Mapping Blood Lead Levels in China during 1980-2040 with Machine Learning.

Lead poisoning is globally concerning, yet limited testing hinders effective interventions in most countries. We aimed to create annual maps of county-specific blood lead levels in China from 1980 to 2040 using a machine learning model. Blood lead data from China were sourced from 1180 surveys published between 1980 and 2022. Additionally, regional statistical figures for 15 natural and socioeconomic variables were obtained or estimated as predictors. A machine learning model, using the random forest algorithm and 2973 generated samples, was created to predict county-specific blood lead levels in China from 1980 to 2040. Geometric mean blood lead levels in children (i.e., age 14 and under) decreased significantly from 104.4 µg/L in 1993 to an anticipated 40.3 µg/L by 2040. The number exceeding 100 µg/L declined dramatically, yet South Central China remains a hotspot. Lead exposure is similar among different groups, but overall adults and adolescents (i.e., age over 14), females, and rural residents exhibit slightly lower exposure compared to that of children, males, and urban residents, respectively. Our predictions indicated that despite the general reduction, one-fourth of Chinese counties rebounded during 2015-2020. This slower decline might be due to emerging lead sources like smelting and coal combustion; however, the primary factor driving the decline should be the reduction of a persistent source, legacy gasoline-derived lead. Our approach innovatively maps lead exposure without comprehensive surveys.

Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Piperlongumine inhibits esophageal squamous cell carcinoma in vitro and in vivo by triggering NRF2/ROS/TXNIP/NLRP3-dependent pyroptosis.

Pyroptosis, a type of programmed cell death, is characterized by cell swelling with bubbles, and the release of inflammatory cell cytokines. Piperlongumine (PL) is a natural bioactive product extracted from Piper longum L, which can effectively exert anti-tumor activities in cancer. However, the effects and the exact molecular mechanisms of PL in esophageal squamous cell carcinoma (ESCC) remain unclear. This research aimed to investigate the role and mechanism of PL on ESCC in vitro and in vivo. In vitro, the MTT results showed that the IC50 of PL in ESCC cells was 28.55 µM. Moreover, PL significantly suppressed malignant behavior by promoting pyroptosis of ESCC cells by inhibiting proliferation, migration, invasion, and colony formation of KYSE-30 cells, up-regulating expressions of ASC, Cleaved-caspase-1, NLRP3, and GSDMD, while inducing the generation of ROS. Further, NRF2 knockdown promoted TXNIP expression, while overexpression of NRF2 inhibited TXNIP expression. However, after PL treatment, this effect was reversed. In addition, PL significantly inhibited the malignant behavior of ESCC cells while the inhibitory effects were reversed by DMF (NRF2 activator) or NAC (ROS eliminator) treatment. Finally, PL markedly increased expressions of ASC, Cleaved-caspase-1, NLRP3, GSDMD, and the generation of ROS while the effects were reversed by TXNIP knockdown or RUS (TXNIP inhibitor) treatment. In vivo, the KYSE-30 xenograft model confirmed that PL inhibited the growth of ESCC transplanted tumors by promoting cell pyroptosis. In conclusion, the results suggested that PL inhibited the malignant behavior of ESCC cells in vitro and tumorigenesis of ESCC in vivo by inhibiting NRF2 and promoting ROS-TXNIP-NLRP3-mediated pyroptosis.

Exploring the nonlinear partitioning mechanism of volatile organic contaminants between soil and soil vapor using machine learning.

Traditional phase equilibrium models usually depend on simplified assumptions and empirical parameters, which are difficult to obtain during regular site investigations. As a result, they often under- or over-estimate soil vapor concentrations for assessing the risks of volatile organic compound (VOC)-contaminated sites. In this study, we develop several machine learning models to predict soil vapor concentrations using 2225 soil-soil vapor data pairs collected from seven contaminated sites in northern China. Compared to the classic dual equilibrium desorption model, the random forest (RF) model can provide more accurate predictions of soil vapor concentrations by at least 1-2 orders of magnitude. Among the employed covariates, soil concentration and organic carbon-water partition coefficient are two of the most significant explanatory covariates affecting soil vapor concentrations. Further examination of the developed RF model reveals the phase equilibrium behavior of VOCs in soil is that: the soil vapor concentration increases with soil concentration at different rates in the first two intervals but remains almost unchanged in the last interval; the solid-vapor partitioning interface may still exist at up to 15% mass water content in our simulations. These findings can help site investigators perform more accurate risk assessments at VOC-contaminated sites.

