Environmental stressors altered the groundwater microbiome and nitrogen cycling: A focus on influencing mechanisms and pathways.

Nitrogen cycling, as an important biogeochemical process in groundwater, strongly impacts the energy and matter flow of groundwater ecology. Phthalate esters (PAEs) were screened as key environmental stressors in the groundwater of Beijing, contributing to the alteration of microbial community structure and functions; thus, it could be deduced that these stressors might influence nitrogen cycling that is almost exclusively mediated by microorganisms. Identification of the influences of PAEs on groundwater nitrogen cycling and exploration of the potential influence mechanisms and pathways are vital but still challenging. This study explored the influence mechanisms and pathways of the environmental stressor PAE on nitrogen cycling in groundwater collected from a typical monitoring station in Beijing based on high-throughput sequencing and bioinformatics analysis combined with mediation analysis methods. The results suggested that among the 5 detected PAEs, dimethyl phthalate and diethyl phthalate significantly negatively impacted nitrogen cycling processes, especially nitrogen fixation and denitrification processes (p < 0.05), in groundwater. Their influences were fully or partially mediated by functional microorganisms, particularly assigned keystone genera (such as Dechloromonas, Aeromonas and Noviherbaspirillum), whose abundance was significantly inhibited by these PAEs via dysregulation of carbohydrate metabolism and activation of defense mechanisms. These findings confirmed that the influences of environmental stressors PAEs on nitrogen cycling in groundwater might be mediated by the "PAE stress-groundwater microbiome-nitrogen cycling alteration" pathway. This study may advance the understanding of the consequences of environmental stressors on groundwater ecology and support the ecological hazard assessment of groundwater stressors.

Sources and transformation of nitrogen in shallow aquifers with progressive water table recovery using geochemical and isotopic approaches.

Groundwater level recovery has a significant effect on the sources and transformation of nitrogen in groundwater, but there are still few studies on the influences of the water table on the sources and transformation of nitrogen in groundwater using field data. In this study, the changes in groundwater level, geochemical composition, and isotopic signatures of NO3- and NH4+ during a period of groundwater level recovery at a pilot site were analyzed in detail. The water table underwent progressive recovery of almost 1.6 m in 16 months. At a depth of 5.5 m below the surface, both low NH4+ and high NO3- appeared in the groundwater, whereas below that depth, both high NH4+ and low NO3- simultaneously appeared in the groundwater. The main sources of NO3- were manure and septic waste, and NH4+ fertilizers. The main sources of NH4+ were mineral fertilizers. The main transformation process were nitrification and denitrification at a depth of 5.5 m below the surface; below that depth, the main transformation processes were denitrification and dissimilatory nitrate reduction to ammonium (DNRA). This study provides a theoretical understanding of the relationship between the changing water table and nitrogen in groundwater level recovery areas.

Cross-domain policy adaptation with dynamics alignment.

The implementation of robotic reinforcement learning is hampered by problems such as an unspecified reward function and high training costs. Many previous works have used cross-domain policy transfer to obtain the policy of the problem domain. However, these researches require paired and aligned dynamics trajectories or other interactions with the environment. We propose a cross-domain dynamics alignment framework for the problem domain policy acquisition that can transfer the policy trained in the source domain to the problem domain. Our framework aims to learn dynamics alignment across two domains that differ in agents' physical parameters (armature, rotation range, or torso mass) or agents' morphologies (limbs). Most importantly, we learn dynamics alignment between two domains using unpaired and unaligned dynamics trajectories. For these two scenarios, we propose a cross-physics-domain policy adaptation algorithm (CPD) and a cross-morphology-domain policy adaptation algorithm (CMD) based on our cross-domain dynamics alignment framework. In order to improve the performance of policy in the source domain so that a better policy can be transferred to the problem domain, we propose the Boltzmann TD3 (BTD3) algorithm. We conduct diverse experiments on agent continuous control domains to demonstrate the performance of our approaches. Experimental results show that our approaches can obtain better policies and higher rewards for the agents in the problem domains even when the dataset of the problem domain is small.

Asymmetric synthesis of the sex pheromone of the apple leafminer, Lyonetia prunifoliella.

Lyonetia prunifoliella is a significant pest in orchards and damages apple. The sex pheromones of this pest were prepared via a new and concise method. The central to our method were Evans' chiral auxiliaries, the addition of chiral Grignard reagent to aldehyde and Wittig coupling.

