Elucidating the role of liver enzymes as markers and regulators in ovarian cancer: a synergistic approach using Mendelian randomization, single-cell analysis, and clinical evidence.

OBJECTIVE: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4). RESULTS: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed. CONCLUSION: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC.

Wild-type distributions of minimum inhibitory concentrations and epidemiological cut-off values-laboratory and clinical utility.

The characterization of wild-type minimum inhibitory concentration (MIC) and zone diameter distributions with the setting of epidemiological cut-off values (ECOFFs or ECVs) provides a reference for the otherwise relative MIC values in the international system for antimicrobial susceptibility testing. Distributions of MIC values for a species and an agent follow a log-normal distribution, which in the absence of resistance mechanisms is monomodal and designated wild type (WT). The upper end of the WT distribution, the ECOFF, can be identified with statistical methods. In the presence of phenotypically detectable resistance, the distribution has at least one more mode (the non-WT), but despite this, the WT is most often identifiable using the same methods. The ECOFF provides the most sensitive measure of resistance development in a species against an agent. The WT and non-WT modes are independent of the organism´s response to treatment, but when the European Committee on Antimicrobial Susceptibility Testing (EUCAST) determines the clinical breakpoints, the committee avoids breakpoints that split WT distributions of target species. This is to avoid the poorer reproducibility of susceptibility categorization when breakpoints split major populations but also because the EUCAST has failed to identify different clinical outcomes for isolates with different MIC values inside the wild-type distribution. In laboratory practice, the ECOFF is used to screen for and exclude resistance and allows the comparison of resistance between systems with different breakpoints from different breakpoint organizations, breakpoints evolving over time, and different breakpoints between human and animal medicine. The EUCAST actively encourages colleagues to question MIC distributions as presented on the website (https://www.eucast.org/mic_and_zone_distributions_and_ecoffs) and to contribute MIC and inhibition zone diameter data.

Unveiling Local Aging Patterns Following Accelerated Stress Testing of High-Performance Polymer Electrolyte Fuel Cells.

This study presents an in-depth analysis of heterogeneous aging patterns in membrane electrode assemblies (MEAs) subjected to diverse accelerated stress test (AST) conditions, simulating carbon corrosion (CC AST) and Pt particle size growth in fully humidified (Pt AST-Wet) and underhumidified (Pt AST-Dry) H2/N2 atmospheres. Multimodal characterization techniques are used to focus on heterogeneous aging patterns, primarily examining the variations in current distributions and Pt particle size maps. The findings reveal distinct characteristics of current distributions for all the AST cases, with substantial changes and strong current gradients in the CC AST case, indicative of severe performance degradation. Notably, despite significant differences in Pt particle size growth at the end-of-life (EOL), the Pt AST-Wet and Pt AST-Dry cases show minor changes in spatial current distributions. Moreover, a preferential growth of Pt particles under serpentine flow field bends in the Pt AST-Wet case is observed for the first time. This study provides crucial insights into the role of mass transport properties in shaping fuel cell performance, and highlights the need to consider factors beyond electrochemically-active surface area (ECSA) when assessing fuel cell durability.

Improved test-retest reliability of R 2 * $$ {\mathrm{R}}_2

PURPOSE: This study aimed to evaluate the potential of 3D EPI for improving the reliability of T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -weighted data and quantification of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ decay rate and susceptibility (χ) compared with conventional gradient-echo (GRE)-based acquisition. METHODS: Eight healthy subjects in a wide age range were recruited. Each subject received repeated scans for both GRE and EPI acquisitions with an isotropic 1 mm resolution at 3 T. Maps of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and χ were quantified, and their interscan differences were used to evaluate the test-retest reliability. Interprotocol differences of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and χ between GRE and EPI were also measured voxel by voxel and in selected regions of interest to test the consistency between the two acquisition methods. RESULTS: The quantifications of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and χ using EPI protocols showed increased test-retest reliability with higher EPI factors up to 5 as performed in the experiment and were consistent with those based on GRE. CONCLUSION: The result suggests that multishot multi-echo 3D EPI can be a useful alternative acquisition method for T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -weighted MRI and quantification of R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and χ with reduced scan time, improved test-retest reliability, and similar accuracy compared with commonly used 3D GRE.

