Elucidating the role of hepatic enzymes in spontaneous abortion: a Mendelian randomization approach.

Background: While the hepatic enzymes Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) are crucial for liver function, their role in Spontaneous Abortion (SA) has not been thoroughly explored. Utilizing Mendelian Randomization (MR), this study aims to clarify the putative causal relationship between AST/ALT levels and SA. Methods: Genome-wide association study (GWAS) summary data for SA (finn-b-O15_ABORT_SPONTAN), AST (ukb-d-30650_raw), and ALT (ukb-d-30620_raw) were acquired from the Integrative Epidemiology Unit OpenGWAS database. Bidirectional MR analysis was conducted using MR-Egger, Weighted Median, Simple Mode, Weighted Mode, and Inverse Variance Weighted (IVW) algorithms, and the robustness of MR results was assessed through sensitivity analyses including Heterogeneity, Horizontal Pleiotropy, and Leave-One-Out (LOO) tests. The causal role of AST and ALT's coaction in SA was explored via multivariable MR (MVMR) analysis. Results: The MR results via the IVW algorithm revealed a causal relation between both AST and ALT and SA (AST: P = 0.013; ALT: P = 0.017), identifying them as risk factors for SA (AST: odd ratio (OR) = 1.019; ALT: OR = 1.012). Sensitivity analysis substantiated the reliability of these results. Moreover, not notably causality was found between SA and AST/ALT (P > 0.05). Through MVMR analysis, AST and ALT demonstrated functional complementarity in the occurrence of SA, attributable to counterbalanced causalities (AST: P = 0.128; ALT: P = 0.899). Conclusion: The study substantiates a causal linkage between transaminase levels and SA, enhancing our understanding of their biological interaction and the regulatory mechanisms at play. These insights could have implications for identifying novel biomarkers and therapeutic targets for SA.

In Situ Analysis of Binder Degradation during Catalyst-Accelerated Stress Test of Polymer Electrolyte Membrane Fuel Cells.

High-oxygen-permeability ionomers (HOPIs) are being actively developed to enhance the performance and durability of high-power polymer electrolyte membrane fuel cells (PEMFCs). While methods for evaluating binder performance are well-established, techniques for assessing binder durability and measuring its degradation in situ during the AST process remain limited. This study examines the distribution of relaxation times (DRT) and Warburg-like response (WLR) methods as in situ analysis techniques during the catalyst-accelerated stress test (AST) process. We conducted catalyst-ASTs (0.6-0.95 V cycling) for 20,000 cycles, monitoring changes using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and linear sweep voltammetry (LSV). Contrary to expectations, during the catalyst-AST, the ion transport resistance of the binder decreased, indicating no binder degradation. Scanning electron microscopy/energy dispersive spectrometer (SEM/EDS) analysis revealed that the degradation rate of the catalyst and the support was relatively higher than that of the binder, leading to a reduction in catalyst layer thickness and improved binder network formation. By applying the DRT method during the catalyst-AST process, we were able to measure the increase in oxygen reduction reaction (ORR) resistance and the decrease in proton transport resistance in situ. This allowed for the real-time detection of the reduction in catalyst layer thickness and improvements in ionomer networks due to catalyst and support degradation. These findings provide new insights into the complex interplay between catalyst degradation and binder performance, contributing to the development of more durable PEMFC components.

A multicenter evaluation of a novel microfluidic rapid AST assay for Gram-negative bloodstream infections.