Screening of hazardous groundwater pollutants responsible for microbial ecological consequences by integrated nontargeted analysis and high-throughput sequencing technologies.

Organic contaminants, especially hydrophobic organic contaminants (HOCs), pose potential ecological threats even at environmental concentrations. Characterization of HOC profiles and identification of key environmental stressors are vital but still challenging in groundwater quality management. In this study, a strategy for identifying the key environmental stressors among HOCs in groundwater based on integrated chemical monitoring technologies and microbial ecology analysis methods was proposed and applied to typical groundwater samples. Specifically, the characteristics of HOCs were systematically analyzed based on nontargeted and targeted approaches, and microbial community assembly and specific biomarker analysis were combined to determine the major ecological processes and key environmental stressors. The results showed that a total of 234 HOCs were detected in groundwater collected from Tongzhou, Beijing; among them, phthalate esters (PAEs) were screened out as key environmental stressors, considering that they made relatively higher microbial ecology contributions. Furthermore, their influences on the structure and function of the groundwater microbial community were evaluated by adopting high-throughput sequencing and bioinformatics analysis technologies. These findings confirmed PAEs as vital determinants driving microbial assembly, shifting community structure, and regulating community function in groundwater; in addition, the findings validated the feasibility and suitability of the proposed strategy.

Digital Image Restoration Based on Multicontour Batch Scanning.

In order to explore the problem of digital image restoration, the authors propose a research on digital image restoration based on multicontour batch scanning. This method recommends key technical problems and solutions based on information represented by multicontour batch scans, exploring research in digital image restoration. Research has shown that the research on digital image restoration based on multicontour batch scanning is about 40% more efficient than traditional methods. Aiming at the new application of digital image inpainting, the application of image inpainting in image compression is studied in depth, and the technical principles of image inpainting and image compression are complemented.

Paeoniflorin prevents aberrant proliferation and differentiation of intestinal stem cells by controlling C1q release from macrophages in chronic colitis.

The pathological features of inflammatory bowel disease necessitate therapeutic strategies aimed at restoring intestinal mucosal barrier function in addition to controlling inflammation. Paeoniflorin, a bioactive herbal constituent isolated from the root of Paeonia albiflora Pall, has been reported to protect against acute colitis in mice. However, the direct molecular target of paeoniflorin in preventing colitis remains elusive. Here, we evaluated the therapeutical effects of Paeoniflorin using IL-10-/- chronic colitis model, and explored the precise mechanism of action involved. Our results demonstrated that intragastric administration of Paeoniflorin significantly ameliorated inflammatory response and restored the aberrant intestinal proliferation and differentiation in IL-10-/-colitis mice. By utilizing a chemical biology approach, we identified C1qa, a crucial component of C1q, is the direct target of Paeoniflorin. Binding of Paeoniflorin to C1qa prevented the cleavage of C1q on macrophages, resulting in the aggregation of surface membrane-anchored C1q and the diminished C1q secretion. The excessive surface membrane-anchored C1q significantly enhanced the phagocytic capability of macrophages and promoted the elimination of infiltrated bacteria and inflammatory cells in mouse colon. The reduced C1q secretion conferred by Paeoniflorin dampened Wnt/ß-catenin signaling activation, thereby rectifying the aberrant proliferation and differentiation of intestinal stem cells (ISCs). In summary, our study demonstrates that Paeoniflorin can orchestrate mucosal healing and intestinal inflammation elimination through C1q-bridged macrophage-ISCs crosstalk, highlighting a novel strategy to treat chronic colitis by restoring mucosal homeostasis via targeting C1q.

Shifts in microbial community structure and function in polycyclic aromatic hydrocarbon contaminated soils at petrochemical landfill sites revealed by metagenomics.