Rapid submillimeter QSM and R2* mapping using interleaved multishot 3D-EPI at 7 and 3 Tesla.

PURPOSE: To explore the high signal-to-noise ratio (SNR) efficiency of interleaved multishot 3D-EPI with standard image reconstruction for fast and robust high-resolution whole-brain quantitative susceptibility (QSM) and R 2 ∗ $$ {R}_2^{\ast } $$ mapping at 7 and 3T. METHODS: Single- and multi-TE segmented 3D-EPI is combined with conventional CAIPIRINHA undersampling for up to 72-fold effective gradient echo (GRE) imaging acceleration. Across multiple averages, scan parameters are varied (e.g., dual-polarity frequency-encoding) to additionally correct for B 0 $$ {\mathrm{B}}_0 $$ -induced artifacts, geometric distortions and motion retrospectively. A comparison to established GRE protocols is made. Resolutions range from 1.4 mm isotropic (1 multi-TE average in 36 s) up to 0.4 mm isotropic (2 single-TE averages in approximately 6 min) with whole-head coverage. RESULTS: Only 1-4 averages are needed for sufficient SNR with 3D-EPI, depending on resolution and field strength. Fast scanning and small voxels together with retrospective corrections result in substantially reduced image artifacts, which improves susceptibility and R 2 ∗ $$ {R}_2^{\ast } $$ mapping. Additionally, much finer details are obtained in susceptibility-weighted image projections through significantly reduced partial voluming. CONCLUSION: Using interleaved multishot 3D-EPI, single-TE and multi-TE data can readily be acquired 10 times faster than with conventional, accelerated GRE imaging. Even 0.4 mm isotropic whole-head QSM within 6 min becomes feasible at 7T. At 3T, motion-robust 0.8 mm isotropic whole-brain QSM and R 2 ∗ $$ {R}_2^{\ast } $$ mapping with no apparent distortion in less than 7 min becomes clinically feasible. Stronger gradient systems may allow for even higher effective acceleration rates through larger EPI factors while maintaining optimal contrast.

Accelerated free-breathing liver fat and R 2 * quantification using multi-echo stack-of-radial MRI with motion-resolved multidimensional regularized reconstruction: Initial retrospective evaluation.

PURPOSE: To improve image quality, mitigate quantification biases and variations for free-breathing liver proton density fat fraction (PDFF) and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ quantification accelerated by radial k-space undersampling. METHODS: A free-breathing multi-echo stack-of-radial MRI method was developed with compressed sensing with multidimensional regularization. It was validated in motion phantoms with reference acquisitions without motion and in 11 subjects (6 patients with nonalcoholic fatty liver disease) with reference breath-hold Cartesian acquisitions. Images, PDFF, and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed using different radial view k-space sampling factors and reconstruction settings. Results were compared with reference-standard results using Bland-Altman analysis. Using linear mixed-effects model fitting (p < 0.05 considered significant), mean and SD were evaluated for biases and variations of PDFF and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ , respectively, and coefficient of variation on the first echo image was evaluated as a surrogate for image quality. RESULTS: Using the empirically determined optimal sampling factor of 0.25 in the accelerated in vivo protocols, mean differences and limits of agreement for the proposed method were [-0.5; -33.6, 32.7] s-1 for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and [-1.0%; -5.8%, 3.8%] for PDFF, close to those of a previous self-gating method using fully sampled radial views: [-0.1; -27.1, 27.0] s-1 for R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and [-0.4%; -4.5%, 3.7%] for PDFF. The proposed method had significantly lower coefficient of variation than other methods (p < 0.001). Effective acquisition time of 64 s or 59 s was achieved, compared with 171 s or 153 s for two baseline protocols with different radial views corresponding to sampling factor of 1.0. CONCLUSION: This proposed method may allow accelerated free-breathing liver PDFF and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ mapping with reduced biases and variations.

