Plant-microbe involvement: How manganese achieves harmonious nitrogen-removal and carbon-reduction in constructed wetlands.

Carbon deficits in inflow frequently lead to inefficient nitrogen removal in constructed wetlands (CWs) treating tailwater. Solid carbon sources, commonly employed to enhance denitrification in CWs, increase carbon emissions. In this study, MnO2 was incorporated into polycaprolactone substrates within CWs, significantly enhancing NH4+-N and NO3--N removal efficiencies by 48.26-59.78 % and 96.84-137.23 %, respectively. These improvements were attributed to enriched nitrogen-removal-related enzymes and increased plant absorption. Under high nitrogen loads (9.55 ± 0.34 g/m3/d), emissions of greenhouse gases (CO2, CH4, and N2O) decreased by 147.23-202.51 %, 14.53-86.76 %, and 63.36-87.36 %, respectively. N2O emissions were reduced through bolstered microbial nitrogen removal pathways by polycaprolactone and MnO2. CH4 accumulation was mitigated by the increased methanotrophs and dampened methanogenesis, modulated by manganese. Additionally, manganese-induced increases in photosynthetic pigment contents (21.28-64.65 %) fostered CO2 sequestration through plant photosynthesis. This research provides innovative perspectives on enhancing nitrogen removal and reducing greenhouse gas emissions in constructed wetlands with polymeric substrates.

Different oxygen affinities of methanotrophs and Comammox Nitrospira inform an electrically induced symbiosis for nitrogen loss.

Aerobic methanotrophs establish a symbiotic association with denitrifiers to facilitate the process of aerobic methane oxidation coupled with denitrification (AME-D). However, the symbiosis has been frequently observed in hypoxic conditions continuing to pose an enigma. The present study has firstly characterized an electrically induced symbiosis primarily governed by Methylosarcina and Hyphomicrobium for the AME-D process in a hypoxic niche caused by Comammox Nitrospira. The kinetic analysis revealed that Comammox Nitrospira exhibited a higher apparent oxygen affinity compared to Methylosarcina. While the coexistence of comammox and AME-D resulted in an increase in methane oxidation and nitrogen loss rates, from 0.82 ± 0.10 to 1.72 ± 0.09 mmol CH4 d-1 and from 0.59 ± 0.04 to 1.30 ± 0.15 mmol N2 d-1, respectively. Furthermore, the constructed microbial fuel cells demonstrated a pronounced dependence of the biocurrents on AME-D due to oxygen competition, suggesting the involvement of direct interspecies electron transfer in the AME-D process under hypoxic conditions. Metagenomic and metatranscriptomic analysis revealed that Methylosarcina efficiently oxidized methane to formaldehyde, subsequently generating abundant NAD(P)H for nitrate reduction by Hyphomicrobium through the dissimilatory RuMP pathway, leading to CO2 production. This study challenges the conventional understanding of survival mechanism employed by AME-D symbionts, thereby contributing to the characterization responsible for limiting methane emissions and promoting nitrogen removal in hypoxic regions.