Common phenotypic methods for antimicrobial susceptibility testing (AST) of bacteria are slow, labor intensive, and display considerable technical variability. The QuickMIC system provides rapid AST using a microfluidic linear gradient. Here, we evaluate the performance of QuickMIC at four different laboratories with regard to speed, precision, accuracy, and reproducibility in comparison to broth microdilution (BMD). Spiked (n = 411) and clinical blood cultures (n = 148) were tested with the QuickMIC Gram-negative panel and compared with BMD for the 12 on-panel antibiotics, and 10 defined strains were run at each site to measure reproducibility. Logistic and linear regression analysis was applied to explore factors affecting assay performance. The overall essential agreement and categorical agreement between QuickMIC and BMD were 95.6% and 96.0%, respectively. Very major error, major error, and minor error rates were 1.0%, 0.6%, and 2.4%, respectively. Inter-laboratory reproducibility between the sites was high at 98.9% using the acceptable standard of ±1 twofold dilution. The mean in-instrument analysis time overall was 3 h 13 min (SD: 29 min). Regression analysis indicated that QuickMIC is robust with regard to initial inoculum and delay time after blood culture positivity. We conclude that QuickMIC can be used to rapidly measure MIC directly from blood cultures in clinical settings with high reproducibility, precision, and accuracy. The microfluidics-generated linear gradient ensures high reproducibility between laboratories, thus allowing a high level of trust in MIC values from single testing, at the cost of reduced measurement range compared to BMD. IMPORTANCE: Increasing antimicrobial resistance underscores the need for new diagnostic solutions to guide therapy, but traditional antimicrobial susceptibility testing (AST) is often inadequate in time-critical diseases such as sepsis. This work presents a novel and rapid AST system with a rapid turnaround of results, which may help reduce the time to guided therapy, possibly allowing early de-escalation of broad-spectrum empirical therapy as well as rapid adjustments to treatments when coverage is lacking.

Spherical echo-planar time-resolved imaging (sEPTI) for rapid 3D quantitative T 2 * and susceptibility imaging.

PURPOSE: To develop a 3D spherical EPTI (sEPTI) acquisition and a comprehensive reconstruction pipeline for rapid high-quality whole-brain submillimeter T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and QSM quantification. METHODS: For the sEPTI acquisition, spherical k-space coverage is utilized with variable echo-spacing and maximum kx ramp-sampling to improve efficiency and signal incoherency compared to existing EPTI approaches. For reconstruction, an iterative rank-shrinking B0 estimation and odd-even high-order phase correction algorithms were incorporated into the reconstruction to better mitigate artifacts from field imperfections. A physics-informed unrolled network was utilized to boost the SNR, where 1-mm and 0.75-mm isotropic whole-brain imaging were performed in 45 and 90 s at 3 T, respectively. These protocols were validated through simulations, phantom, and in vivo experiments. Ten healthy subjects were recruited to provide sufficient data for the unrolled network. The entire pipeline was validated on additional five healthy subjects where different EPTI sampling approaches were compared. Two additional pediatric patients with epilepsy were recruited to demonstrate the generalizability of the unrolled reconstruction. RESULTS: sEPTI achieved 1.4 × $$ \times $$ faster imaging with improved image quality and quantitative map precision compared to existing EPTI approaches. The B0 update and the phase correction provide improved reconstruction performance with lower artifacts. The unrolled network boosted the SNR, achieving high-quality T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and QSM quantification with single average data. High-quality reconstruction was also obtained in the pediatric patients using this network. CONCLUSION: sEPTI achieved whole-brain distortion-free multi-echo imaging and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and QSM quantification at 0.75 mm in 90 s which has the potential to be useful for wide clinical applications.

Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.