Estimation of Bone Mineral Density in the Femoral Neck and Lumbar Spine using Texture Analysis of Chest and Pelvis Computed Tomography Hounsfield Unit.

OBJECTIVE: This study aimed to establish an academic basis for using a computed tomography (CT) model for predicting osteoporosis in the clinical setting by illustrating the effectiveness of morphometric texture analysis. We introduce texture analysis and quantitative approaches using CT Hounsfield units (HU) to screen osteoporosis. METHODS: From March 6th, 2013, to August 11th, 2020, a total of 4,333 cases (1,766 patients) were included in the study. After applying exclusion criteria concerning the patient status and scan interval between CT and DXA, we selected only 1,647 samples (736 patients) and analyzed both their CT and DXA bone mineral density (BMD) results. BMD was measured in the femoral neck and L1 spine body. A region of interest (ROI) was extracted from each patient's CT as the maximum trabecular area of the L1 spine body and femoral neck. A total of 45 texture features were extracted from every ROI using gray-level co-occurrence matrices. Machine-learning techniques, including linear regression (LR) and artificial neural network (ANN), were applied to predict BMD. RESULTS: We assigned samples to (1) Set 1 (857 lumbar spine samples in chest model, L1 spine DXA BMD), (2) Set 2 (392 lumbar spine samples in lumbar spine CT model, L1 spine DXA BMD), (3) Set 3 (1,249 lumbar spine samples in both chest and lumbar spine CT model, L1 spine DXA BMD), (4) Set 4 (398 femoral neck samples in hip and pelvis CT model, femoral neck DXA BMD), and (5) Set 5 (a total of 1,647 samples). When we applied LR, the correlation coefficients between estimated and reference values for Sets 1, 2, 3, and 4 were 0.783, 0.784, 0.757, and 0.652, respectively. For total samples (Set 5), LR and ANN provided correlation coefficients of 0.707 and 0.782, respectively. CONCLUSION: The modality using morphometric texture analysis with CT HU can be an additional diagnostic tool for osteoporosis and an alternative for DXA.

Hepatic arterial infusion chemotherapy versus transarterial chemoembolization for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: We carried out a systematic review and meta-analysis to assess the safety and effectiveness of hepatic arterial infusion chemotherapy (HAIC) compared with transarterial chemoembolization (TACE) for patients with unresectable hepatocellular carcinoma (uHCC). METHODS: Eligible studies were searched by MEDLINE, the Cochrane Library, Embase, and Web of Science from January 1995 to January 2022, investigating eligible literature comparing HAIC and TACE for patients with HCC. The main outcome measures included progression-free survival (PFS), overall survival (OS), adverse events (AEs), objective response rate (ORR), and diseases control rate (DCR). RESULTS: Eight literature and 1028 patients were enrolled in this meta-analysis. The pooled PFS, OS, ORR, and DCR were HR = 0.89 (95% CI, 0.81-0.98), HR = 0.84 (95% CI, 0.75-0.93), OR = 2.77 (95% CI, 2.01-3.80), and OR = 4.64 (95% CI, 2.40-8.99), respectively. The adverse events of HAIC were lower than TACE. CONCLUSION: Our meta-analysis revealed that HAIC can achieve a better effect and survival benefits than TACE in patients with uHCC.

Newly found variations of the right posterior portal vein identified radiologically in 1,003 Chinese patients: a cross-sectional study.