Water extract of moschus alleviates erastin-induced ferroptosis by regulating the Keap1/Nrf2 pathway in HT22 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Moschus, first described in the Shennong's Classic of the Materia medicine, is a scarce and precious animal medicine. Modern pharmacological researches have suggested that Moschus has neuroprotective actions, and its mechanism is related to anti-inflammatory, antioxidant, and anti-apoptosis effects. Ferroptosis is one of the major pathologies of Alzheimer's disease (AD) and is widely implicated in the pathogenesis and progression of AD. Although previous studies have suggested that Moschus possesses neuroprotective effect, whether Moschus could mitigate neuronal damages by inhibiting the onset of ferroptosis is unknown in model cells of AD. AIM OF THE STUDY: The aim of study was to explore the water extract of Moschus (WEM) on ferroptosis caused by erastin and the potential mechanism. MATERIALS AND METHODS: Erastin was used to stimulate HT22 cells to form ferroptosis model to evaluate the anti-ferroptosis effect of WEM by cell counting kit-8 and lactic dehydrogenase (LDH) tests. The malondialdehyde (MDA) and glutathione (GSH) kits are used for detection of MDA and GSH levels, and 2',7'-dichlorofluorescein diacetate and C11 BODIPY 581/591 fluorescence probe are used for evaluation of reactive oxygen species (ROS) and lipid peroxide (LOOH) levels. And Western blot was used to test nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), and ferroptosis associated proteins including glutathione peroxidase 4 (GPX4), cystine/glutamate antiporter subunit (SLC7A11), ferritin heavy chain 1 (FTH1), ferroportin1 (FPN1), transferrin receptor (TFRC). In addition, the Nrf2 inhibitor ML385 was applied to verify whether WEM prevents erastin-induced ferroptosis by activating the Keap1/Nrf2 pathway. RESULTS: After WEM treatment, erastin-induced HT22 cell survival was significantly elevated, the accumulation of intracellular MDA, ROS, and LOOH were significantly reduced, the level of GSH and expressions of ferroptosis inhibitors GPX4 and SLC7A11 were significantly increased, and iron metabolism-related proteins TFRC, FPN1, and FTH1 were regulated. These effects of WEM are implemented by activating the Keap1/Nrf2 pathway. CONCLUSIONS: This study demonstrated that WEM could perform neuroprotective effects by alleviating ferroptosis, verified that WEM treatment of AD can be mediated by the Keap1/Nrf2 pathway, and provided theoretical support for the application of WEM in the treatment of AD.

Knowledge domains and emerging trends of Genome-wide association studies in Alzheimer's disease: A bibliometric analysis and visualization study from 2002 to 2022.

OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive decline in cognitive and behavioral function. Studies have shown that genetic factors are one of the main causes of AD risk. genome-wide association study (GWAS), as a novel and effective tool for studying the genetic risk of diseases, has attracted attention from researchers in recent years and a large number of studies have been conducted. This study aims to summarize the literature on GWAS in AD by bibliometric methods, analyze the current status, research hotspots and future trends in this field. METHODS: We retrieved articles on GWAS in AD published between 2002 and 2022 from Web of Science. CiteSpace and VOSviewer software were applied to analyze the articles for the number of articles published, countries/regions and institutions of publication, authors and cited authors, highly cited literature, and research hotspots. RESULTS: We retrieved a total of 2,751 articles. The United States had the highest number of publications in this field, and Columbia University was the institution with the most published articles. The identification of AD-related susceptibility genes and their effects on AD is one of the current research hotspots. Numerous risk genes have been identified, among which APOE, CLU, CD2AP, CD33, EPHA1, PICALM, CR1, ABCA7 and TREM2 are the current genes of interest. In addition, risk prediction for AD and research on other related diseases are also popular research directions in this field. CONCLUSION: This study conducted a comprehensive analysis of GWAS in AD and identified the current research hotspots and research trends. In addition, we also pointed out the shortcomings of current research and suggested future research directions. This study can provide researchers with information about the knowledge structure and emerging trends in the field of GWAS in AD and provide guidance for future research.

First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

Effect and Potential Mechanism of Immunotherapy on Cognitive Deficits in Animal Models of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: Immunotherapy has been reported to ameliorate Alzheimer's disease (AD) in the animal model; however, the immunologic approaches and mechanisms have not been specifically described. Thus, the systematic review and meta-analysis were conducted to explore the effect and potential mechanism of immunotherapy on AD animal experiments based on behavioral indicators. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Cochrane Collaboration guidelines and the inclusion/exclusion criteria of immunotherapy in animal studies, 15 studies were systematically reviewed after extraction from a collected database of 3,742 publications. Finally, the effect and mechanism of immunotherapy on AD models were described by performing multiple subgroup analyses. RESULTS: After immunotherapy, the escape latency was reduced by 18.15 seconds and the number of crossings over the platform location was increased by 1.60 times in the Morris Water Maze. Furthermore, compared to the control group, active and passive immunization could markedly ameliorate learning and memory impairment in 3 × Tg AD animal models, and active immunization could ameliorate the learning and memory ability of the APPswe/PS1ΔE9 AD animal model. Meanwhile, it could be speculated that cognitive dysfunction was improved by immunotherapy, perhaps mainly via reducing Aß40, Aß42, and Tau levels, as well as increasing IL-4 levels. CONCLUSION: Immunotherapy significantly ameliorated the cognitive dysfunction of AD animal models by assessing behavioral indicators.

