Epidemiology, risk factors, and vaccine effectiveness for SARS-CoV-2 infection among healthcare workers during the omicron pandemic in Shanghai, China.

Background: The COVID-19 pandemic has exposed healthcare workers (HCWs) to serious risk of infection. The aims of our study were to investigate the epidemiological characteristics and risk factors of SARS-CoV-2 infection among HCWs, and evaluate the vaccine effectiveness (VE) during the Omicron pandemic in Shanghai, China. Methods: Active surveillance of COVID-19 was performed among HCWs who worked in Shanghai General Hospital from December 2022 to January 2023. A case-control study was conducted by questionnaire survey to analyse the infection-related risk factors. A retrospective cohort study was explored to evaluate VE against primary infection. Results: During the Omicron outbreak, 2,008 of 2,460 (81.6%) HCWs were infected with SARS-CoV-2. The infection rate was higher in women, younger age groups, nurses and medical technicians. Among the 1,742 participants in the questionnaire, 1,463 (84.0%) were tested positive, and 95.1% of them developed symptoms. Most of the infections (53.0%) were acquired outside the hospital. The risk factors associated with higher odds of infection were working in the emergency department (aOR 3.77, 95% CI 1.69-8.38) and medical examination area (aOR 2.47, 95% CI 1.10-5.51). The protective factors associated with lower odds of infection were previous infection with SARS-CoV-2 (aOR 0.01, 95% CI 0-0.07) and receiving four doses of vaccines (aOR 0.40, 95% CI 0.17-0.97). For frontline HCWs, those who had oral-nasal exposure to coworkers were more likely to be infected (aOR 1.74, 95% CI 1.21-2.51). In VE analysis, the risk of primary infection was lower in HCWs who received the emergency heterologous booster (the fourth dose) during the epidemic (aHR 0.25, 95% CI 0.15-0.40), resulting in an adjusted-VE of 75.1%. Conclusions: In response to future pandemic, it is important for public health policies to aim at protecting HCWs through risk-differentiated infection control measures, strengthening personal protection and recommending vaccination to vulnerable individuals before the arrival of Omicron wave.

Conditions that promote transcellular neutrophil migration in vivo.

Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have previously shown that genetically replacing VE-cadherin with a VE-cadherin-α-catenin (VEC-αC) fusion construct-which binds constitutively to actin-obstructs junctions, and blocks leukocyte extravasation in lung, skin and postcapillary venules of cremaster muscle. However, neutrophil recruitment into the inflamed peritoneal cavity was unimpaired. Investigating reasons for this, here, we visualized neutrophil diapedesis by 3D intravital video microscopy in the cremaster muscle and omentum, the major site of neutrophil recruitment into the peritoneal cavity. We found that 80% of neutrophil-extravasation occurred through HEVs in the omentum, which was unimpaired by VEC-αC. In addition, in larger venules (60-85 µm) of both tissues, less than 15% of neutrophils extravasated transcellularly in WT mice. However, in VEC-α-C mice, transcellular diapedesis increased severalfold in the omentum, but not in the cremaster. In line with this, omental venules expressed higher levels of ICAM-1 and atypical chemokine receptor 1. Furthermore, only in the omentum, VEC-αC expression caused reduced elongation of venular endothelium in flow-direction, suggesting different biomechanical properties. Collectively, VEC-αC does not inhibit paracellular transmigration in all types of venules and can modulate the diapedesis route.

In Vitro Evaluation of Chito-Oligosaccharides on Disappearance Rate of Nutrients, Rumen Fermentation Parameters, and Micro-Flora of Beef Cattle.

The study aimed to investigate the effect of dietary chitosan oligosaccharides (COS) meal levels on the nutrient disappearance rate, rumen fermentation, and microflora of beef cattle in vitro. A total of 24 fermentation tanks were randomly divided into four treatments containing 0% COS (CON), 0.02% COS, 0.04% COS, and 0.08% COS for an 8-day experiment period, with each treatment comprising six replicates. The disappear rates of DM, CP, EE, and total gas production were quadratically increased with increasing COS levels. The disappear rates of DM, CP, EE, and ADF were greatest, whereas the total gas production was lowest in the 0.08% COS group. The pH, NH3-N, MCP, the content of propionate, isobutyrate, butyrate, valerate, and the A/P were quadratically increased with increasing COS levels, while the A/P were linearly decreased. The pH, MCP, and the content of propionate, and butyrate were highest, whereas the NH3-N and the content of acetate, isobutyrate, valerate, and the A/P were lowest in the 0.08% COS group. Microbiomics analysis showed that the rumen microbial diversity was not altered between the CON and the 0.08% COS group. However, the relative abundance of Methanosphaera, Ruminococcus, Endomicrobium, and Eubacterium groups was increased, and the relative abundance of pathogenic bacteria Dorea and Escherichia-Shigella showed a decrease in the 0.08% COS group. Overall, the 0.08% COS was the most effective among the three addition levels, resulting in an increase in the disappearance rate of in vitro fermented nutrients and improvements in rumen fermentation indexes and microbial communities. This, in turn, led to the maintenance of rumen health.