Background: The anatomy of the right posterior portal vein (RPPV) plays an important role in planning hepatic resection, living transplantation and interventional radiological procedures, yet the incidence of variations of RPPV without a common trunk in Chinese persons is still unclear. Therefore, we conducted this study and discussed its clinical implications. Methods: A retrospective analysis of multidetector computed tomography (MDCT) scans was performed in 1,933 patients with various abdominal pathologies between September 28, 2018 through May 23, 2019. After excluding 930 patients, a total of 1,003 patients were included in this study. Variations of the RPPV without a common trunk were classified according to classification standards. Results: A total of 1,003 patients were included. RPPV without a common trunk was found in 216 (21.54%, 216/1,003) patients. Among them, we identified three variations of the origin from the right portal vein (RPV): first separate origin of P6, P7, or simultaneous separate origin of P6 and P7, and the incidences of these three variations were 1.50% (15/1,003), 6.58% (66/1,003) and 13.46% (135/1,003), respectively. Among 1,003 patients included in this study, 787 patients (78.46%, 787/1,003) showed that RPPV normally divided into P6 and P7 branches. Conclusions: Variations of the RPPV without a common trunk were not rare in Chinese population. Knowledge of this anatomic variation of the RPPV is extremely important for hepatic and transplant surgeons and interventional radiologists.

Succinate and inosine coordinate innate immune response to bacterial infection.

Macrophages restrict bacterial infection partly by stimulating phagocytosis and partly by stimulating release of cytokines and complement components. Here, we treat macrophages with LPS and a bacterial pathogen, and demonstrate that expression of cytokine IL-1ß and bacterial phagocytosis increase to a transient peak 8 to 12 h post-treatment, while expression of complement component 3 (C3) continues to rise for 24 h post-treatment. Metabolomic analysis suggests a correlation between the cellular concentrations of succinate and IL-1ß and of inosine and C3. This may involve a regulatory feedback mechanism, whereby succinate stimulates and inosine inhibits HIF-1α through their competitive interactions with prolyl hydroxylase. Furthermore, increased level of inosine in LPS-stimulated macrophages is linked to accumulation of adenosine monophosphate and that exogenous inosine improves the survival of bacterial pathogen-infected mice and tilapia. The implications of these data suggests potential therapeutic tools to prevent, manage or treat bacterial infections.

Database examination, multivariate analysis, and machine learning: Predictions of vapor intrusion attenuation factors.

Traditional soil vapor intrusion (VI) models usually rely on preset conceptual scenarios, simplifying the influences of limiting environmental covariates in determining indoor attenuation factors relative to subsurface sources. This study proposed a technical framework and applied it to predict VI attenuation factors based on site-specific parameters recorded in the United States Environmental Protection Agency (USEPA)'s and the California Environmental Protection Agency (CalEPA)'s VI databases, which can overcome the limitations of traditional VI models. We examined the databases with multivariate analysis of variance to identify effective covariates, which were then employed to develop VI models with three machine learning algorithms. The results of multivariate analysis show that the effective covariates include soil texture, source depth, foundation type, lateral separation, surface cover, and land use. Based on these covariates, the predicted attenuation factors by these new models are generally within one order of magnitude of the observations recorded in the databases. Then the developed models were employed to generate the generic indoor attenuation factors to subsurface vapor (i.e., the 95th percentile of selected dataset), the values of which are different between the USEPA's and CalEPA's databases by one order of magnitude, although comparable to recommendations by the USEPA and literature, respectively. Such a difference may reflect the significant regional disparity in factors such as building structures or operational conditions (e.g., indoor air exchange rates), which necessitates generating generic VI attenuation factors on a state-specific basis. This study provides an alternative for VI risk screens on a site-specific basis, especially in states with a good collection of datasets. Although the proposed technical framework is used for the VI databases, it can be equally applied to other environmental science problems.

Postoperative clinical outcomes and radiological healing according to deep and superficial layer detachment in first facet involving subscapularis tendon tear.