AST-3424 is a novel and highly tumor-selective prodrug. AST-3424 is activated by AKR1C3 to release a toxic bis-alkylating moiety, AST 2660. In this study, we have investigated the essential role of DNA repair in AST-3424 mediated pharmacological activities in vitro and in vivo. We show here that AST-3424 is effective as a single therapeutic agent against cancer cells to induce cytotoxicity, DNA damage, apoptosis and cell cycle arrest at G2 phase in a dose- and AKR1C3-dependent manner in both p53-proficient H460 (RRID:CVCL_0459) and p53-deficient HT-29 cells (RRID:CVCL_0320). The combination of abrogators of G2 checkpoint with AST-3424 was only synergistic in HT-29 but not in H460 cells. The enhanced activity of AST-3424 in HT-29 cells was due to impaired DNA repair ability via the attenuation of cell cycle G2 arrest and reduced RAD51 expression. Furthermore, we utilized a BRCA2 deficient cell line and two PDX models with BRCA deleterious mutations to study the increased activity of AST-3424. The results showed that AST-3424 exhibited enhanced in vitro cytotoxicity and superior and durable in vivo anti-tumor effects in cells deficient of DNA repair protein BRCA2. In summary, we report here that when DNA repair capacity is reduced, the in vitro and in vivo activity of AST-3424 can be further enhanced, thus providing supporting evidence for the further evaluation of AST-3424 in the clinic.

Effectiveness of sarcopenia screening markers in predicting out-of-hospital death in the oldest (≥80 years) older.

OBJECTIVE: The goal of this investigation was to elucidate the correlation between sarcopenia screening indicators (aspartate transaminase/alanine transaminase (AST/ALT) and creatinine/cystatin C*100 (Cr/CysC*100)) and the risk of out-of-hospital (OFH) death among the very advanced age (≥80 years) population. METHODS: We conducted a retrospective cohort investigation, involving internal medicine inpatients aged ≥80 years of age, who sought treatment at a teaching hospital in western China. We obtained OFH mortality information from telephonic interviews. Subsequently, we employed Cox proportional hazards models to analyze the links between AST/ALT and Cr/CysC*100 and OFH all-cause mortality among the very advanced age (≥80 years old) population. RESULTS: In all, we recruited 398 subjects, among which 51.51% were male. The median age of OFH deceased male patients was 85 years, and the same for female patients was 87 years. The total quantity of OFH deaths was 164 (41.21%). Among the oldest male population, those who died OFH exhibited enhanced AST/ALT, relative to those who survived (death vs. survival: 1.5 vs 1.3, P=0.008). However, among the oldest female, there was no difference in AST/ALT between patients who expired OFH, and those who survived. Among the oldest elders (male and female), Cr/CysC*100 did not significantly differ between surviving and OFH deceased patients. Additional analysis involving the Cox proportional hazards model revealed that among the oldest male population, an enhanced AST/ALT denoted an augmented risk of OFH death (hazard ratios (HRs) =1.797, 95%CI: 1.2-2.691). However, Cr/CysC*100 was not correlated with OFH mortality risk. Among the oldest female population, neither AST/ALT nor Cr/CysC*100 was correlated with OFH mortality risk. CONCLUSIONS: Enhanced AST/ALT was correlated with an augmented OFH mortality risk among the oldest male, but not female population. Alternately, Cr/CysC*100 was not linked to OFH mortality risk among any population.

Advances in genotypic antimicrobialresistance testing: a comprehensive review.

Antimicrobial resistance (AMR) represents a substantial threat to global public health, complicating the treatment of common infections and leading to prolonged illness and escalated healthcare expenses. To effectively combat AMR, timely and accurate detection is crucial for AMR surveillance and individual-based therapy. Phenotypic antibiotic resistance testing (AST) has long been considered the gold standard in clinical applications, serving as the foundation for clinical AMR diagnosis and optimized therapy. It has significantly contributed to ensuring patients' health and the development of novel antimicrobials. Despite advancements in automated culture-based AST technologies, inherent limitations impede the widespread use of phenotypic AST in AMR surveillance. Genotypic AST technologies offer a promising alternative option, exhibiting advantages of rapidity, high sensitivity, and specificity. With the continuous advancement and expanding applications of genotypic AST technologies, such as microfluidics, mass spectrometry, and high-resolution melting curve analysis, new vigor has been injected into the development and clinical implementation of genotypic AST technologies. In this narrative review, we discuss the principles, applications, and advancements of emerging genotypic AST methods in clinical settings. The comprehensive review aims to highlight the significant scientific potential of emerging genotypic AST technologies in clinical AMR diagnosis, providing insights to enhance existing methods and explore novel approaches.