Journal requirement for data sharing statements in clinical trials: a cross-sectional study.

OBJECTIVE: Data sharing statements are considered routine in clinical trial reporting, and represent a step towards data transparency. The International Committee of Medical Journal Editors (ICMJE) require clinical trials to publish data sharing statements. To assess requirement for data sharing statements by biomedical journals, and to explore associations between journal characteristics and requirement for data sharing statements. STUDY DESIGN AND SETTING: In this cross-sectional study, we included all biomedical journals that published clinical trials from January 1st, 2019 to December 31st, 2022 and that were indexed by the Journal Citation Reports. The study outcome was the journal requirement for data sharing statements. Multivariable logistic regression analyses were used to assess the relationship between journal characteristics and requirement for data sharing statements. RESULTS: Of the 3,229 biomedical journals included in the analyses, 2,345 (72.6%) required authors to include data sharing statements. Journals published in the UK (OR, 3.19 [95% CI, 2.43 to 4.22]) and endorsing the Consolidated Standards of Reporting Trials (CONSORT) (OR, 3.30 [95% CI, 2.78 to 3.92]) had greater odds of requiring data sharing statements. Journals that were Open Access, non-English language, in the Journal Citation Reports group of clinical medicine, and on the ICMJE list had lower odds of requiring data sharing statements, with ORs ranging from 0.18 to 0.81. CONCLUSION: Despite ICMJE recommendations, more than 27% of biomedical journals do not require clinical trials to include data sharing statements, highlighting room for improved transparency.

The physicochemical interacting mechanisms and real-time spectral induced polarization monitoring of lead remediation by an aeolian soil.

Compared to traditional lead-remediating materials, natural-occurring paleosol is ubiquitous and could be a promising alternative due to its rich content in calcite, a substance known for its lead-removal ability via carbonate dissolution-PbCO3 precipitation process. Yet, the capability of paleosol to remediate aqueous solutions polluted with heavy metals, lead included, has rarely been assessed. To fill this gap, a series of column permeation experiments with influent Pb2+ concentrations of 2000, 200, and 20 mg/L were conducted and monitored by the spectral induced polarization technique. Meanwhile, the SEM-EDS, XRD, XPS, FTIR and MIP tests were carried out to unveil the underlying remediation mechanisms. The Pb-retention capacity of paleosol was 1.03 mmol/g. The increasing abundance of Pb in the newly-formed crystals was confirmed to be PbCO3 by XRD, SEM-EDS and XPS. Concurrently, after Pb2+ permeation, the decreasing calcite content in paleosol sample from XRD test, and the appearance of Ca2+ in the effluent confirmed that the dissolution of CaCO3 followed by the precipitation of PbCO3 was the major mechanism. The accumulated Pb (i.e., the diminished Ca) in paleosol was inversely proportional (R2 >0.82) to the normalized chargeability (mn), an SIP parameter denoting the quantity of polarizable units (primarily calcite).

Anti-resonant hollow core fiber with excellent bending resistance in the visible spectral range.

The development of wideband guided hollow-core anti-resonant fiber (HC-ARF) that covers the sensitive range of the human eye's visible spectrum is progressing rapidly. However, achieving low-loss wideband transmission with a small bending radius remains a challenging issue to be addressed. In light of this, we propose a novel, to our knowledge, HC-ARF with a nested double-semi-elliptical cladding structure in the visible spectral region. By employing finite element method simulations, we investigate the confinement loss, bending loss, and single-mode performance of this fiber design. The result shows that the confinement loss of this new fiber exhibits below 10-5 dB·m-1 across almost the entire visible band range, with a minimum loss of 1.55 × 10-7 dB·m-1 achieved for λ = 650 nm. Furthermore, this fiber demonstrates excellent resistance to bending and can maintain an ultra-low bending loss as low as 3 × 10-7 dB·m-1 even under extreme bending conditions with a radius of only 3 cm. Notably, its 3-dB bending radius reaches just 3.5 cm for λ = 532 nm. Additionally, it exhibits outstanding single-mode conductivity under various bending scenarios and achieves a high extinction ratio of up to 104 for higher-order modes after parameter optimization for specific wavelengths.

Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear. METHODS: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c. FINDINGS: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c. INTERPRETATION: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions. FUNDING: A full list of funding bodies can be found in the Sources of funding section.

Molecular Dynamics Simulation of the Interaction within the Carboxymethyl Cellulose-Modified Montmorillonite Lamellae at Aggressive CuCl2 Concentrations.