BACKGROUND: Subscapularis tendon insertion at the first facet has separate layers (deep and superficial). The purpose of this study is to evaluate postoperative clinical outcomes and radiological healing according to each layer of detachment in the first facet involving subscapularis tendon tear. METHODS: Eighty-three patients who underwent arthroscopic repair due to First facet involving the scapularis tendon tear accompanying small to medium sized posterosuperior cuff tear were classified into three groups (group A: deep layer partial detachment, group B: deep layer complete detachment, but no superficial layer detachment, and group C: deep layer and superficial layer complete detachment). Subscapularis tendon healing was evaluated using computed tomography arthrogram and clinical result was evaluated using American Shoulder and Elbow Surgeons (ASES) shoulder score, Constant score and University of California Los Angeles (UCLA) shoulder score. RESULTS: Retear rate of the subscapularis tendon was 2.2%, 18.2%, and 33.3% in group A, group B, and group C, respectively. These rates showed statistically significant difference among the three groups, which were classified by deep and superficial layer detachment in the first facet (p=0.003). Group A showed significant difference in subscapularis tendon healing compared with group B and group C (p=0.018 and p<0.001, respectively), but there was no statistical difference between group B and group C (p=0.292). Regarding clinical outcomes, there was no significant difference among three groups in ASES and UCLA score at final follow-up (p=0.070 and p=0.106, respectively). CONCLUSIONS: Complete detachment of deep layer may be related with retear occurrence regardless with detachment of superficial layer, but clinical outcome may not be related with each layer detachment in the first facet involving subscapularis tendon tear.

Characterization of vapor intrusion sites with a deep learning-based data assimilation method.

Appropriate characterization of site soils is essential for accurate risk assessment of soil vapor intrusion (VI). In this study, we develop a data assimilation method based on deep learning (i.e., ES(DL)) to estimate the distribution of soil properties with limited measurements. Two hypothetical VI scenarios are employed to demonstrate site characterization using the ES(DL) method, followed by validation with a laboratory sandbox experiment and then one practical site application. The results show that the ES(DL) method can provide reasonable estimates of the effective diffusion coefficient distributions and corresponding emission rates (into the building) in all four cases. The spatial heterogeneity of site soils can be characterized by considerably enough measurements (i.e., 15 sampling points in the first hypothetical case); otherwise, layered characterization is recommended at the cost of neglecting horizontal heterogeneity of site soils. This new method provides an alternative to characterize VI sites with relatively fewer sampling efforts.

Sleep quality, anxiety and depression in advanced lung cancer: patients and caregivers.

OBJECTIVE: To investigate the clinical implications of sleep quality, anxiety and depression in patients with advanced lung cancer (LC) and their family caregivers (FCs). METHODS: A total of 98 patients with advanced LC and their FCs (n=98) were recruited from the Oncology Department in Nanfang Hospital. The Pittsburgh Sleep Quality Index (PSQI), consisting of seven components that evaluate subjective sleep quality, sleep latency, duration of sleep, sleep efficiency, sleep disturbances, sleep medication usage and daytime dysfunction, was used to assess sleep quality. Using the tool of Zung Self-rating Anxiety Scale (SAS) and Zung Self-rating Depression Scale (SDS), we tested the patients' status of anxiety and depression, respectively. RESULTS: The prevalences of poor sleep quality, anxiety and depression in patients were 56.1%, 48.9% and 56.1%, respectively, while those in FCs were 16.3%, 32.6% and 25.5%, respectively. Patients had higher PSQI, SAS and SDS scores than did FCs (p<0.05). Significant correlations were found between the patients' and FCs' scores of PSQI/SAS/SDS (p<0.05). Multivariate Cox regression analyses indicated that sleep disturbances in patients (HR 0.413, 95% CI 0.21 to 0.80, p=0.01) and the global PSQI score of FCs (HR 0.31, 95% CI 0.14 to 0.71, p=0.00) were independent risk factors for patients' first-line progression-free survival (PFS). Moreover, patients' sleep latency (HR 2.329, 95% CI 1.36 to 3.96, p=0.00) and epidermal growth factor receptor mutations (HR 1.953, 95% CI 1.12 to 3.38, p=0.01) were significant prognostic factors for their overall survival (OS). CONCLUSIONS: We demonstrated that presence of sleep disturbances in patients with advanced LC and the global PSQI Score of their FCs may be risk predictors for patients' poor first-line PFS. Patients' sleep latency was a potential risk factor for their OS.

Sex difference in lipid levels in first-diagnosed drug-naïve depression patients: A case-control and 12-weeks follow-up study.

