Cost Effectiveness of Fremanezumab in Episodic and Chronic Migraine Patients from a Japanese Healthcare Perspective.

BACKGROUND AND OBJECTIVES: Fremanezumab is an effective treatment for episodic (EM) and chronic migraine (CM) patients in Japan, but its cost effectiveness remains unknown. The objective of this study was to determine the cost effectiveness of fremanezumab compared with standard of care (SOC) in previously treated EM and CM patients from a Japanese healthcare perspective. METHODS: Estimated regression models were implemented in a probabilistic Markov model to inform effectiveness and health-related quality-of-life data for fremanezumab and SOC. The model was further populated with data from the literature. The adjusted Japanese healthcare perspective included productivity losses. The main model outcomes were quality-adjusted life-years (QALYs), costs (2022 Japanese Yen [¥]), and incremental outcomes including the incremental cost-effectiveness ratio (ICER). Analyses were performed separately for the EM and CM patients and combined. Costs and effects were discounted at an annual rate of 2.0%. RESULTS: The mean QALYs over a 25-year time horizon for the EM and CM populations combined were 13.03 for SOC and 13.15 for fremanezumab. The associated costs were ¥27,550,292 for SOC and ¥28,371,048 for fremanezumab. QALYs were higher and costs lower for EM patients compared with CM patients for both fremanezumab and SOC. The deterministic ICERs of fremanezumab versus SOC were ¥6,334,861 for EM, ¥7,393,824 for CM, and ¥6,530,398 for EM and CM combined. Indirect costs and choice of mean migraine days model distribution had a substantial impact on the ICER. CONCLUSION: Using fremanezumab in a heterogeneous mixture of Japanese EM and CM patients resulted in a reduction of monthly migraine days and thus more QALYs compared with SOC. The cost effectiveness of fremanezumab versus SOC in EM and CM patients resulted in an ICER of ¥6,530,398, from an adjusted Japanese public healthcare perspective.

Fremanezumab is an effective treatment for episodic and chronic migraine patients in Japan, but it is unknown how the costs relate to the health benefits. The current research determined the relation between costs and effects of fremanezumab compared with the current standard of care in Japanese clinical practice, to see if the costs are justified by the health benefits. A model was used to inform the treatment effect of fremanezumab and standard of care. Data on costs, the frequency in which health care was used, and impairment of work due to migraine were also included in the model and obtained from the literature. The main outcomes were the number of years that patients were alive while taking their quality of life into account, costs, and the difference in these outcomes between patients who were treated with fremanezumab and those receiving standard of care. Subsequently, it was estimated how costs and effects related to one another and whether the costs were justified by the health benefits. The outcomes showed that patients treated with fremanezumab had a better quality of life compared with those receiving standard of care, while the costs associated with fremanezumab were higher. Compared with standard of care, the health benefits of treating patients with fremanezumab were justified by the costs within an acceptable range. Taking the absence from work due to illness into account had a substantial impact on the model outcomes.

Macro-meso damage characteristics of coal body under different pressure relief conditions.

The mining of the protective coal seam usually produces different pressure relief effects on the different areas of protected coal seam, the reason is that the stress paths of protected seam coal body in different areas caused by mining effect are different. In order to explore the differential pressure relief damage effect of coal body under different pressure relief conditions, the stress evolution path of coal body in different areas of the protected coal seam is obtianed by using theoretical analysis and the macro-micro damage characteristics of coal body under different stress paths by using numerical simulation in this paper. The results show that: The damage characteristics of the sample models are basically the same in the in-situ stress recovery stage and the mining disturbance stage of the two stress paths. With ith the sequence of stress stages experienced by the sample model, the distribution of acoustic emission events concentrates in the high-intensity area and the porosity continues to decrease. The number of cracks increases slowly in the stage of in-situ stress recovery stage, most of which are tensile cracks, while the number of cracks increases sharply in the mining disturbance stage, most of which are shear cracks. The difference of the deformation and macro meso damage characteristics of the sample models under the two stress paths is mainly reflected in the post mining pressure relief stage. At the post mining pressure relief stage of path 1, the number of cracks in the sample has little growth, and most of them are small energy tensile cracks, and the porosity increases, which verifies its obvious pressure relief activation antireflection effect; At this stage of path 2, the crack growth of the sample is obvious, and most of them are high-energy shear cracks, and the porosity continues to decrease. Compared with path 1, the pressure relief expansion effect of the sample model is suppressed and the compression damage continues to develop in this stage of path 2.