Quantification of the in vivo brain ultrashort-T2* component in healthy volunteers.

PURPOSE: Recent work has shown MRI is able to measure and quantify signals of phospholipid membrane-bound protons associated with myelin in the human brain. This work seeks to develop an improved technique for characterizing this brain ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component in vivo accounting for T 1 $$ {\mathrm{T}}_1 $$ weighting. METHODS: Data from ultrashort echo time scans from 16 healthy volunteers with variable flip angles (VFA) were collected and fitted into an advanced regression model to quantify signal fraction, relaxation time, and frequency shift of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component. RESULTS: The fitted components show intra-subject differences of different white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ signal fraction in the corticospinal tracts measured at 0.09 versus 0.06 in other white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ frequency shift in the body of the corpus callosum at - $$ - $$ 1.5 versus - $$ - $$ 2.0 ppm in other white matter structures. CONCLUSION: The significantly different measured components and measured T 1 $$ {\mathrm{T}}_1 $$ relaxation time of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component suggest that this method is picking up novel signals from phospholipid membrane-bound protons.

Mapping pathogenic bacteria resistance against common antibiotics and their potential susceptibility to methylated white kidney bean protein.

As antibiotics cannot inhibit multidrug-resistant bacteria (MDR), continuous research is mandatory to find other antibacterials from natural resources. Native legume proteins and their modified forms exhibited broad spectra of high antimicrobial activities. Sixteen bacterial isolates were mapped for antibiotic resistance, showing resistance in the range of (58-92%) and (42-92%) in the case of the Gram-negative and Gram-positive bacteria, respectively. White native Phaseolus vulgaris protein (NPP) was isolated from the seeds and methylated (MPP). The MIC range of MPP against 7 MDR bacteria was 10-25 times lower than NPP and could (1 MIC) considerably inhibit their 24 h liquid growth. MPP showed higher antibacterial effectiveness than Gentamycin, the most effective antibiotic against Gram-positive bacteria and the second most effective against Gram-negative bacteria. However, MPP recorded MICs against the seven studied MDR bacteria in the 1-20 µg/mL range, the same for Gentamycin. The combination of Gentamycin and MPP produced synergistic effects against the seven bacteria studied, as confirmed by the Transmission Electron Microscopic images. The antimicrobial activity of MPP against the seven MDR bacteria remained stable after two years of cold storage at 8-10 °C as contrasted to Gentamycin, which lost 20-72% of its antimicrobial effectiveness.

Elevation of S2-bound α1-acid glycoprotein is associated with chronic hepatitis C virus infection and hepatocellular carcinoma.

There is an urgent need for new high-quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2-bound α1-acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2-bound AGP in the early detection of HCC. In a retrospective case-control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct-acting antiviral agents (n = 93), we measured S2-bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow-up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty-one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction-associated steatotic liver disease and HCC of different etiologies were analysed. S2-bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2-bound AGP for the early detection of HCC during treatment and follow-up. Interestingly, S2-bound AGP levels correlated with aspartate aminotransferase (ρ = .56, p = 9.5×10-15) and liver elastography (ρ = .67, p = 2.2×10-16). Of note, S2-bound AGP decreased in patients chronically infected with HCV after treatment-induced HCV clearance. Fucosylated S2-bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2-bound AGP as a novel tumour marker requires further investigation.

Fecal microbiota transplantation alleviates mild-moderate COVID-19 associated diarrhoea and depression symptoms: A prospective study of a randomized, double-blind clinical trial.