AIM: Patients with depression have a high prevalence of developing dyslipidemia. In this study, we aim to investigate the difference of serum lipids, including total cholesterol (TCH), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), between the depressed patients and healthy controls. Sex differences in lipids and their psychological correlations were also included. METHODS: The study included 56 healthy controls (males/females = 26/30) and 110 first-diagnosed drug-naïve outpatients (males/females = 35/75). A total of 42 patients (males/females = 14/28) were followed for 3 months. RESULTS: A significant difference was found in TCH and LDL-C among healthy control and patients. Interestingly, female patients with first-diagnosed, drug-naïve depression had lower atherogenic indices than male patients. After 3 months of antidepressants therapy, female patients exhibited detrimental changes in serum lipids, namely increased TG and atherogenic index. Moreover, correlation analysis showed significant correlations between changes of depression inventory (HAMD and BDI) score and serum lipids (TCH, HDL-C) in depressed patients. CONCLUSION: We found that dyslipidemia was more common in female patients with depression during therapy with antidepressants. Moreover, the altered serum lipids and atherogenic index might be a hallmark of female patients. Further investigation of sex differences in lipid metabolism of depression is warranted.

Glutamine promotes antibiotic uptake to kill multidrug-resistant uropathogenic bacteria.

The prevalence of multidrug-resistant bacteria has been increasing rapidly worldwide, a trend that poses great risk to human and animal health and creates urgent need for pharmaceutical and nonpharmaceutical approaches to stop the spread of disease due to antimicrobial resistance. Here, we found that alanine, aspartate, and glutamate metabolism was inactivated, and glutamine was repressed in multidrug-resistant uropathogenic Escherichia coli using a comparative metabolomics approach. Exogenous glutamine promoted ß-lactam­, aminoglycoside-, quinolone-, and tetracycline-induced killing of uropathogenic E. coli and potentiated ampicillin to eliminate multidrug-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella peneumoniae, Edwardsiella tarda, Vibrio alginolyticus, and Vibrio parahaemolyticus. Glutamine-potentiated ampicillin-mediated killing was effective against biofilms of these bacteria in a mouse urinary tract infection model and against systemic infection caused by E. coli, P. aeruginosa, A. baumannii, or K. peneumoniae in a mouse model. Exogenous glutamine stimulated influx of ampicillin, leading to the accumulation of intracellular antibiotic concentrations that exceeded the amount tolerated by the multidrug-resistant bacteria. Furthermore, we demonstrated that exogenous glutamine promoted the biosynthesis of nucleosides including inosine, which in turn interacted with CpxA/CpxR and up-regulated OmpF. We validated the physiological relevance of the mechanism by showing that loss of purF, purH, cpxA, or ompF elevated antibiotic resistance in antibiotic-sensitive strains. In addition, glutamine retarded the development of ampicillin resistance. These results may facilitate future development of effective approaches for preventing or managing chronic, multidrug-resistant bacterial infections, bacterial persistence, and difficult-to-treat bacterial biofilms.

Open Characterization of Vaping Liquids in Canada: Chemical Profiles and Trends.

Currently, there is a lack of comprehensive data on the diversity of chemicals present in vaping liquids. To address this gap, a non-targeted analysis of 825 vaping liquids collected between 2017 and 2019 from Canadian retailers was conducted. Prior to mass spectrometry analysis, samples were diluted 1:500 v/v with methanol or acetonitrile. Chemical compound separation and analysis was carried out using gas chromatography and triple quadrupole mass spectrometry (GC-MS/MS) systems operated in the full scan mode and mass range of 35-450 m/z. Mass spectrum for each sample was obtained in electron ionization at 70 eV and processed. Non-targeted identification workflow included use of automated mass spectral deconvolution and identification system (AMDIS), where required, as well as a number of commercially available spectral libraries. In order to validate identities, an in-house database of expected compounds previously detected in vaping liquids was used along with genuine analytical standards for compounds of interest. This resulted in a dataset of over 1,500 unique detected chemicals. Approximately half of these chemical compounds were detected only once in a single product and not in multiple products analyzed. For any sample analyzed, on average, 40% of the chemical constituents appeared to have flavouring properties. The remainder were nicotine and related alkaloids, processing, degradation or indirect additives, natural extractives and compounds with unknown roles. Data published here from the project on the Open Characterization of vaping liquids is unique as it offers a detailed understanding of products' flavour chemical profiles, the presence and frequency of chemicals of potential health concern, as well as trends and changes in products' chemical complexity over a three-year period. Non-targeted chemical surveillance such as this present valuable tools to public health officials and researchers in responding to emergent issues such as vaping associated lung injury or informing chemical based strategies which may be aimed at addressing product safety or appeal.

