosatrienoic acid processing and degradation pathways in a Chinese population. Subjects with a higher GRS showed higher GDM susceptibility with higher fasting plasma glucose and area under the curve of glucose and poorer ß-cell function.

Acrylamide interferes with autophagy and induces apoptosis in Neuro-2a cells by interfering with TFEB-regulated lysosomal function.

Acrylamide (ACR), a well-documented human neurotoxicant that is widely exists in starchy foods. More than 30% of human daily energy is provided by ACR-containing foods. Evidence indicated that ACR can induce apoptosis and inhibit autophagy, but the mechanisms are limited. Transcription Factor EB (TFEB) is a major transcriptional regulator of the autophagy-lysosomal biogenesis that regulates autophagy processes and cell degradation. Our study aimed to investigated the potential mechanisms of TFEB-regulated lysosomal function in ACR-caused autophagic flux inhibition and apoptosis in Neuro-2a cells. Our results found that ACR exposure inhibited the autophagic flux, as revealed by the elevated LC3-II/LC3-I and p62 levels and a notable increased autophagosomes. ACR exposure reduced the amounts of LAMP1 and mature cathepsin D and caused an accumulation of ubiquitinated proteins, which suggests lysosomal dysfunction. In addition, ACR increased cellular apoptosis via decreasing Bcl-2 expression, increasing Bax and cleaved caspase-3 expression, and raising the apoptotic rate. Interestingly, TFEB overexpression alleviated the ACR-induced lysosomal dysfunction, and then mitigated the autophagy flux inhibition and cellular apoptosis. On the other hand, TFEB knockdown exacerbated the ACR-induced lysosomal dysfunction, autophagy flux inhibition, and cellular apoptosis. These findings strongly suggested that TFEB- regulated lysosomal function is responsible for ACR-caused autophagic flux inhibition and apoptosis in Neuro-2a cells. The present study hopes to explore new sensitive indicators in the mechanism of ACR neurotoxicity and thus provide new targets for the prevention and treatment of ACR intoxication.

A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.

BACKGROUND: The congenital disorder of glycosylation associated with ALG1 (ALG1-CDG) is a rare autosomal recessive disease. Due to the deficiency of ß1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi-organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype-phenotype correlation. METHOD: Clinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants. RESULTS: The proband was a 13-month-old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less-conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations. CONCLUSIONS: The case reported herein adds to the mutations identified in ALG1-CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.

Neural Network Based Classification of Breast Cancer Histopathological Image from Intraoperative Rapid Frozen Sections.

Breast cancer is the leading cause of cancer-related mortality in women worldwide. Despite the rapid developments in diagnostic techniques and medical sciences, pathologic diagnosis is still recognized as the gold standard for disease diagnose. Pathologic diagnosis is a time-consuming task performed for pathologists, needing profound professional knowledge and long-term accumulated diagnostic experience. Therefore, the development of automatic and precise histopathological image classification is essential for medical diagnosis. In this study, an improved VGG network was used to classify the breast cancer histopathological image from intraoperative rapid frozen sections. We adopt a transformed loss function by adding a penalty to cross-entropy in our training stage, which improved the accuracy on test data by 4.39%. Laplacian-4 was used for the enhancement of images, which contributes to the improvement of the accuracy. The accuracy of the proposed model on training data and test data reached 88.70% and 82.27%, respectively, which outperforms the original model by 9.39% of accuracy in test data. The process time was less than 0.25 s per image on average. Meanwhile, the heat maps of predictions were given to show the evidential regions in histopathological images, which could drive improvements in the accuracy, speed, and clinical value of pathological diagnoses. In addition to helping with the actual diagnosis, this technology may be a benefit to pathologists, surgeons, and patients. It might prove to be a helpful tool for pathologists in the future.

Activation of the phenylpropanoid pathway in Citrus sinensis collapsed vesicles during segment drying revealed by physicochemical and targeted metabolomics analysis.

Segment drying is a common internal physiological disorder in citrus fruit, and vesicles get granulated or collapsed. This study aimed to probe whether and how the phenylpropanoid metabolism changes in vesicles during collapse of blood orange (Citrus sinensis cv. Tarocco). Vesicle collapse led to a decrease in the content of nutrients and flavonoids, while an increase in lignin content. This disorder was further associated with the increasing enzyme activities and gene expression levels of both the general phenylpropanoid pathway and branch pathway of lignin synthesis, while decreasing enzyme activities and gene expression levels of branch pathway of flavonoids synthesis. Targeted metabolomics analysis of 14 metabolites of the lignin pathway revealed that lignin precursors were accumulated in collapsed vesicles. We provide solid evidence that phenylpropanoid metabolism could be activated, and, intriguingly, metabolic flux may be shuttled to lignin precursors synthesis rather than flavonoids synthesis in vesicles during collapse of blood orange.

Insights into antibiotic stewardship of lake-rivers-basin complex systems for resistance risk control.