Investigations of the microbial community structures, potential functions and polycyclic aromatic hydrocarbon (PAH) degradation-related genes in PAH-polluted soils are useful for risk assessments, microbial monitoring, and the potential bioremediation of soils polluted by PAHs. In this study, five soil sampling sites were selected at a petrochemical landfill in Beijing, China, to analyze the contamination characteristics of PAHs and their impact on microorganisms. The concentrations of 16 PAHs were detected by gas chromatography-mass spectrometry. The total concentrations of the PAHs ranged from ND to 3166.52 µg/kg, while phenanthrene, pyrene, fluoranthene and benzo [ghi]perylene were the main components in the soil samples. According to the specific PAH ratios, the PAHs mostly originated from petrochemical wastes in the landfill. The levels of the total toxic benzo [a]pyrene equivalent (1.63-107.73 µg/kg) suggested that PAHs might result in adverse effects on soil ecosystems. The metagenomic analysis showed that the most abundant phyla in the soils were Proteobacteria and Actinobacteria, and Solirubrobacter was the most important genus. At the genus level, Bradyrhizobium, Mycobacterium and Anaeromyxobacter significantly increased under PAH stress. Based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, the most abundant category of functions that are involved in adapting to contaminant pressures was identified. Ten PAH degradation-related genes were significantly influenced by PAH pressure and showed correlations with PAH concentrations. All of the results suggested that the PAHs from the petrochemical landfill could be harmful to soil environments and impact the soil microbial community structures, while microorganisms would change their physiological functions to resist pollutant stress.

Polycyclic aromatic hydrocarbon and n-alkane pollution characteristics and structural and functional perturbations to the microbial community: a case-study of historically petroleum-contaminated soil.

Characterization of the typical petroleum pollutants, polycyclic aromatic hydrocarbons (PAHs) and n-alkanes, and indigenous microbial community structure and function in historically contaminated soil at petrol stations is critical. Five soil samples were collected from a petrol station in Beijing, China. The concentrations of 16 PAHs and 31 n-alkanes were measured by gas chromatography-mass spectrometry. The total concentrations of PAHs and n-alkanes ranged from 973 ± 55 to 2667 ± 183 µg/kg and 6.40 ± 0.38 to 8.65 ± 0.59 mg/kg (dry weight), respectively, which increased with depth. According to the observed molecular indices, PAHs and n-alkanes originated mostly from petroleum-related sources. The levels of ΣPAHs and the total toxic benzo[a]pyrene equivalent (ranging from 6.41 to 72.54 µg/kg) might exert adverse biological effects. Shotgun metagenomic sequencing was employed to investigate the indigenous microbial community structure and function. The results revealed that Proteobacteria and Actinobacteria were the most abundant phyla, and Nocardioides and Microbacterium were the important genera. Based on COG and KEGG annotations, the highly abundant functional classes were identified, and these functions were involved in allowing microorganisms to adapt to the pressure from contaminants. Five petroleum hydrocarbon degradation-related genes were annotated, revealing the distribution of degrading microorganisms. This work facilitates the understanding of the composition, source, and potential ecological impacts of residual PAHs and n-alkanes in historically contaminated soil.

Reversible Information of Encrypted Image Based on Feature Difference Detection and Wavelet Transform.

Aiming at the shortcomings of the existing lossless digital watermarking algorithm based on frequency domain in reversibility and embedding capacity, this study proposes a lossless digital image watermarking algorithm based on fractional wavelet transform, which is used for large-capacity reversible information hiding of images. First, the image is transformed by LeGall5/3 fractional wavelet, and then, the watermark is embedded in the high-frequency subband by the histogram shift method. In order to obtain maximum embedding capacity and reduce image distortion, the methods of selecting embedding parameters and stopping parameters are proposed, respectively. At the same time, in order to prevent overflow and reduce additional information, a new method of generating position map is proposed. The experimental results show that Lena is the result of multilayer embedding based on the algorithm in this study. In order to better observe the distortion phenomenon and enlarge the image, the Lena test image is the watermark image obtained after two and three layers of embedding, and its embedding capacity can be 2.7 bpp. It is proved that wavelet transform is suitable for encrypted images to implement covert communication.

Renal Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Liver Cirrhosis: A Nationwide Cohort Study.