To elucidate the degradation mechanism of the CMC-modified MMT composite at aggressive Cu2+ concentrations, large scale molecular dynamics simulation was conducted for CuCl2 concentrations ranging from 0 to 800 mM. Both CMC and MMT followed the Langmuir isotherm for Cu2+ adsorption, and the adsorption capacity of CMC (8.75 mmol/g) was much higher than that of MMT (0.83 mmol/g). Despite the CMC mass ratio being only 4.1%, it adsorbed up to 34.3% of the total adsorbed Cu2+. The Cu2+ attraction ability hierarchy of oxygen-containing functional groups in the CMC is as follows: carboxylic oxygens > alcoholic oxygens > carbinolic oxygens > bridging oxygens > glucose oxygens. Carboxyls were the most effective in chelating and complexing with Cu2+, and they could be intentionally added in artificially synthesized polymer-MMT composites for Cu2+ containment. Formation of the Cu2+ cation bridge between CMC and MMT at aggressive CuCl2 concentrations contributed to the transition of CMC density distribution from unimodality to bimodality and enhanced resistance of polymer elution. As the CuCl2 concentration increased, the stoichiometric ratio between the chelated Cu2+ and carboxylic oxygens increased from 1:2 to 1:1, suggesting the evolution of the Cu2+ chelation mechanism.

Impact Response Features and Penetration Mechanism of UHMWPE Subjected to Handgun Bullet.

Ensuring military and police personnel protection is vital for urban security. However, the impact response mechanism of the UHMWPE laminate used in ballistic helmets and vests remains unclear, making it hard to effectively protect the head, chest, and abdomen. This study utilized 3D-DIC technology to analyze UHMWPE laminate's response to 9 mm lead-core pistol bullets traveling at 334.93 m/s. Damage mode and response characteristics were revealed, and an effective numerical calculation method was established that could reveal the energy conversion process. The bullet penetrated by 1.03 mm, causing noticeable fiber traction, resulting in cross-shaped failure due to fiber compression and aggregation. Bulge transitioned from circular to square, initially increasing rapidly, then slowing. Maximum in-plane shear strain occurred at ±45°, with values of 0.0904 and -0.0928. Model accuracy was confirmed by comparing strain distributions. The investigation focused on bullet-laminate interaction and energy conversion. Bullet's kinetic energy is converted into laminate's kinetic and internal energy, with the majority of erosion energy occurring in the first four equivalent sublaminates and the primary energy change in the system occurring at 75 µs in the fourth equivalent sublayer. The results show the damage mode and energy conversion of the laminate, providing theoretical support for understanding the impact response mechanism and improving the efficiency of protective energy absorption.

Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

Enhanced interactions among gut mycobiomes with the deterioration of glycemic control.

BACKGROUND: The gut mycobiome is closely linked to health and disease; however, its role in the progression of type 2 diabetes mellitus (T2DM) remains obscure. Here, a multi-omics approach was employed to explore the role of intestinal fungi in the deterioration of glycemic control. METHODS: 350 participants without hypoglycemic therapies were invited for a standard oral glucose tolerance test to determine their status of glycemic control. The gut mycobiome was identified through internal transcribed spacer sequencing, host genetics were determined by genotyping array, and plasma metabolites were measured with untargeted liquid chromatography mass spectrometry. FINDINGS: The richness of fungi was higher, whereas its dissimilarity was markedly lower, in participants with T2DM. Moreover, the diversity and composition of fungi were closely associated with insulin sensitivity and pancreatic ß-cell functions. With the exacerbation of glycemic control, the co-occurrence network among fungus taxa became increasingly complex, and the complexity of the interaction network was inversely associated with insulin sensitivity. Mendelian randomization analysis further demonstrated that the Archaeorhizomycetes class, Fusarium genus, and Neoascochyta genus were causally linked to impaired glucose metabolism. Furthermore, integrative analysis with metabolomics showed that increased 4-hydroxy-2-oxoglutaric acid, ketoleucine, lysophosphatidylcholine (20:3/0:0), and N-lactoyl-phenylalanine, but decreased lysophosphatidylcholine (O-18:2), functioned as key molecules linking the adverse effect of Fusarium genus on insulin sensitivity. CONCLUSIONS: Our study uncovers a strong association between disturbance in gut fungi and the progression of T2DM and highlights the potential of targeting the gut mycobiome for the management of T2DM. FUNDINGS: This study was supported by MOST and NSFC of China.

Association of preoperative coronavirus disease 2019 with mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery: An observational cohort study.