Highly discriminative and adaptive feature extraction method based on NMF-MFCC for event recognition of Φ-OTDR.

To enhance the capability of phase-sensitive optical time domain reflectometers (Φ-OTDR) to recognize disturbance events, an improved adaptive feature extraction method based on NMF-MFCC is proposed, which replaces the fixed filter bank used in the traditional method to extract the mel-frequency cepstral coefficient (MFCC) features by a spectral structure obtained from the Φ-OTDR signal spectrum using nonnegative matrix factorization (NMF). Three typical events on fences are set as recognition targets in our experiments, and the results show that the NMF-MFCC features have higher distinguishability, with the corresponding recognition accuracy reaching 98.47%, which is 7% higher than that using the traditional MFCC features.

Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway.

Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of "regulation of menstruation with blood activation, relief of swelling and pain" and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC-MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC-MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.

Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta-analysis of preclinical studies.

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aß deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD.

Antibacterial Activity and Mechanism of Peptide PV-Q5 against Vibrio parahaemolyticus and Escherichia coli, Derived from Salt-Fermented Penaeus vannamei.

The increasing threat posed by antibiotic-resistant pathogens has prompted a shift to the use of naturally-derived antimicrobial peptides (AMPs) in place of chemical preservatives in controlling foodborne pathogens. In this study, ten peptides were identified from salt-fermented shrimps (Penaeus vannamei) using ultra-performance liquid chromatography-mass spectrometry. One of the peptides, designated PV-Q5 (QVRNFPRGSAASPSALASPR), with most features of an AMP, was further explored and found to possess strong antibacterial activity against Vibrio parahaemolyticus and Escherichia coli, with a minimum inhibitory concentration of 31.25 µg/mL. Moreover, PV-Q5 increased bacterial cell membrane permeability and ruptured bacteria cell membranes, as revealed by transmission electron microscopy. Circular dichroism analysis showed that the conformation of PV-Q5 was a random coil in phosphate-buffered saline and α-helical in sodium dodecyl sulfate, which is conducive for interaction with bacteria cell membranes. These findings indicated that PV-Q5 could find potential use in food preservation to control foodborne pathogenic bacteria.

Correlation between percutaneous patent foramen ovale closure and recurrence of unexplained syncope.

Background: The relationship between patent foramen ovale (PFO) and unexplained syncope remains to be illustrated. Therefore, this study aimed to explore the outcomes and prognostic factors for syncope recurrence after PFO closure. Methods: Patients with both large right-to-left shunting (RLS) PFO and unexplained syncope who visited the cardiovascular department of Xiangya Hospital Central South University from 1 January 2017 to 31 December 2021 were consecutively enrolled in our study. The recurrence rate of syncope was compared between the non-closure group (n = 20) and the closure group (n = 91). Results: A total of 111 patients were finally included. After 31.11 ± 14.30 months of follow-up, only 11% of patients in the closure group had recurrent syncope, which was much lower than that of the non-closure group (11.0 vs. 35%, P = 0.018). We further investigated the possible prognostic factors for syncope recurrence in the closure group and found syncope occurring more than five times preoperatively, hypertension, and residual RLS at 12-month follow-up were significantly correlated with a higher number of recurrences. Conclusions: PFO closure reduced the recurrence rate of unexplained syncope. The efficacy of prevention was prognosticated by factors including the presence or absence of syncope induction, the frequency of syncope episodes, and the presence or absence of hypertension. Syncope recurrence was also related to residual shunts post closure.