BACKGROUND: The use of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) carries a risk of renal function deterioration in cirrhotic patients with ascites. However, whether the long-term use of ACEis/ARBs is safe in cirrhotic patients without ascites remains unknown. METHODS: In this nationwide cohort study, we identified 311,361 newly diagnosed cirrhotic patients between January 1997 and December 2013. To avoid indication and immortal time biases, patients receiving regular ACEi/ARB therapy, defined as the ACEi/ARB cohort, were matched to patients receiving regular calcium channel blockers (CCBs), defined as the CCB cohort, at a ratio of 1 : 1 by age, sex, and propensity scores for comorbidities and medications (2,188 patients in each cohort). Cumulative incidence rates and multivariate analyses of end-stage renal disease (ESRD) risk were adjusted for competing mortality. RESULTS: The 10-year cumulative incidence rates of ESRD were 2.32% (95% confidence interval [CI]: 1.45-3.20) in the ACEi/ARB cohort and 1.70% (95% CI: 1.03-2.36) in the CCB cohort (P = 0.610). In multivariate analyses, ACEi/ARB use was not associated with a higher risk of ESRD in cirrhotic patients (hazard ratio [HR] = 1.15; 95% CI: 0.69-1.94, P = 0.591). In the sensitivity test, the 10-year cumulative incidence rates of ESRD in cirrhotic patients with ascites were 6.50% (95% CI: 0.54-12.46) and 1.24% (95% CI: 0.00-2.71) in ACEi/ARB and CCB cohorts, respectively (P = 0.090). CONCLUSIONS: Long-term ACEi/ARB use was not associated with a higher risk of ESRD in cirrhotic patients. However, the risk of ESRD tended to increase in cirrhotic patients with ascites.

Association of Daily Aspirin Therapy With Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B.

Importance: Antiviral therapy cannot erase hepatocellular carcinoma (HCC) risk in patients with chronic hepatitis B, and it is not indicated for most hepatitis B virus (HBV) carriers. Another effective way of reducing HCC risk needs to be developed. Aspirin may prevent cancer development, but clinical evidence in patients with HBV-related HCC remains limited. Objective: To investigate the association of daily aspirin therapy with HBV-related HCC risk. Design, Setting, and Participants: In this Taiwan nationwide cohort study, we screened 204 507 patients with chronic hepatitis B for the period January 1, 1997, to December 31, 2012. After excluding patients with confounding conditions, 2123 patients who continuously received daily aspirin for 90 or more days (treated group) were randomly matched 1:4 with 8492 patients who had never received antiplatelet therapy (untreated group) by means of propensity scores, consisting of the follow-up index date, baseline characteristics, and potentially chemopreventive drug use during follow-up. Data were analyzed from August 1 to November 30, 2018. Exposures: Daily aspirin therapy during the study period. Main Outcomes and Measures: Both cumulative incidence of and hazard ratios (HRs) for HCC development were analyzed after adjusting patient mortality as a competing risk event. Results: Of the 10 615 patients included in the analysis, 7690 (72.4%) were men; mean (SD) age was 58.8 (11.8) years. The cumulative incidence of HCC in the treated group was significantly lower than that in the untreated group in 5 years (5.20%; 95% CI, 4.11%-6.29% vs 7.87%; 95% CI, 7.15%-8.60%; P < .001). In the multivariable regression analysis, aspirin therapy was independently associated with a reduced HCC risk (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Sensitivity subgroup analyses also verified this association (all HRs <1.0). In addition, older age (HR, 1.01 per year; 95% CI, 1.00-1.02), male sex (HR, 1.75; 95% CI, 1.43-2.14), and cirrhosis (HR, 2.89; 95% CI, 2.45-3.40) were independently associated with an increased HCC risk, but nucleos(t)ide analogue (HR, 0.54; 95% CI, 0.41-0.71) or statin (HR, 0.62; 95% CI, 0.42-0.90) use was correlated with a decreased HCC risk. Conclusions and Relevance: Daily aspirin therapy may be associated with a reduced risk of HBV-related HCC.

Risk of skin cancer in psoriasis patients receiving long-term narrowband ultraviolet phototherapy: Results from a Taiwanese population-based cohort study.

BACKGROUND: Narrowband ultraviolet B (NB-UVB) phototherapy is a widely used treatment for various dermatoses. The risk of skin cancer following long-term NB-UVB phototherapy has rarely been explored in skin phototypes III-V. METHODS: We conducted a nationwide-matched cohort study and identified a total of 22 891 psoriasis patients starting NB-UVB phototherapy from the Taiwan National Health Insurance Database during the period 2000-2013. Cumulative incidences of skin cancers were compared between subjects receiving less than 90 UVB treatments (S-cohort, N = 13 260) and age- as well as propensity score-matched subjects receiving more than or equal to 90 UVB treatments (L-cohort, N = 3315). RESULTS: There were no significant differences in the overall cumulative incidences of skin cancers between the two cohorts (log-rank t test, P = 0.691) during the follow-up periods. The S-cohort had a significantly lower prevalence of actinic keratosis when compared with the L-cohort (0.54% vs 1.00%, P = 0.005). CONCLUSION: Long-term NB-UVB phototherapy does not increase skin cancer risk compared with short-term NB-UVB phototherapy in psoriasis patients with skin phototypes III-V.