STUDY OBJECTIVE: To assess the impact of preoperative infection with the contemporary strain of severe acute respiratory coronavirus 2 (SARS-CoV-2) on postoperative mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery. DESIGN: An ambidirectional observational cohort study. SETTING: A tertiary and teaching hospital in Shanghai, China. PATIENTS: All adult patients (≥ 18 years of age) who underwent elective, noncardiac surgery under general anesthesia at Huashan Hospital of Fudan University from January until March 2023 were screened for eligibility. A total of 2907 patients were included. EXPOSURE: Preoperative coronavirus disease 2019 (COVID-19) positivity. MEASUREMENTS: The primary outcome was 30-day postoperative mortality. The secondary outcomes included postoperative pulmonary complications (PPCs), myocardial injury after noncardiac surgery (MINS), acute kidney injury (AKI), postoperative delirium (POD) and postoperative sleep quality. Multivariable logistic regression was used to assess the risk of postoperative mortality and morbidity imposed by preoperative COVID-19. MAIN RESULTS: The risk of 30-day postoperative mortality was not associated with preoperative COVID-19 [adjusted odds ratio (aOR), 95% confidence interval (CI): 0.40, 0.13-1.28, P = 0.123] or operation timing relative to diagnosis. Preoperative COVID-19 did not increase the risk of PPCs (aOR, 95% CI: 0.99, 0.71-1.38, P = 0.944), MINS (aOR, 95% CI: 0.54, 0.22-1.30; P = 0.168), or AKI (aOR, 95% CI: 0.34, 0.10-1.09; P = 0.070) or affect postoperative sleep quality. Patients who underwent surgery within 7 weeks after COVID-19 had increased odds of developing delirium (aOR, 95% CI: 2.26, 1.05-4.86, P = 0.036). CONCLUSIONS: Preoperative COVID-19 or timing of surgery relative to diagnosis did not confer any added risk of 30-day postoperative mortality, PPCs, MINS or AKI. However, recent COVID-19 increased the risk of POD. Perioperative brain health should be considered during preoperative risk assessment for COVID-19 survivors.

EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential.

EH domain-containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear-cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N-terminal of EHD2 is attached to the cell membrane, while its C-terminal binds to the actin-binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.

Erratum: [Corrigendum] miR­137 suppresses proliferation, migration and invasion of colon cancer cell lines by targeting TCF4.

[This corrects the article DOI: 10.3892/ol.2018.8364.].

ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.

Can the width of lower tongue base preoperative sonography measurements predict hypoxemia during esophagogastroduodenoscopy under sedation in ASA I-II patients?

AIM: The most common complication during esophagogastroduodenoscopy (EGD) under sedation is hypoxemia. There is a scarcity of indicators to predict the risk of hypoxemia during EGD under sedation accurately. The width of the lower tongue base measured by ultrasound (US) is considered to be a significant predictor of the presence and severity of obstructive sleepapnea syndrome (OSAS), which develops hypoxemia by a similar mechanism to EGD under sedation. This study aimed to observe its ability to predict hypoxemia during EGD under sedation.Material and methodsː Adult patients undergoing EGD under sedation at our hospital after assessment in the anesthesia clinic were enrolled in the study. The width of the lower tongue base was measured as the distance between the lingual arteries (DLA) on both sides of the inferior lateral margin of the tongue by US. The primary outcome was hypoxemia defined as the SpO2 <90% for longer than 10 seconds during EGD under sedation. ResultsːA total of 304 patients were successfully included, and hypoxemia was reported in 32 patients (10.5%). The DLA prediction criterion for hypoxemia was >31 mm. The DLA was correlated with hypoxemia (Spearman correlation coefficient, 0.455; p<0.001) and owned the highest area under the receiver operating characteristic curve (0.927; 99% CI, 0.891 to 0.953, compared with that of the other predictors, p< 0.001) with hypoxemia.Conclusionsː The width of the lower tongue base, measured as the DLA by US examination can be used to effectively predict the risk of hypoxemia during EGD under sedation.

Predicting Rate Constants of Alkane Cracking Reactions Using Machine Learning.

Calculating the thermal rate constants of elementary combustion reactions is of great importance in theoretical chemistry. Machine learning has become a powerful, data-driven method for predicting rate constants nowadays. Recently, the molecular similarity combined with the topological indices were proposed to represent the hydrogen abstraction reactions of alkane [J. Chem. Inf. Model. 2023, 63, 5097-5106], which are, however, not applicable to alkane cracking reactions, another important class of combustion reactions, due to the cleavage of the C-C bond. In this work, a new feature selection scheme is proposed to describe both bimolecular and unimolecular cracking reactions. Molecular descriptors are elaborately selected individually for both reactants and products from those generated by the open-source software RDKit. Machine learning models combined with these molecular descriptors are proven to have the ability to accurately predict rate constants of both the hydrogen abstraction reactions of alkanes by CH3 and the alkane cracking reactions. The average deviation of the XGB-FNN model for prediction is around 60% for the hydrogen abstraction reactions of alkanes and 100% for the alkane cracking reactions. It is expected that the descriptors proposed in this work can be applied to build machine learning models for other reactions.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.