Concise method for high-precision vibration recovery of Φ-OTDR based on the GF-FastICA algorithm.

To efficiently restore the vibration signals of a phase-sensitive optical time domain reflectometer (Φ-OTDR), the GF-FastICA joint algorithm is proposed, which combines guided filtering with fast independent component analysis (FastICA). The marked region of vibration is precisely located by guided filtering. FastICA deals with the optimal phase mixing matrix of the marked region to separate the vibration signals from the noise-containing phase signals. The experimental results show that the GF-FastICA achieves a correlation coefficient of 0.998 for 5-Hz vibration signal recovery from a 14.3-km sensing fiber, verifying the potency of the algorithm. Compared with the traditional method and FastICA only, GF-FastICA improves the root mean square error (RMSE) metric by an order of magnitude, which is approaching an experience value of 10-3.

Morinda officinalis polysaccharides inhibit the expression and activity of NOD-like receptor thermal protein domain associated protein 3 in inflammatory periodontal ligament cells by upregulating silent information regulator sirtuin 1.

OBJECTIVES: This study aims to investigate the effect of morinda officinalis polysaccharides (MOP) in inflammatory microenvironment on the expression of silent information regulator sirtuin 1 (SIRT1) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) in periodontal ligament cells. METHODS: Thirty rats were randomly divided into control group (n=6) and model group (n=24). The model group used orthodontic wire ligation to establish periodontitis, and six rats from each group were killed after 3 weeks. The successful modeling was confirmed by Micro-CT. The remaining rats in the model group were randomly divided into natural recovery group, normal saline (NS) group, and MOP group. In the MOP group, MOP [200 mg/(kg·3d), 50 µL for 4 weeks] was injected into the palatal side of the left maxillary first molar of the rats, while the NS group was injected with equal volume of NS. The natural recovery group did not undergo any treatment. The left maxilla tissues of the rats were collected, and pathological changes in perio-dontal ligament cells were observed by hematoxylin-eosin (HE) staining. The expression of SIRT1 and NLRP3 was detected by immunohistochemistry. Cultivate periodontal ligament fibroblasts in vitro and detect the effect of MOP on cell activity using CCK-8. The 4th generation cells were divided into control group, inflammation group (10 µg/mL lipopolysaccharide), and experimental group (5 µmol/L MOP, 5 µmol/L MOP+10 µg/mL lipopolysaccharide). The expression of SIRT1 and NLRP3 was detected by quantitative realtime polymerase chain reaction (qRT-PCR) and Western blot analyses. The acetylation of NLRP3 and the contents of interleukin (IL)-1ß and IL-18 were detected by immunoprecipitation and enzyme-linked immunosorbent assay, respectively. Statistical analysis of data was conducted using Prism 9.0 software. RESULTS: In the vivo experiments, the expression of NLRP3 and SIRT1 in the MOP group decreased significantly compared with that in the natural recovery group and NS group, while the expression of SIRT1 increased (P<0.05) and inflammatory cell infiltration decreased. In the in vitro experiments, the expression of NLRP3 mRNA and protein in the inflammation group increased (P<0.05), while the expression of SIRT1 significantly decreased (P<0.01); MOP upregulated the expression of SIRT1 in inflammatory cells (P<0.05), reduced the expression of NLRP3 and its acetylation level significantly (P<0.05), suppressed the content of IL-1ß and IL-18 in the supernatant (P<0.01). CONCLUSIONS: The SIRT1 expression decreased, and that of NLRP3 expression increased in inflammatory periodontal ligament cells. MOP intervention promoted SIRT1 expression, resulting in the inhibition of NLRP3. Meanwhile, the acetylation level of NLRP3 reduced through deacetylation, leading to the decreased activity of NLRP3. Thus, MOP acted as inflammatory suppressor.

High-efficient disturbance event recognition method of ϕ-OTDR utilizing region-segmentation differential phase signals.