A Highly Proton-Conductive 3D Ionic Cadmium-Organic Framework for Ammonia and Amines Impedance Sensing.

Lately, the progressive study of metal-organic frameworks (MOFs) for the detection of ammonia and amines has made infusive achievements. Nevertheless, the investigation of proton-conductive MOFs used to detect the low concentrations of ammonia and amine gases at different relative humidities (RHs) at room temperature is relatively restricted. Herein, by solvothermal reaction of Cd(NO3)2 with 2-methyl-1 H-imidazole-4,5-dicarboxylic acid (H3MIDC), a three-dimensional ionic MOF {Na[Cd(MIDC)]} n (1) bearing ordered one-dimensional channels was successfully synthesized. Our research indicates that the uncoordination carboxylate sites are beneficial to proton transfer and the recognition of ammonia and amine compounds. The optimized proton conductivity of 1 reaches a high value of 1.04 × 10-3 S·cm-1 (100 °C, 98% RH). The room temperature sensing properties of ammonia and amine gases were explored under 68, 85, and 98% RHs, respectively. Satisfactorily, the detection limits of MOF 1 toward ammonia, methylamine, dimethylamine, trimethylamine, and ethylamine are 0.05, 0.1, 0.5, 1, and 4 ppm, respectively, which is one of the best room-temperature sensors for ammonia among previous sensors based on proton-conductive MOFs. The proton conducting and sensing mechanisms were highlighted as well.

Enhancing Proton Conductivity of a 3D Metal-Organic Framework by Attaching Guest NH3 Molecules.

By reaction of a newly designed organic ligand, [3-(naphthalene-1-carbonyl)-thioureido] acetic acid (C10H7C(O)NHC(S)NHCH2COOH; H3L), with Cu(OAc)2, a metal-organic framework [(CuI4CuII4L4)·3H2O] n (1) containing unique mixed-valence [CuI4Cu4IIL4] subunits has been successfully synthesized and structurally characterized. MOF 1 displays a three-dimensional open framework bearing one-dimensional channels. Consequently, a new derivative MOF [CuI4CuII4L4] n-NH3 (2) is procured upon exposure of 1 to NH3 vapors from 28 wt % aqueous NH3 solution, which bears 2 NH3 and 4 H2O molecules in accordance with the elemental and thermal analyses. Both 1 and 2 exhibit relatively high water stability, whose proton conduction properties under water vapor have been researched. Notably, 2 shows an ultrahigh proton conductivity of 1.13 × 10-2 S cm-1, which is 2 orders of magnitude larger than that of MOF 1 (4.90 × 10-4 S cm-1) under 100 °C and 98% RH. On the basis of the structural data, Ea values, H2O and ammonia vapor absorptions, and PXRD measurements, the proton transfer mechanisms were suggested. This is an efficient and convenient way to obtain suitable and highly proton-conducting materials by attaching NH3 molecules.

A Water-Stable Proton-Conductive Barium(II)-Organic Framework for Ammonia Sensing at High Humidity.

In view of environmental protection and the need for early prediction of major diseases, it is necessary to accurately monitor the change of trace ammonia concentration in air or in exhaled breath. However, the adoption of proton-conductive metal-organic frameworks (MOFs) as smart sensors in this field is limited by a lack of ultrasensitive gas-detecting performance at high relative humidity (RH). Here, the pellet fabrication of a water-stable proton-conductive MOF, Ba( o-CbPhH2IDC)(H2O)4] n (1) ( o-CbPhH4IDC = 2-(2-carboxylphenyl)-1 H-imidazole-4,5-dicarboxylic acid) is reported. The MOF 1 displays enhanced sensitivity and selectivity to NH3 gas at high RHs (>85%) and 30 °C, and the sensing mechanism is suggested. The electrochemical impedance gas sensor fabricated by MOF 1 is a promising sensor for ammonia at mild temperature and high RHs.

A Highly Stable Two-Dimensional Copper(II) Organic Framework for Proton Conduction and Ammonia Impedance Sensing.