Tracing nitrate origins and transformation processes in groundwater of the Hohhot Basin's Piedmont strong runoff zone through dual isotopes and hydro-chemical analysis.

Nitrate, which poses a serious threat to the drinking water supply, is one of the most prevalent anthropogenic groundwater contaminants worldwide. With the development of the chemical industry, the nitrate pollution of groundwater in the Piedmont strong runoff zone of the Hohhot Basin, which is the main groundwater extraction area, is becoming increasingly severe. The special hydrogeological and complex pollution conditions in the study area make it difficult to identify nitrate sources and transformation processes. In order to identify the results more accurately, this study combined water chemistry, multivariate statistical analysis and isotope tracer methods to determine the sources and transformation processes of nitrate in the study area. The results showed that the groundwater in the eastern part of the study area (ESA) was clearly affected by anthropogenic activities, and its nitrate was mainly from nitrification of ammonia in industrial wastewater, nitrate in industrial wastewater (the sum of the two contributions was 62.2 %), and nitrate in manure (20.5 %). The hydrogeochemical characteristics of groundwater in the western part of the study area (WSA) are the same as those of natural groundwater in the Piedmont strong-runoff zone. The nitrate in groundwater in the WSA was mainly derived from soil nitrogen (63.8 %) and ammonia fertilizer (28.8 %). Nitrification and denitrification occurred only locally in the aquifer of the study area and were more pronounced in the ESA. Meanwhile, the transformation processes of nitrate in groundwater in the ESA and WSA was significantly influenced by contamination with chlorinated hydrocarbon volatile organic compounds and hydrogeological conditions, respectively. These findings provide a scientific basis for the development of groundwater pollution prevention measures in the study area and guide the traceability of nitrate in groundwater in areas with similar hydrogeological and pollution conditions.

Multiply robust estimators in longitudinal studies with missing data under control-based imputation.

Longitudinal studies are often subject to missing data. The recent guidance from regulatory agencies, such as the ICH E9(R1) addendum addresses the importance of defining a treatment effect estimand with the consideration of intercurrent events. Jump-to-reference (J2R) is one classical control-based scenario for the treatment effect evaluation, where the participants in the treatment group after intercurrent events are assumed to have the same disease progress as those with identical covariates in the control group. We establish new estimators to assess the average treatment effect based on a proposed potential outcomes framework under J2R. Various identification formulas are constructed, motivating estimators that rely on different parts of the observed data distribution. Moreover, we obtain a novel estimator inspired by the efficient influence function, with multiple robustness in the sense that it achieves n1/2-consistency if any pairs of multiple nuisance functions are correctly specified, or if the nuisance functions converge at a rate not slower than n-1/4 when using flexible modeling approaches. The finite-sample performance of the proposed estimators is validated in simulation studies and an antidepressant clinical trial.

ZJUT-EIFD: A Synchronously Collected External and Internal Fingerprint Database.

External fingerprints (EFs) based only on epidermal information are vulnerable to spoofing attacks and non-ideal skin conditions. To solve such shortcomings, internal fingerprints (IFs) collected using optical coherence tomography (OCT) have been proposed and widely researched. However, the development of IF is limited by the lack of in-depth researches on the IF and the EF-IF interoperability, which is partially caused by the lack of public OCT database. The obvious gap in the applications of EF and IF recognition motivated us to design and publish a comprehensive fingerprint database containing both traditional EFs and OCT IFs, denoted as ZJUT-EIFD. To the best of our knowledge, ZJUT-EIFD is the first public database that combines OCT and total internal reflection (TIR) via synchronous acquisition, with 399 different fingers from 60 subjects. In this article, the composition of the database, the quality of EFs and IFs, and the verification performance of different types of fingerprints were detailed. In addition, potential application directions of ZJUT-EIFD were demonstrated. ZJUT-EIFD can serve benchmarks and interoperability tests for EF-IF research, which will promote the research and development of EF and IF.