Currently, the emergence of the endemic Coronavirus disease (COVID-19) situation still poses a serious threat to public health. However, it remains elusive about the role of fecal microbiota transplantation in treating COVID-19. We performed a randomized, double-blind, placebo-controlled clinical trial enrolling a cohort of 40 COVID-19 patients with mild-moderate symptoms. Our results showed that fecal microbiota transplantation provided an amelioration in diarrhoea (p = 0.026) of digestive system and depression (p = 0.006) of neuropsychiatric-related symptom in COVID-19 patients, respectively. Meanwhile, we found that the number of patients with diarrhoea decreased from 19 to 0 on day 7 after fecal microbiota transplantation treatment, and it was statistically changed compared to the placebo group (p = 0.047). Of note, the serum concentration of aspartate aminotransferase-to-alanine aminotransferase ratio (AST/ALT, fecal microbiota transplantation, pre vs. post: 0.966 vs. 0.817), a biomarker for predicting long COVID-19, was significantly reduced by fecal microbiota transplantation. In all, our study supports that fecal microbiota transplantation could be a novel therapeutic strategy for COVID-19 patients with diarrhoea and depressive symptoms, which is potentially valuable in ameliorating long COVID-19 symptoms.

Bacteriuria and phenotypic antimicrobial susceptibility testing in 45 min by point-of-care Sysmex PA-100 System: first clinical evaluation.

PURPOSE: This study compared the results of the new Sysmex PA-100 AST System, a point-of-care analyser, with routine microbiology for the detection of urinary tract infections (UTI) and performance of antimicrobial susceptibility tests (AST) directly from urine. METHODS: Native urine samples from 278 female patients with suspected uncomplicated UTI were tested in the Sysmex PA-100 and with reference methods of routine microbiology: urine culture for bacteriuria and disc diffusion for AST. RESULTS: The analyser delivered bacteriuria results in 15 min and AST results within 45 min. Sensitivity and specificity for detection of microbiologically confirmed bacteriuria were 84.0% (89/106; 95% CI: 75.6-90.4%) and 99.4% (155/156; 95% CI: 96.5-100%), respectively, for bacterial species within the analyser specifications. These are Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterococcus faecalis and Staphylococcus saprophyticus, which are common species causing uncomplicated UTI. Overall categorical agreement (OCA) for AST results for the five antimicrobials tested in the Sysmex PA-100 (amoxicillin/clavulanic acid, ciprofloxacin, fosfomycin, nitrofurantoin and trimethoprim) ranged from 85.4% (70/82; 95%CI: 75.9-92.2%) for ciprofloxacin to 96.4% (81/84; 95% CI: 89.9-99.3%) for trimethoprim. The Sysmex PA-100 provided an optimal treatment recommendation in 218/278 cases (78.4%), against 162/278 (58.3%) of clinical decisions. CONCLUSION: This first clinical evaluation of the Sysmex PA-100 in a near-patient setting demonstrated that the analyser delivers phenotypic AST results within 45 min, which could enable rapid initiation of the correct targeted treatment with no further adjustment needed. The Sysmex PA-100 has the potential to significantly reduce ineffective or unnecessary antibiotic prescription in patients with UTI symptoms.

Molecular characteristics and antimicrobial resistance profiles of Staphylococcus aureus isolates from burns.

BACKGROUND: Burns are a problem that affects millions of individuals around the world. OBJECTIVE: This research aimed to analyze the genetic characteristics and antibiotic resistance of Staphylococcus aureus strains isolated from patients with burns. Identifying the genetic variations of three local strains of Staphylococcus aureus isolated from burns. MATERIALS AND METHODS: Swab samples were collected from eighty sources (burns). Using sterile swabs containing media collected from patients treated at Baqubah Teaching Hospital between July 2022 and the end of September 2022, these samples were then cultured on blood agar and brain heart infusion agar. A total of twenty-four hours were spent incubating the cultured samples in an aerobic environment at 37 °C. During this time, isolated growing colonies showed characteristic growth, color, and hemolysis, while suspicious colonies were cultured for further identification. RESULTS: Our results indicated the presence of several polymorphisms that were distributed in the investigated samples. However, almost all observed variations were concentrated only in the S2 isolates. The construction of phylogenetic trees confirmed this notion by positioning these S2-based amplicons to distinct categories within Staph. aureus organisms. Furthermore, the phylogenetic tree offered additional tools for the guaranteed identity of the samples that were analyzed. Consequently, the utilization of the PCR-sequencing approach in three DNA samples belonging to these local bacterial isolates has resulted in the confirmation of the identity of this strain. However, particular emphasis should be placed on S2 isolate as it has special variants that differ from its mates, in terms of its metabolic as well as phylogenetic consequences. Therefore, S2 isolates may represent a new strain that requires a whole genome sequencing strategy to validate its identity within Staph. aureus organisms. S.aureus resistance was 100% (Augmentin and Tetracycline), and 90% (Azithromycin and Trimethoprim), while Cefotaxime and Chloramphenicol recorded (75%, and 85%) respectively.