Myo-Inositol Restores Tilapia's Ability Against Infection by Aeromonas sobria in Higher Water Temperature.

Bacterial infection presents severe challenge to tilapia farming, which is largely influenced by water temperature. However, how water temperature determines tilapias' survival to infection is not well understood. Here, we address this issue from the perspective of metabolic state. Tilapias were more susceptible to Aeromonas sobria infection at 33°C than at 18°C, which is associated with differential metabolism of the fish. Compared to the metabolome of tilapia at 18°C, the metabolome at 33°C was characterized with increased an tricarboxylic acid cycle and a reduced level of myo-inositol which represent the most impactful pathway and crucial biomarker, respectively. These alterations were accompanied with the elevated transcriptional level of 10 innate immune genes with infection time, where il-1b, il-6, il-8, and il-10 exhibited a higher expression at 33°C than at 18°C and was attenuated by exogenous myo-inositol in both groups. Interestingly, exogenous myo-inositol inactivated the elevated TCA cycle via inhibiting the enzymatic activity of succinate dehydrogenase and malate dehydrogenase. Thus, tilapias showed a higher survival ability at 33°C. Our study reveals a previously unknown relationship among water temperature, metabolic state, and innate immunity and establishes a novel approach to eliminate bacterial pathogens in tilapia at higher water temperature.

Investigating the role of vadose zone breathing in vapor intrusion from contaminated groundwater.

The fluctuation of the groundwater table can cause upward and downward advection of soil gas within the vadose zone, just like breathing. In this study, we developed a three-dimensional numerical model and used it to investigate the role of vadose zone breathing in vapor intrusion, through which subsurface volatile chemicals migrate into the concerned building at contaminated sites. The developed model was first applied to a sand tank experiment, followed by examining the influences of fluctuation amplitude and period of water table, soil textures, and groundwater level depth. Our results suggest that the indoor pollutant concentration can be increased by about three times with the oscillatory water table of 0.4 m amplitude and 4 d period. Within one cycle of vadose zone breathing, the indoor pollutant concentration is found to vary by about 7 orders of magnitude. The results also show that, compared to the groundwater level depth, the soil texture plays a significant role in determining vapor intrusion risks. Specifically, when soil particles increase from 0.25 mm to 0.44 mm, the indoor pollutant concentration tends to increase and becomes more sensitive to groundwater table fluctuation.

Serine Metabolism Tunes Immune Responses To Promote Oreochromis niloticus Survival upon Edwardsiella tarda Infection.

Overactive immune response is a critical factor triggering host death upon bacterial infection. However, the mechanism behind the regulation of excessive immune responses is still largely unknown, and the corresponding control and preventive measures are still to be explored. In this study, we find that Nile tilapia, Oreochromis niloticus, that died from Edwardsiella tarda infection had higher levels of immune responses than those that survived. Such immune responses are strongly associated with metabolism that was altered at 6 h postinfection. By gas chromatography-mass spectrometry-based metabolome profiling, we identify glycine, serine, and threonine metabolism as the top three of the most impacted pathways, which were not properly activated in the fish that died. Serine is one of the crucial biomarkers. Exogenous serine can promote O. niloticus survival both as a prophylactic and therapeutic upon E. tarda infection. Our further analysis revealed exogenous serine flux into the glycine, serine, and threonine metabolism and, more importantly, the glutathione metabolism via glycine. The increased glutathione synthesis could downregulate reactive oxygen species. Therefore, these data together suggest that metabolic modulation of immune responses is a potential preventive strategy to control overactive immune responses. IMPORTANCE Bacterial virulence factors are not the only factors responsible for host death. Overactive immune responses, such as cytokine storm, contribute to tissue injury that results in organ failure and ultimately the death of the host. Despite the recent development of anti-inflammation strategies, the way to tune immune responses to an appropriate level is still lacking. We propose that metabolic modulation is a promising approach in tuning immune responses. We find that the metabolomic shift at as early as 6 h postinfection can be predictive of the consequences of infection. Serine is a crucial biomarker whose administration can promote host survival upon bacterial infection either in a prophylactic or therapeutic way. Further analysis demonstrated that exogenous serine promotes the synthesis of glutathione, which downregulates reactive oxygen species to dampen immune responses. Our study exemplifies that the metabolite(s) is a potential therapeutic reagent for overactive immune response during bacterial infection.