High-intensity ultrasound promoted the maturation of high-salt liquid-state soy sauce: A mean of enhancing quality attributes and sensory properties.

High-intensity ultrasound was used as a means to promote maturation of soy sauce. The optimal conditions for ultrasound treatment were 90℃ at an ultrasound intensity of 39.48 W/cm2 for 60 min. The total reducing sugars and soluble salt-free solids content was significantly increased after ultrasound-assisted maturation. The free amino acid content was significantly decreased, mainly due to the Maillard reaction (MR). The promoted MR produced several types of flavor compounds, including esters, pyrazines, and ketones, which imparted an attractive aroma to the maturated soy sauce. The proportion of peptides with a molecular weight of 1-5 kDa provided umami as an important flavor characteristic, and the content in the ultrasound-matured soy sauce (10.19 %) was significantly higher than that in the freshly prepared soy sauce (8.34 %) and the thermally treated sample (8.89 %). Ultrasound-assisted maturation would improve product quality and meanwhile, shorten the duration and reduce the cost for the soy sauce industry.

VET: Vasculature Extraction Transformer for Single-Scan Optical Coherence Tomography Angiography.

Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality for analyzing skin microvasculature, enabling non-invasive diagnosis and treatment monitoring. Traditional OCTA algorithms necessitate at least two-repeated scans to generate microvasculature images, while image quality is highly dependent on the repetitions of scans (e.g., 4-8). Nevertheless, a higher repetition count increases data acquisition time, causing patient discomfort and more unpredictable motion artifacts, which can result in potential misdiagnosis. To address these limitations, we proposed a vasculature extraction pipeline based on the novelty vasculature extraction transformer (VET) to generate OCTA images by using a single OCT scan. Distinct from the vision Transformer, VET utilizes convolutional projection to better learn the spatial relationships between image patches. This study recruited 15 healthy participants. The OCT scans were performed in five various skin sites, i.e., palm, arm, face, neck, and lip. Our results show that in comparison to OCTA images obtained by the speckle variance OCTA (peak-signal-to-noise ratio (PSNR): 16.13) and eigen-decomposition OCTA (PSNR: 17.08) using four repeated OCT scans, OCTA images extracted by the proposed pipeline exhibit a better PSNR (18.03) performance while reducing the data acquisition time by 75%. Visual comparisons show that the proposed pipeline outperformed traditional OCTA algorithms, particularly in the imaging of lip and face areas, where artifacts are commonly encountered. This study is the first to demonstrate that the VET can efficiently extract high-quality vasculature images from a single, rapid OCT scan. This capability significantly enhances diagnostic accuracy for patients and streamlines the imaging process.

Oblique lateral interbody fusion with internal fixations in the treatment for cross-segment degenerative lumbar spine disease (L2-3 and L4-5) finite element analysis.