Antimicrobial susceptibility testing of bone and joint pathogens using isothermal microcalorimetry.

The rise in osteomyelitis and periprosthetic joint infections, in combination with increasing life expectancy and the prevalence of diabetes, underscores the urgent need for rapid and accurate diagnostic tools. Conventional culture-based methods are often time-consuming and prone to false-negatives, leading to prolonged and inappropriate antibiotic treatments. This study aims to improve osteomyelitis diagnostics by decreasing the time to detection and the time to an antibiotic susceptibility result to enable a targeted treatment using isothermal microcalorimetry (IMC). IMC measures heat flow in real-time, providing insights into bacterial metabolism without the need for labeling. Using clinical isolates from bone infections, assessing their response to antibiotics through IMC, we demonstrated that IMC could detect bacteria within 4 h and determine antimicrobial susceptibility profiles within 2-22 h (median 4.85, range 1.28-21.78). This is significantly faster than traditional methods. A decision tree, based on antibiotic susceptibility, accurately categorized pathogens, achieving high accuracy (74-100%), sensitivity (100%), and specificity (65-100%). These findings suggest that IMC could redefine diagnostics of bone and joint infections and potentially infections in general, offering timely and precise treatment guidance, thereby improving patient outcomes and reducing health care burdens. Further optimization and clinical validation are needed to fully integrate IMC into routine diagnostics.

The impact of agar depth on antimicrobial susceptibility testing by disc diffusion.

Introduction. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) specifies the agar depth (4±0.5 mm) when performing antimicrobial susceptibility testing (AST). Since the infrastructure to produce standardized agar may be lacking in settings with limited resources, we wanted to examine to what extent variation in agar depth affects the inhibition zone diameters of quality control (QC) strains and AST of clinical isolates.Methods. The inhibition zone diameters on Mueller-Hinton II agar with different depths (2-6 mm) were tested for various QC strain-antimicrobial agent combinations using Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213. The relationship between zone diameters at different agar depths and MICs was investigated for 35 clinical isolates (E. coli, Klebsiella pneumoniae, S. aureus and P. aeruginosa) from Sierra Leone using MICs as the reference.Results. The inhibition zone diameters were within the acceptance ranges as defined by the EUCAST for the majority of QC strains and antimicrobials, independent of the agar depth. At extreme agar depths, inhibition zones were more frequently out of range. The accuracy of AST varied for clinical isolates at different agar depths for categorical agreement (85.8-94.6%), major error rate (0.4-2.1%) and very major error rate (VME: 3.3-12.5%).Conclusions. Even if the QC strains were in the acceptance range at different agar depths, this does not rule out unacceptably high VME rates (>3%) in clinical isolates.

The Etiological and Antimicrobial Susceptibility Profiles of the Bacteria Obtained from Ovine Caseous Lymphadenitis Cases in the Çankiri Region, Türkiye.

Sheep caseous lymphadenitis (CLA) causes significant economic losses in the livestock sector by causing a loss in the quantity and quality of animal products and a loss in the breeding value of animals. Although the primary agent in CLA's etiology is Corynebacterium pseudotuberculosis, some other opportunistic microorganisms also play a role. Therefore, the control and treatment of CLA necessitates the identification of the relevant etiological agents. This study aimed to conduct an in vitro culture and molecular characterization (PCR analysis and 16S rRNA sequencing) of the bacteria involved in sheep CLA cases reported in the Çankiri province of Türkiye and determine the antibiotic susceptibility of the case isolates. In total, 82 (16.4%) of 500 sheep in five farms were diagnosed with CLA. Following the culture of the superficial abscesses samples, C. pseudotuberculosis was identified in 30 (36.59%) as a result of PCR, Pseudomonas spp. in 8 (9.76%), and Enterobacter cancerogenus in 1 (1.22%), as a result of 16S rRNA sequencing. These data revealed extensive heterogeneity among the Pseudomonas isolates, with hints of derivation from a common ancestry for some and phylogenetic similarity to isolates from Germany, Malaysia, and India. In contrast to the high susceptibility to cefoperazone and lincomycin, the high resistances of C. pseudotuberculosis and Pseudomonas spp. isolates to cephalothin, ceftiofur, cloxacillin, amoxicillin, and bacitracin were remarkable. Based on these findings, it was concluded that for an effective treatment and control of ovine CLA cases, there is a need to consider the possible involvement of opportunistic bacteria other than the primary causative agent, C. pseudotuberculosis. It also contributed to increasing the country-specific sequence data and establishing new taxa from a universal perspective.