We demonstrate a disturbance event recognition method based on region segmentation, which utilizes differential phase signals of a phase-sensitive optical time-domain reflectometer (ϕ-OTDR) to recognize disturbance events efficiently. The long-haul sensing fiber is divided into subsensing regions; whereas the phase signals at the two end points of the subsensing regions are subtracted, unwrapped, and differenced to represent the disturbance information. Feature extraction and classification are performed separately on the subsensing regions datasets. The experimental results indicate that the average recognition accuracy of the region-segmentation-based event recognition method is up to 92.9%. Compared to the method without region segmentation, this proposed method improves the average recognition accuracy by 8%; whereas the recognition time of three disturbance events on a 14.8-km sensing system is only 0.39 s. The proposed method provides significant support for the development of disturbance event recognition of the ϕ-OTDR sensor system.

Cost Early-Warning Model System of Large-Scale Construction Project.

China's construction industry has been suffering from high cost, high efficiency, and maladjustment of management. The traditional management mode makes the construction project face the risk of cost overruns and delays, which cannot achieve the effect of cost control. Therefore, by summarizing the characteristics of construction projects and the classification of costs, this paper analyzes the foundation of earned value management method in construction and combines it with cost management; in addition, the actual development of Company A is taken as an example, where a cost early-warning system suitable for construction projects is constructed, including the design of the organizational structure, operation platform, and early-warning model of this system, which can improve the cost management level of construction enterprises to a certain extent.

Assessing the Equity of Accessibility to Urban Green Space: A Study of 254 Cities in China.

Urban green space has environmental benefits of purifying the air, reducing the heat island effect and providing the social and economic benefits of rest places and social platforms. An integrated and organized green space system is important for fully realizing the positive functions of an urban ecosystem. Previous studies have considered green space supply and demand, but few studies have examined large-scale, diverse and small-scale systems, making it difficult to conduct a comparative study of urban green space accessibility and equity under the same conditions (such as data sources and calculation methods). Using the two-step floating catchment area method, this study evaluates the equity of 254 urban green spaces in China within four ranges of accessibility: 1 km, 2.5 km, 5 km and 10 km. The study also considers urban house price in the research. The results show the following: (1) There are large differences in the accessibility of green space between different cities in China. Within the accessibility threshold of 10 km, the city with the most accessible urban green spaces has an accessibility level that is 27,813 times that of the city with the lowest accessibility. (2) Within the range of walking/cycling, there are significant inequalities in green space access in the 254 cities; the inequality of green space accessibility in most of the studied cities is at the "dangerous" level. (3) The two-step floating catchment area method indicates that the social superiority (high social class) represented by high housing prices is associated with a greater opportunity to access urban green space services. This paper highlights the main problems associated with the accessibility of urban green space in China and proposes targeted development recommendations. These recommendations provide a reference for urban managers to develop effective green space development policies and realize the optimal allocation of urban green space.

Identified Seaweed Compound Diphenylmethane Serves as an Efflux Pump Inhibitor in Drug-Resistant Escherichia coli.

Drug efflux pumps are one of the major elements used by antibiotic-resistant bacteria. Efflux pump inhibitors (EPIs) are potential therapeutic agents for adjunctive therapy, which can restore the activity of antibiotics that are no longer effective against pathogens. This study evaluated the seaweed compound diphenylmethane (DPM) for its EPI activity. The IC50 and modulation results showed that DPM has no antibacterial activity but can potentiate the activity of antibiotics against drug-resistant E. coli. Time-kill studies reported that a combination of DPM and erythromycin exhibited greater inhibitory activity against drug-resistant Escherichia coli. Dye accumulation and dye efflux studies using Hoechst 33342 and ethidium bromide showed that the addition of DPM significantly increased dye accumulation and reduced dye efflux in drug-resistant E. coli, suggesting its interference with dye translocation by an efflux pump. Using MALDI-TOF, it was observed that the addition of DPM could continuously reduce antibiotic efflux in drug-resistant E. coli. Additionally, DPM did not seem to damage the E. coli membranes, and the cell toxicity test showed that it features mild human-cell toxicity. In conclusion, these findings showed that DPM could serve as a potential EPI for drug-resistant E. coli.