Effect of SGLT-2 Inhibitors on Non-alcoholic Fatty Liver Disease among Patients with Type 2 Diabetes Mellitus: Systematic Review with Meta-analysis and Trial Sequential Analysis of Randomized Clinical Trials.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) is a common problem associated with obesity and type 2 diabetes mellitus (T2DM). There have been anecdotal reports of the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2Is) in improving liver function parameters in those with concomitant T2DM and NAFLD/NASH. We sought to systematically evaluate the evidence of SGLT2Is in improving liver function parameters in T2DM patients with NAFLD, considering the risks of random error based on trial sequential analysis (TSA). We also performed a meta-analysis based on a random-effects model. METHODS: A systematic literature search was performed using the Medline, Cochrane, and Embase databases from inception to 20 October 2018. Primary outcome for meta-analyses was the changes in hepatic enzyme levels (alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase). We also performed a meta-analysis on changes in insulin resistance, glycemic, and lipid parameters using SGLT2Is as a secondary objective. RESULTS: Eight eligible randomized controlled studies were eligible for analysis. Meta-analysis showed the efficacy of two SLT2Is, dapagliflozin, and canagliflozin in reducing these enzymes level. TSA showed that canagliflozin significantly reduced the gamma-glutamyl transpeptidase level by weighted mean difference (-5.474, 95% confidence interval (CI): -6.289??-4.659) compared to others comparators, and the evidence is conclusive. Dapagliflozin also had a statistically significant reduction in glycated hemoglobin, which is a parameter of glycemic control and homeostatic model assessment for insulin sensitivity (HOMA-IR), which is a parameter of insulin sensitivity by a weight mean difference, -0.732 (95% CI: -1.087??-0.378) and -0.804 (95% CI: -1.336??0.272), respectively. CONCLUSIONS: This study indicated that canagliflozin effectively improves liver function parameters among patients with diabetes, while dapagliflozin is more effective in improving glycemic indices and insulin sensitivity.

Enterovirus D68 in hospitalized children with respiratory symptoms in Guangdong from 2014 to 2018: Molecular epidemiology and clinical characteristics.

BACKGROUND: Enterovirus D68 (EV-D68) is an emerging pathogen in humans. EV-D68 causes a wide range of respiratory symptoms in children and has the propensity to cause severe complications. EV-D68 outbreaks are rarely investigated in mainland China. Therefore, in this study, we aimed to investigate the prevalence of EV-D68 in children and to describe the clinical manifestations as well as the phylogeny of EV-D68 in Guangdong Province from 2014 to 2018. METHODS: Nasopharyngeal swabs were collected from hospitalized children with respiratory symptoms and screened for respiratory pathogens by fluorescence quantitative PCR and culture. The EV-positive samples were subsequently typed by sequencing the 5'-untranslated region and EV-D68-specific VP1 capsid gene. A phylogenetic tree was constructed by the maximum-likelihood method based on the VP1 gene using ClustalW. RESULTS: A total of 1,498 (59.8%) out of 2,503 children were screened positive for ≥1 virus species. Among the 158 (6.31%) EV-positive samples, 17 (0.68%) were identified as EV-D68. Most EV-D68 cases (n = 14) were diagnosed with pneumonia and bronchial pneumonia. No deaths were found in EV-D68 cases. Wheezing occurred in EV-D68 cases more frequently (70.59% vs. 43.26%, P = 0.040) than that of other EVs. All the EV-D68 were of clade B3, which were highly similar to the strains circulating in China. CONCLUSION: EV-D68 was the predominant enterovirus type in hospitalized children with respiratory symptoms in Guangdong Province. All the EV-D68 strains belong to clade B3. The development of diagnostic tools is warranted in order to monitor EV-D68 infections in China.