Towards a Standardized Classification of the Hepatobiliary Manifestations in Cystic Fibrosis (CFHBI): A Joint ESPGHAN/NASPGHAN Position Paper.

The broad spectrum of hepatobiliary involvement in cystic fibrosis (CF) has been commonly referred to as cystic fibrosis liver disease (CFLD). However, differences in the definitions of CFLD have led to variations in reported prevalence, incidence rates, and standardized recommendations for diagnosis and therapies. Harmonizing the description of the spectrum of hepatobiliary involvement in all people with CF (pwCF) is deemed essential for providing a reliable account of the natural history, which in turn supports the development of meaningful clinical outcomes in patient care and research. Recognizing this necessity, The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) commissioned and tasked a committee to develop and propose a systematic classification of the CF hepatobiliary manifestations to increase uniformity, accuracy, and comparability for clinical, registry, and research purposes. This report describes the committee's combined expert position statement on hepatobiliary involvement in CF, which has been endorsed by NASPGHAN and ESPGHAN. We recommend using CFHBI (Cystic Fibrosis Hepato-Biliary Involvement) as the updated term to describe and classify all hepatobiliary manifestations in all pwCF. CFHBI encompasses the current extensive spectrum of phenotypical, clinical, or diagnostic expressions of liver involvement observed in pwCF. We present a schematic categorization of CFHBI, which may also be used to track and classify the changes and development of CFHBI in pwCF over time. The proposed classification for CFHBI is based on expert consensus and has not been validated for clinical practice and research purposes. Achieving validation should be an important aim for future research.

Predictive markers of metabolically healthy obesity in children and adolescents: can AST/ALT ratio serve as a simple and reliable diagnostic indicator?

This study aimed to estimate the prevalence of metabolically healthy obesity (MHO) according to two different consensus-based criteria and to investigate simple, measurable predictive markers for the diagnosis of MHO. Five hundred and ninety-three obese children and adolescents aged 6-18 years were included in the study. The frequency of MHO was calculated. ROC analysis was used to estimate the predictive value of AST/ALT ratio, waist/hip ratio, MPV, TSH, and Ft4 cut-off value for the diagnosis of MHO. The prevalence of MHO was 21.9% and 10.2% according to 2018 and 2023 consensus-based MHO criteria, respectively. AST/ALT ratio cut-off value for the diagnosis of MHO was calculated as ≥ 1 with 77% sensitivity and 52% specificity using Damanhoury et al.'s criteria (AUC = 0.61, p = 0.02), and 90% sensitivity and 51% specificity using Abiri et al.'s criteria (AUC = 0.70, p = 0.01). Additionally, using binomial regression analysis, only the AST/ALT ratio is independently and significantly associated with the diagnosis of MHO (p = 0.03 for 2018 criteria and p = 0.04 for 2023 criteria). CONCLUSION: The ALT/AST ratio may be a useful indicator of MHO in children and adolescents. WHAT IS KNOWN: • Metabolically healthy obesity refers to people who are obese but do not have any of the standard cardio-metabolic risk factors. • Metabolically healthy obesity is not entirely harmless; the metabolic characteristics of individuals with this phenotype are less favorable than those of healthy lean groups. Moreover, it is not a constant state, and there may be a transition to metabolically unhealthy phenotypes over time. WHAT IS NEW: • The prevalence of MHO is 21.9% and 10.2% according to 2018 and 2023 consensus-based metabolically healthy obesity criteria, respectively. • The ALT/AST ratio may be a useful indicator of metabolically healthy obesity in children and adolescents.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Sex Differences in the Association Between AST/ALT and Incidence of Type 2 Diabetes in Japanese Patients with Nonalcoholic Fatty Liver Disease: A Retrospective Cohort Study.