Multi-segmental lumbar degenerative disease, including intersegmental disc degeneration, is found in clinical practice. Controversy still exists regarding the treatment for cross-segment degeneration. Oblique Lateral Interbody Fusion (OLIF) with several internal fixations was used to treat cross-segment lumbar degenerative disease. A whole lumbar spine model was extracted from CT images of the whole lumbar spine of patients with lumbar degeneration. The L2-3 and L4-5 intervertebral spaces were fused with OLIF using modeling software, the Pedicle screws were performed on L2-3 and L4-5, and different internal fixations were performed on L3-4 in Finite Element (FE) software. Among the six 10 Nm moments of different directions, the L3-4 no surgery (NS) group had the relatively largest Range of Motion (ROM) in the whole lumbar spine, while the L2-5 Long segmental fixation (LSF)group had the smallest ROM and the other groups had similar ROM. The ROM in the L1-2 and L5-S1 was relatively close in the six group models, and the articular cartilage stress and disc stress on the L1-2 and L5-S1 were relatively close. In contrast, the L3-4 ROM differed relatively greatly, with the LSF ROM the smallest and the NS ROM the largest, and the L3-4 Coflex (Coflex) group more active than the L3-4 Bacfuse (Bacfuse) group and the L3-4 translaminar facet screw fixation (TFSF) group. The stress on the articular cartilage and disc at L3-4 was relatively greater in the NS disc and articular cartilage, and greater in the Coflex group than in the Bacfuse and TFSF groups, with the greatest stress on the internal fixation in the TFSF group, followed by the Coflex group, and relatively similar stress in the Bacfuse, LSF, and NS groups. In the TFSF group, the stress on the internal fixation was greater than the yield strength among different directional moments of 10 Nm, which means it is unsuitable to be an internal fixation. The LSF group had the greatest overall ROM, which may lead to postoperative low back discomfort. The NS group has the greatest overall ROM, but its increased stress on the L3-4 disc and articular cartilage may lead to accelerated degeneration of the L3-4 disc and articular cartilage. The Coflex and Bacfuse groups had a reduced L3-4 ROM but a greater stress on disc compared to the LSF group, which may lead to disc degeneration in the long term. However, their stress on the articular cartilage was relatively low. Coflex and Bacfuse can still be considered better surgical options.

3D CNN-based fingerprint anti-spoofing through optical coherence tomography.

Optical coherence tomography (OCT) is a noninvasive high-resolution imaging technology that can accurately acquire the internal characteristics of tissues within a few millimeters. Using OCT technology, the internal fingerprint structure, which is consistent with external fingerprints and sweat glands, can be collected, leading to high anti-spoofing capabilities. In this paper, an OCT fingerprint anti-spoofing method based on a 3D convolutional neural network (CNN) is proposed, considering the spatial continuity of 3D biometrics in fingertips. Experiments were conducted on self-built and public datasets to test the feasibility of the proposed anti-spoofing method. The anti-spoofing strategy using a 3D CNN achieved the best results compared with classic networks.

Causal relationship between sarcopenia and osteoarthritis: a bi-directional two-sample mendelian randomized study.

BACKGROUND: Previous studies have shown that osteoarthritis (OA) and sarcopenia (SP) are closely related to each other, but the causal relationships between them have not been established. The aim of this study was to investigate the causal associations between OA and SP via a bi-directional Mendelian randomization (MR) approach. METHODS: A bi-directional two-sample MR was adopted to research the causal relationship between SP and OA. The instrumental variables for SP and four types of OA: KOA, HOA, total knee replacement (TKR) and total hip replacement (THR) were derived from published large genome-wide association studies (GWAS). The inverse variance weighted (IVW), MR-Egger and weighted median estimator (WME) methods were used to estimate bi-directional causal effects. RESULTS: Low grip strength (GS) did not have a causal effect on four types of OA (KOA: OR = 1.205, 95% CI 0.837-1.734, p = 0.316; HOA: OR = 1.090, 95% CI 0.924-1.609, p = 0.307; TKR: OR = 1.190, 95% CI 1.084-1.307, p = 0.058; THR: OR = 1.035, 95% CI 0.792-1.353, p = 0.798), while appendicular lean mass (ALM) had a causal effect on four types of OA (KOA: OR = 1.104, 95% CI 1.041-1.171, p = 0.001; HOA: OR = 1.151, 95% CI 1.071-1.237, p < 0.001; TKR: OR = 1.114, 95% CI 1.007-1.232, p < 0.001; THR: OR = 1.203, 95% CI 1.099-1.316, p < 0.001). In the reverse direction, KOA or HOA did not have a significant causal effect on both GS and ALM (KOA-GS: OR = 1.077, 95% CI 0.886-1.309, p = 0.458; KOA-ALM: Beta = 0.004, p = 0.892; HOA-GS: OR = 1.038, 95% CI 0.981-1.099, p = 0.209; HOA-ALM: Beta = - 0.017, p = 0.196; TKR-GS: OR = 0.999, 95% CI 0.739-1.351, p = 0.997; TKR-ALM: Beta = 0.018, p = 0.501; THR-GS: OR = 1.037, 95% CI 0.978-1.101, p = 0.222; THR-ALM: Beta = - 0.023, p = 0.081). CONCLUSIONS: The present study suggests that SP may have a causal effect on OA through changes in muscle composition rather than muscle strength, while little evidence was provided for the causal effect of OA on SP.