Antibiotic stewardship is hindered by a lack of consideration for complicated environmental fate of antibiotics and their role in resistance development, while the current methodology of eco-toxicological risk assessment has not been fully protective against their potential to select for antibiotic resistance. To address this problem, we established a novel methodologic framework to perform comprehensive environmental risk assessment of antibiotics in terms of resistance development, which was based on selection effect, phenotype resistance level, heteroresistance frequency, as well as prevalence and stability of antibiotic resistance genes. We tracked the contribution of antibiotic load reduction to the mitigation of environmental risk of resistance development by fate and transport modeling. The method was instantiated in a lake-river network-basin complex system, taking the Taihu Basin as a case study. Overall, antibiotic load posed no eco-toxicological risk but an average medium-level environmental risk for resistance development in Taihu Lake. The effect of antibiotic load on resistance risk was both seasonal-dependent and category-dependent, while quinolones posed the greatest environmental risk for resistance development. Mass-flow analysis indicated that temporal-spatial variation in hydrological regime and antibiotic fate together exerted a significant effect on antibiotic load in the system. By apportioning antibiotic load to riverine influx, we identified the hotspots for load reduction and predicted the beneficial response of resistance risk under load-reduction scenarios. Our study proposed a risk-oriented strategy of basin-scaled antibiotic load reduction for environmental risk control of resistance development.

The effect of haptoglobin genotype on the association of asymmetric dimethylarginine and DDAH 1 polymorphism with diabetic macroangiopathy.

BACKGROUND: Dimethylarginine dimethylaminohydrolase (DDAH) 1 maintains the bioavailability of nitric oxide by degrading asymmetric dimethylarginine (ADMA). Here, we aimed to investigate the effect of haptoglobin (Hp) genotype on the association of ADMA and DDAH 1 polymorphism with diabetic macroangiopathy. METHODS: In stage 1, 90 Chinese participants with type 2 diabetes were enrolled to measure a panel of targeted metabolites, including ADMA, using tandem mass spectrometry (BIOCRATES AbsoluteIDQ™ p180 kit). In stage 2, an independent cohort of 2965 Chinese patients with type 2 diabetes was recruited to analyze the effect of Hp genotype on the association between DDAH 1 rs233109 and diabetic macroangiopathy. Hp genotypes were detected using a validated assay based on the TaqMan method. DDAH 1 rs233109 was genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy using the MassARRAY platform. RESULTS: In stage 1, serum ADMA levels correlated with common Hp genotypes (ß ± SE = - 0.049 ± 0.023, P = 0.035), but not with diabetic macroangiopathy (P = 0.316). In stage 2, the distribution of DDAH 1 rs233109 genotype frequencies was 15% (CC), 47% (TC), and 38% (TT), which was in Hardy-Weinberg equilibrium (P = 0.948). A significant Hp genotype by rs 233109 genotype interaction effect on diabetic macroangiopathy was found (P = 0.017). After adjusting for confounders, patients homozygous for rs233109 CC were more likely to develop diabetic macroangiopathy than those carrying TT homozygotes in the Hp 2-2 subgroup [odds ratio = 1.750 (95% confidence interval, 1.101-2.783), P = 0.018]. CONCLUSION: Hp genotype affects the association between DDAH 1 rs233109 and diabetic macroangiopathy in Chinese patients with type 2 diabetes.

Accurate Diagnosis and Survival Prediction of Bladder Cancer Using Deep Learning on Histological Slides.

(1) Background: Early diagnosis and treatment are essential to reduce the mortality rate of bladder cancer (BLCA). We aimed to develop deep learning (DL)-based weakly supervised models for the diagnosis of BLCA and prediction of overall survival (OS) in muscle-invasive bladder cancer (MIBC) patients using whole slide digitized histological images (WSIs). (2) Methods: Diagnostic and prognostic models were developed using 926 WSIs of 412 BLCA patients from The Cancer Genome Atlas cohort. We collected 250 WSIs of 150 BLCA patients from the Renmin Hospital of Wuhan University cohort for external validation of the models. Two DL models were developed: a BLCA diagnostic model (named BlcaMIL) and an MIBC prognostic model (named MibcMLP). (3) Results: The BlcaMIL model identified BLCA with accuracy 0.987 in the external validation set, comparable to that of expert uropathologists and outperforming a junior pathologist. The C-index values for the MibcMLP model on the internal and external validation sets were 0.631 and 0.622, respectively. The risk score predicted by MibcMLP was a strong predictor independent of existing clinical or histopathologic indicators, as demonstrated by univariate Cox (HR = 2.390, p < 0.0001) and multivariate Cox (HR = 2.414, p < 0.0001) analyses. The interpretability of DL models can help in the analysis of critical regions associated with tumors to enrich the information obtained from WSIs. Furthermore, the expression of six genes (ANAPC7, MAPKAPK5, COX19, LINC01106, AL161431.1 and MYO16-AS1) was significantly associated with MibcMLP-predicted risk scores, revealing possible potential biological correlations. (4) Conclusions: Our study developed DL models for accurately diagnosing BLCA and predicting OS in MIBC patients, which will help promote the precise pathological diagnosis of BLCA and risk stratification of MIBC to improve clinical treatment decisions.