OBJECTIVES/INTRODUCTION: The purpose of the current study was to investigate the association between Aspartate Transaminase (AST)/Alanine transaminase(ALT) and type 2 diabetes (T2DM) in nonalcoholic fatty liver disease (NAFLD) patients and to determine whether there were sex differences. METHODS: In the retrospective study, we collected data on NAFLD patients (1, 896 men and 465 women) at Murakami Memorial Hospital from 2004 to 2015. Data were stratified by sex to investigate the association between AST/ALT and T2DM incidence by sex. Multiple regression analysis, smooth curve fitting model and subgroup analysis were used to determine the correlation, non-linear relationship and threshold effect between AST/ALT and T2DM. RESULTS: In our study, 157 men and 40 women developed T2DM at follow-up. After adjusting for risk factors, AST/ALT was significantly associated with T2DM in men with NAFLD but not in women with NAFLD. The risk of T2DM increased as the AST/ALT ratio decreased. Besides, in male NAFLD patients, AST/ALT showed a non-linear relationship with T2DM, with an inflection point value of 0.964. When the AST to ALT ratio was below the threshold (AST/ALT <0.964), AST/ALT was significantly negatively associated with T2DM (HR = 0.177, 95% CI 0.055-0.568; P = 0.0036). In contrast, when AST/ALT >0.964, no significant association was found (HR = 3.174, 95% CI 0.345-29.167; P = 0.3074). Moreover, subgroup analysis showed that GGT could alter the relationship between AST/ALT and T2DM. In the group with GGT ≤ 40, AST/ALT was strongly associated with T2DM (HR = 0.24, 95% CI 0.09-0.66; P = 0.0059). CONCLUSIONS: These results suggested that there were sex differences in the association between AST/ALT and T2DM in NAFLD participants. A non-linear association between AST/ALT and T2DM was observed in males. AST/ALT in the normal GGT group (GGT ≤40) might better facilitate the early screening of T2DM.

Evaluation of an automated rapid phenotypic antimicrobial susceptibility testing (ASTar, Q-linea AB) applied directly on blood cultures bottles positive for Gram-negative pathogens.

We evaluated the performance of a new rapid phenotypic antimicrobial susceptibility test (ASTar; Q-linea AB) on Gram-negative bacilli, directly from positive blood cultures bottles. MIC values obtained by the routine reference method (Microscan, Beckman Coulter) were compared to the ones provided by the tested method (ASTar). ASTar demonstrated an overall essential agreement of 98% and a category agreement of 96.1%. The overall rate of major errors and very major errors was 2.5% and 3.3%, respectively. ASTar can represent a rapid, simple, and reliable method to speed up information about antimicrobial susceptibility of Gram-negative pathogens from positive blood culture bottles.

Exploring Spectrogram-Based Audio Classification for Parkinson's Disease: A Study on Speech Classification and Qualitative Reliability Verification.

Patients suffering from Parkinson's disease suffer from voice impairment. In this study, we introduce models to classify normal and Parkinson's patients using their speech. We used an AST (audio spectrogram transformer), a transformer-based speech classification model that has recently outperformed CNN-based models in many fields, and a CNN-based PSLA (pretraining, sampling, labeling, and aggregation), a high-performance model in the existing speech classification field, for the study. This study compares and analyzes the models from both quantitative and qualitative perspectives. First, qualitatively, PSLA outperformed AST by more than 4% in accuracy, and the AUC was also higher, with 94.16% for AST and 97.43% for PSLA. Furthermore, we qualitatively evaluated the ability of the models to capture the acoustic features of Parkinson's through various CAM (class activation map)-based XAI (eXplainable AI) models such as GradCAM and EigenCAM. Based on PSLA, we found that the model focuses well on the muffled frequency band of Parkinson's speech, and the heatmap analysis of false positives and false negatives shows that the speech features are also visually represented when the model actually makes incorrect predictions. The contribution of this paper is that we not only found a suitable model for diagnosing Parkinson's through speech using two different types of models but also validated the predictions of the model in practice.

Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis With Liver Fibrosis as Predictors of New-Onset Diabetes Mellitus in People With HIV: A Longitudinal Cohort Study.

BACKGROUND: We investigated the association between nonalcoholic fatty liver disease (NAFLD) plus or minus a concurrent diagnosis of nonalcoholic steatohepatitis (NASH) and incident diabetes mellitus (DM) and the risk factors associated with NAFLD or NASH development. METHODS: In this prospective study, we analyzed people with human immunodeficiency virus (HIV; PWH) aged ≥18 years without excessive alcohol consumption or hepatitis coinfections. NAFLD was defined as controlled attenuation parameter ≥248 dB/m, whereas NASH with significant disease activity and liver fibrosis was defined as a FibroScan-AST score ≥0.67. Cox proportional hazard regression was used to investigate the association between NAFLD with or without NASH and new-onset DM. RESULTS: Of 847 PWH, the median age at baseline was 45 years (interquartile range, 38-51; 43% female). Baseline NAFLD was associated with 2.8-fold higher risk of new-onset DM after adjusting for age, sex, family history of DM, antiretroviral therapy duration, smoking, statin use, stavudine/didanosine/zidovudine exposure, time-updated body mass index, hypertension, and dyslipidemia. Combined NAFLD and NASH at baseline had 3.1-fold higher new-onset DM risk. In separate analyses, baseline DM did not predict progression to NAFLD or NASH, but tenofovir alafenamide use was associated with an increased risk of NAFLD (hazard ratio [HR], 2.01; 95% confidence interval [CI], 1.02-4.02) or NASH development (2.31; 95% CI, 1.12-5.11). CONCLUSIONS: NAFLD alone or combined with NASH strongly predicts new-onset DM. This highlights the need for systematic risk assessments and management of NAFLD/NASH, as it may contribute to metabolic complications such as DM and subsequent cardiovascular diseases in PWH.

Validation and Application of Long-Read Whole-Genome Sequencing for Antimicrobial Resistance Gene Detection and Antimicrobial Susceptibility Testing.

Next-generation sequencing applications are increasingly used for detection and characterization of antimicrobial-resistant pathogens in clinical settings. Oxford Nanopore Technologies (ONT) sequencing offers advantages for clinical use compared with other sequencing methodologies because it enables real-time basecalling, produces long sequencing reads that increase the ability to correctly assemble DNA fragments, provides short turnaround times, and requires relatively uncomplicated sample preparation. A drawback of ONT sequencing, however, is its lower per-read accuracy than short-read sequencing. We sought to identify best practices in ONT sequencing protocols. As some variability in sequencing results may be introduced by the DNA extraction methodology, we tested three DNA extraction kits across three independent laboratories using a representative set of six bacterial isolates to investigate accuracy and reproducibility of ONT technology. All DNA extraction techniques showed comparable performance; however, the DNeasy PowerSoil Pro kit had the highest sequencing yield. This kit was subsequently applied to 42 sequentially collected bacterial isolates from blood cultures to assess Ares Genetics's pipelines for predictive whole-genome sequencing antimicrobial susceptibility testing (WGS-AST) performance compared to phenotypic triplicate broth microdilution results. WGS-AST results ranged across the organisms and resulted in an overall categorical agreement of 95% for penicillins, 82.4% for cephalosporins, 76.7% for carbapenems, 86.9% for fluoroquinolones, and 96.2% for aminoglycosides. Very major errors/major errors were 0%/16.7% (penicillins), 11.7%/3.6% (cephalosporins), 0%/24.4% (carbapenems), 2.5%/7.7% (fluoroquinolones), and 0%/4.1% (aminoglycosides), respectively. This work showed that, although additional refinements are necessary, ONT sequencing demonstrates potential as a method to perform WGS-AST on cultured isolates for patient care.