Brown Sequard syndrome in a patient with Klippel-Feil syndrome following minor trauma: a case report and literature review.

BACKGROUND: There are some cases of Klippel-Feil syndrome with spinal cord injury in clinical work. However, there is no literature report on Brown-Sequard syndrome after trauma. We report a case of Brown-Sequard syndrome following minor trauma in a patient with KFS type III. Her Brown-Sequard syndrome is caused by Klippel-Feil syndrome. CASE PRESENTATION: We found a 38-year-old female patient with KFS in our clinical work. She was unconscious on the spot following a minor traumatic episode. After treatment, her whole body was numb and limb activity was limited. Half an hour later, she felt numb and weak in the right limb and weak in the left limb. She had no previous hypertension, diabetes, or coronary heart disease. After one-month treatment of medication, hyperbaric oxygen, rehabilitation, and acupuncture in our hospital, her muscle strength partially recovered, but the treatment effect was still not satisfactory. Then, she underwent surgical treatment and postoperative comprehensive treatment, and rehabilitation training. She was able to take care of herself with assistance, and her condition improved from grade B to grade D according to the ASIA (ASIA Impairment Scale) classification. CONCLUSION: KFS, also known as short neck deformity, is a kind of congenital deformity characterized by impaired formation and faulty segmentation of the cervical spine, often associated with abnormalities of other organs. The cervical deformity in patients with KFS can alter the overall mechanical activity of the spine, as well as the compensatory properties of the spine for decelerating and rotatory forces, thus increasing the chance of spinal cord injury (SCI) following trauma. Many mechanisms can make patients more susceptible to injury. Increased range of motion of the segment adjacent to the fused vertebral body may lead to slippage of the adjacent vertebral body and altered disc stress, as well as cervical instability. SCI can result in complete or incomplete impairment of motor, sensory and autonomic nervous functions below the level of lesion. This woman presented with symptoms of BSS, a rare neurological disorder with incomplete SCI. Judging from the woman's symptoms, we concluded that previously she had KFS, which resulted in SCI without fracture and dislocation following minor trauma, with partial BSS. After the comprehensive treatment of surgery, hyperbaric oxygen, rehabilitation therapy, and neurotrophic drugs, two years later, we found her symptoms significantly improved, with ASIA Impairment Scale from grade B to grade D, and her ability to perform activities of daily living with aids.

Trace analysis of food by surface-enhanced Raman spectroscopy combined with molecular imprinting technology: Principle, application, challenges, and prospects.

Surface-enhanced Raman spectroscopy (SERS) is a rapid detection method with high sensitivity and simple pretreatment, but can be affected by interference from matrix components. By incorporating molecularly imprinted polymers (MIPs) that recognize specific targets, MIP-SERS sensors effectively overcome the interference of complex matrices and offer improved stability and sensitivity. This review provides a comprehensive understanding of the applications of MIP-SERS sensors for the detection of trace toxic substances in food. The underlying mechanism and development of SERS technology and the principle and classification of MIPs technology are discussed. Furthermore, the types of MIP-SERS sensors are introduced, with their advantages and disadvantages systematically illustrated. Recent advances in MIP-SERS technology for the detection of mycotoxins, additives, prohibited dyes, pesticides, veterinary drug residues, and other hazardous substances in food are highlighted. Finally, this review discusses the challenges associated with MIP-SERS technology and proposes future development prospects.

Knockdown of lncRNA NKILA suppresses sevoflurane-induced neuronal cell injury partially by targeting miR-205-5p/ELAVL1 axis.