This work reports the design and fabrication of a proton conductive 2D metal-organic framework (MOF), [Cu(p-IPhHIDC)]n (1) (p-IPhH3 IDC=2-(p-N-imidazol-1-yl)-phenyl-1 H-imidazole-4,5-dicarboxylic acid) as an advanced ammonia impedance sensor at room temperature and 68-98 % relative humidity (RH). MOF 1 shows the optimized proton conductivity value of 1.51×10-3  S cm-1 at 100 °C and 98 % RH. Its temperature-dependent and humidity-dependent proton conduction properties have been explored. The large amount of uncoordinated carboxylate groups between the layers plays a vital role in the resultant conductivity. Distinctly, the fabricated MOF-based sensor displays the required stability toward NH3 , enhanced sensitivity, and notable selectivity for NH3 gas. At room temperature and 68 % RH, it gives a remarkable gas response of 8620 % to 130 ppm NH3 gas and lower detection limit of 2 ppm towards NH3 gas. It is also found that the gas response of the ammonia sensor increases linearly with the increase of NH3 gas concentration under 68-98 % RH and room temperature. Moreover, the sensor indicates excellent reversibility and selectivity toward NH3 versus N2 , H2 , O2 , CO, CO2 , benzene, and MeOH. Based on structural analyses, activation energy calculations, water and NH3 vapor absorptions, and PXRD determinations, proton conduction and NH3 sensing mechanisms are suggested.

Effect of Nucleos(t)ide Analogue Therapy on Risk of Intrahepatic Cholangiocarcinoma in Patients With Chronic Hepatitis B.

BACKGROUND & AIMS: Chronic infection with hepatitis B virus (HBV) increases risk of intrahepatic cholangiocarcinoma (ICC), but it is not clear whether antiviral therapy reduces risk. We investigated the association between nucleos(t)ide analogue therapy and ICC risk. METHODS: We performed a nationwide long-term cohort study using Taiwan's National Health Insurance Research Database to obtain data on 185,843 patients with chronic HBV infection from October 1, 2003 through December 31, 2012. We excluded patients with confounding disorders such as infection with hepatitis C virus, HIV, or other hepatitis-associated viruses; liver flukes; biliary stone diseases; cholangitis; congenital biliary anomalies; biliary tract surgeries; or cancer. We identified 10,062 patients who received nucleos(t)ide analogue therapy (the treated group), and used propensity scores to match them (1:1) with patients who received hepatoprotectants (the untreated group). Cumulative incidences of and hazard ratios (HRs) for ICC development were analyzed. RESULTS: The cumulative incidence of ICC was significantly lower in the treated group after 3 years of therapy (1.28%; 95% CI, 0.56-2.01) than in the untreated group (3.14%; 95% CI, 2.02-4.27) and after 5 years of therapy (1.53%; 95% CI, 0.73-2.33 vs 4.32% in untreated group; 95% CI, 2.96-5.6869). In multivariable regression analysis, nucleos(t)ide analogue therapy was independently associated with a reduced risk of ICC (HR, 0.44; 95% CI, 0.25-0.78; P = .005). Older age (HR 1.05 per year; 95% CI, 1.03-1.07) and cirrhosis (HR, 2.80; 95% CI, 1.52-5.1415) were independently associated with an increased risk of ICC. Sensitivity analyses verified the association between nucleos(t)ide analogue therapy and a reduced ICC risk. CONCLUSION: A nationwide long-term cohort study in Taiwan showed that nucleos(t)ide analogue therapy for chronic HBV infection is significantly associated with a reduced ICC risk.

Precise large deviations of aggregate claims in a size-dependent renewal risk model with stopping time claim-number process.

In this paper, we consider a size-dependent renewal risk model with stopping time claim-number process. In this model, we do not make any assumption on the dependence structure of claim sizes and inter-arrival times. We study large deviations of the aggregate amount of claims. For the subexponential heavy-tailed case, we obtain a precise large-deviation formula; our method substantially relies on a martingale for the structure of our models.

The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow-up duration of 6.32 years in the study cohort, the 10-year cumulative incidence of HCC was 2.73% [95% confidence interval (CI): 1.69-3.76%]. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk [hazard ratio (HR) 6.80, 95% CI: 3.00-15.42; p < 0.001]. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05-1.11) and statin use (HR 0.29, 95% CI: 0.12-0.68) were also identified as independent risk factors. The 10-year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99-18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0-1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.