Pharmacokinetics and Safety of Single-Dose Amphotericin B Colloidal Dispersion in Healthy Chinese Subjects and Population Pharmacokinetic/Pharmacodynamic Analysis to Inform Clinical Efficacy in Invasive Infections Caused by Candida albicans.

PURPOSE: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. METHODS: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. FINDINGS: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. IMPLICATIONS: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.

Adherence to Hepatocellular Carcinoma Surveillance and Perceived Barriers Among High-Risk Chronic Liver Disease Patients in Yunnan, China.

BACKGROUND: Data concerning adherence to hepatocellular carcinoma (HCC) surveillance among chronic liver disease (CLD) patients at high risk of developing HCC in China are limited. We aimed to examine the relationship between HCC-related knowledge dimensions and adherence to HCC surveillance procedures among chronic liver disease patients at high risk of developing HCC and to identify potential barriers. METHODS: A total of 380 patients with chronic liver disease at high risk of developing HCC were recruited between May and August 2018 to complete a survey during the first week of their first hospitalization at the Third People's Hospital of Kunming in China. We followed up each patient up to 7 months by telephone to confirm whether the patient returned to complete investigations for HCC surveillance. Patient's socio-demographic characteristics, HCC-related knowledge, and perceived barriers to HCC surveillance were measured using a structured questionnaire during their hospitalization. Factor analysis was performed on the knowledge questions to reduce the dimensions. Univariate and multivariate analyses were performed to examine the association between dimensions of HCC-related knowledge and patients' adherence to HCC surveillance. RESULTS: A total of 327 eligible patients had been successfully contacted in the follow-up phase. Only a quarter of patients completed HCC surveillance within 7 months after their first admission to hospital. High costs and perceived poor test efficacy were the two major barriers for HCC surveillance. Three common factors were derived from the factor analysis of HCC-related knowledge, namely, "Surveillance", "Lifestyle", and 'Prognosis'. Knowledge of HCC surveillance and lifestyle but not prognosis had an influence on adherence to HCC surveillance. Patients with better surveillance and lifestyle knowledge domain had better adherence to HCC surveillance. CONCLUSION: Adherence to HCC surveillance procedures is low in the study area. Closing the gap in HCC-related knowledge, particularly regarding surveillance and lifestyle, may help to increase adherence rates.

Probable Longer Incubation Period for Elderly COVID-19 Cases: Analysis of 180 Contact Tracing Data in Hubei Province, China.

BACKGROUND: Factors associated with the incubation period of COVID-19 are not fully known. The aim of this study was to estimate the incubation period of COVID-19 using epidemiological contact tracing data, and to explore whether there were different incubation periods among different age gr1oups. METHODS: We collected contact tracing data in a municipality in Hubei province during the full outbreak period of COVID-19. The exposure periods were inferred from the history of travel in Wuhan and/or history of exposure to confirmed cases. The incubation periods were estimated using parametric accelerated failure time models accounting for interval censoring of exposures. RESULTS: The incubation period of COVID-19 follows a Weibull distribution and has a median of 5.8 days with a bootstrap 95% CI: 5.4-6.7 days. Of the symptomatic cases, 95% showed symptoms by 14.3 days (95% CI: 13.0-15.7), and 99% showed symptoms by 18.7 days (95% CI: 16.7-20.9). The incubation periods were not found significantly different between male and female. Elderly cases had significant longer incubation periods than young age cases (HR 1.49 with 95% CI: 1.09-2.05). The median incubation period was estimated at 4.0 days (95% CI: 3.5-4.4) for cases aged under 30, 5.8 days (95% CI: 5.6-6.0) for cases aged between 30 and 59, and 7.7 days (95% CI: 6.9-8.4) for cases aged greater than or equal to 60. CONCLUSION: The current practice of a 14-day quarantine period in many regions is reasonable for any age. Older people infected with SARS-CoV2 have longer incubation period than that of younger people. Thus, more attention should be paid to asymptomatic elderly people who had a history of exposure.