Sevoflurane (Sev) is a wildly used volatile anesthetic agent that induces neurotoxicity. Long non-coding RNAs (lncRNAs) have been demonstrated to be involved in Sev-induced neuronal injury. Here, we investigated the role of NF-kappaB-interacting lncRNA (NKILA) in Sev-treated human cortical neurons (HCN). From RT-qPCR, Sev dose-dependently increased HCN NKILA transcript expression. Neurotoxicity of Sev was detected using MTT, flow cytometry, Western blotting, and inflammatory mediator assays. Consequently, Sev reduced HCN viability and levels of Bcl-2, SOD, and GSH in HCN, and promoted HCN apoptosis rate and levels of cleaved-caspase-3, Bax, MDA, TNF-α, IL-6, and IL-1ß. Silencing NKILA suppressed Sev-induced above effects. DIANA and starbase databases predicted the potential target relationship between miR-205-5p and NKILA or embryonic lethal abnormal vision-like 1 (ELAVL1); dual-luciferase and RIP confirmed these interactions. NKILA could increase ELAVL1 expression by regulating miR-205-5p. miR-205-5p overexpression and ELAVL1 knockdown could mimic effects of NKILA silencing in Sev-induced HCN. Deleting miR-205-5p and restoring ELAVL1 respectively abolished the neuroprotective effect of NKILA knockdown and miR-205-5p upregulation under Sev anesthesia. In conclusion, Sev induced neuronal cell apoptosis, inflammatory response and oxidative stress through NKILA/miR- 205-5p/ELAVL1 axis and caspase-3 and Bax/Bcl-2 pathway. Inhibiting NKILA might be a potential therapeutic strategy for Sev neurotoxicity.

Identification of ammonium source for groundwater in the piedmont zone with strong runoff of the Hohhot Basin based on nitrogen isotope.

Groundwater with high ammonium concentration (HANC groundwater), mostly caused by anthropogenic pollution, is widely distributed in China, which could also result from natural geological genesis. Groundwater in the piedmont zone with strong runoff in the central Hohhot Basin has featured its excessive ammonium concentration since the 1970s. Currently, chemical factories also serve as potential pollution sources. In this study, based on the nitrogen isotopic technique and combined with hydrochemical methods, the sources of high concentration ammonium in the groundwater was identified. The HANC groundwater is mainly distributed in the alluvial-proluvial fan and the interfan depression in the western and central parts of the study area, and a maximum ammonium concentration of 529.32 mg/L was observed in the groundwater in the mid-fan of the Baishitou Gully (BSTG) alluvial-proluvial fan. Although the BSTG mid-fan is part of the piedmont zone with strong runoff, some of the HANC groundwater in this area still presents the typical hydrochemical characteristics in the discharge area. Moreover, an extremely high concentration of volatile organic compounds was observed in groundwater in the BSTG alluvial-proluvial fan, which indicated significant anthropogenic pollution. Besides, 15N-NH4+ is enriched in groundwater in the BSTG root-fan and the interfan depression, which is consistent with the situation of organic nitrogen and exchangeable ammonium in natural sediments, as well as the natural HANC groundwater in other regions of China. These δ15N-NH4+ values indicate that the ammonium of the groundwater in the BSTG root-fan and the interfan depression is derived from natural sediments. The 15N-NH4+ in groundwater is depleted in the BSTG mid-fan, and the δ15N-NH4+ values are similar with those of the pollution sources from the chemical factories in the mid-fan. Both hydrochemical and nitrogen isotopic characteristics indicate significant pollution in the mid-fan, but the ammonium pollution is limited to the area near the chemical factories.

MIPs-SERS Sensor Based on Ag NPs Film for Selective Detection of Enrofloxacin in Food.

The quinolone antibiotics represented by enrofloxacin (ENRO) are harmful to the ecological environment and human health due to illegal excessive use, resulting in increasing food residues and ENRO levels in the environment. To this end, we developed a MIPs-SERS method using surface-enhanced Raman spectroscopy (SERS) and molecularly imprinted polymers (MIPs) to detect ENRO in food matrices. Firstly, a layer of silver nanoparticles (Ag NPs) with the best SERS effect was synthesized on the surface of copper rods as the enhancing material by in situ reductions, and then MIPs targeting ENRO were prepared by the native polymerization reaction, and the MIPs containing template molecules wrapped on the surface of silver nanoparticle films (Ag NPs-MIPs) were obtained. Our results showed that the Ag NPs-MIPs could specifically identify ENRO from the complex environment. The minimum detection limit for ENRO was 0.25 ng/mL, and the characteristic peak intensity of ENRO was linearly correlated to the concentration with a linear range of 0.001~0.1 µg/mL. The experimental results showed that in comparison to other detection methods, the rapid detection of ENRO in food matrices using Ag NPs-MIPs as the substrate is reliable and offers a cost-effective, time-saving, highly selective, and sensitive method for detecting ENRO residues in real food samples.

The distribution characteristics and geological control factors of shallow high-arsenic groundwater in the Hetao Plain, Inner Mongolia, from the perspective of Late Pleistocene-Holocene depositional environments.

The alluvial-lacustrine strata that were formed by the evolution of rivers and lakes in the Hetao Plain during the Late Quaternary have an important influence on the formation and distribution of shallow high-arsenic groundwater. This study analyzed the distribution characteristics and depositional environments of shallow high-arsenic groundwater in study area using 1179 groundwater samples and more than 1100 pieces of drilling data. The indicator kriging statistics and the study results of the Quaternary lithofacies paleogeography show that the study area can be divided into three high-arsenic probabilistic distribution areas, namely, the Houtao Plain (HTP), the Yellow River Channel Belt (YRCB), and the Eastern Hubao Plain (EHBP). The depositional environment of the HTP was shaped by the alluviation of the Yellow River during the Late Pleistocene-Holocene. The YRCB is still affected by the alluviation of the Yellow River presently, and the EHBP was almost unaffected by the Yellow River. The high-arsenic groundwater in the EHBP is mostly distributed in the relatively continuous alluvial-lacustrine strata and has a typical hydrochemical type of HCO3, with the highest Meq(HCO3-/SO42-) and the highest reduction degree of SO42-. By contrast, the high-arsenic groundwater in the alluvial-lacustrine environments of the HTP and the YRCB accounts for only 14.77% and 20.13%, respectively, and has only less than 40% of HCO3 dominant type water. The high-arsenic groundwater in these two areas is generally located in the alluvial or alternating fluvial-lacustrine strata. However, the two areas exist more than three alluvial-lacustrine layers with a thickness of over 2 m each, which play a critical role in the formation of high-arsenic groundwater. Moreover, affected by alluvial aquifers in the same system, the high-arsenic groundwater in both the HTP and the YRCB is not intensively distributed and does not represent a typical HCO3 dominant type. The S2- produced by the massive reduction of SO42- might co-precipitate with Fe and As, which may explain why the EHBP has lower arsenic concentration than the HTP and the YRCB, both of which have a lower reduction degree of SO42-.

Inhibition of circular RNA ASPH reduces the proliferation and promotes the apoptosis of hepatic stellate cells in hepatic fibrosis.

Circular RNAs (circRNAs) are a newly identified form of non-coding RNA that play a crucial role in various pathological processes. However, the expression profile and function of circRNAs in hepatic fibrosis (HF) remain largely unknown. In this study, we showed that a novel circRNA ASPH (circASPH) mediates HF by targeting the miR-139-5p/Notch1 axis. We investigated the expression profile of circRNAs in hepatocyte exosomes of mice with HF using circRNA-sequencing and found significant upregulation of circASPH. Loss- and gain-of-function analysis of circASPH was performed to assess its role in HF. Furthermore, we performed luciferase reporter assay, RNA pull-down, and fluorescence in situ hybridization analyses and confirmed that circASPH directly binds to miR-139-5p. We also found that circASPH was upregulated in liver fibrogenesis. Downregulation of circASPH expression inhibited hepatic stellate cell (HSC) activation and proliferation, induced apoptosis, and attenuated mouse liver fibrogenic injury. Mechanistically, circASPH directly targeted miR-139-5p to regulate the expression of Notch1 in HF. Thus, downregulation of circASPH may suppress the activation of HSCs and HF through the circASPH/miR-139-5p/Notch1 axis. Our findings indicated that circASPH may be a potential biomarker for HF diagnosis and therapy.