Role of oral hypoglycaemic drugs in preventing complication in non-alcoholic fatty liver disease with type 2 diabetes mellitus.

Objective: To determine the prevalence of non-alcoholic fatty liver disease, and the effect of oral hypoglycaemic drugs and lifestyle modifications in reducing fatty liver changes and liver enzymes in these patients. METHODS: The comparative, observational study was conducted at the Department of Pharmacology, Sohail University, Karachi, from October 2022 to October 2023, and comprised patients of either gender having elevated liver enzymes and ultrasound finding of fatty liver changes along with raised glycated haemoglobin, transaminases, total cholesterol and triglycerides. The participants were prescribed oral hypoglycaemic agents by endocrinologists. Those given empaglifazolin + metformin were in group A, empaglifazolin + linglaptin in group B, sitaglaptin + metformin in group C, metformin alone in group D and sitaglaptin alone in group E. Lifestyle modifications were advised in all the treatment groups, while control group F was only advised lifestyle modifications. The intervention lasted 3 months. Investigations included B-mode ultrasound liver, liver enzymes and glycated haemoglobin, which were done at baseline and after the intervention. Data was analysed using SPSS 25. RESULTS: Of 200 patients, 40 were males and 160 were females in ratio of 1:4. The overall mean age was 48±16 years. There were 154(77%) patients who had non-alcoholic fatty liver disease with type 2 diabetes mellitus, while 46(23%) had only fatty liver changes. There were 50(25%) patients in group A, 30(15%) in group B, 30(15%) in group C, 40(20%) in group D, 10(5%) in group E and 40(20%) in group F. Post-intervention improvement was noted in 48(24%) patients, with 20(41.7%) of them being in group A. Conclusion: The prevalence of non-alcoholic fatty liver disease with type 2 diabetes was high. Combination of empagliflozin + metformin along with lifestyle modifications was highly effective in reducing fatty changes and the level of liver enzymes.

The AST/ALT ratio predicts survival and improves oncological therapy decisions in patients with non-small cell lung cancer receiving immunotherapy with or without radiotherapy.

Background and purpose: Immunotherapy, with or without radiotherapy (iRT or ICIs-nonRT), is the standard treatment for non-small cell lung cancer (NSCLC). Nonetheless, the response to the treatment varies among patients. Given the established role of aspartate aminotransferase/alanine transaminase (AST/ALT) ratio in predicting cancer prognosis, we sought to identify whether the pre-treatment AST/ALT ratio has the potential to serve as a prognostic factor for NSCLC patients receiving ICIs-nonRT and iRT. Materials and methods: We retrospectively analyzed NSCLC patients who received immunotherapy between April 2018 and March 2021. Patients were classified into iRT group and ICIs-nonRT group and further classified based on AST/ALT ratio cut-off values. The Kaplan-Meier (KM) method estimated the time-to-event endpoints (progression-free survival (PFS) and overall survival (OS). Results: Of the cohort, 239 underwent ICIs-nonRT and 155 received iRT. Higher AST/ALT ratios correlated with worse outcomes in the ICIs-nonRT group but indicated better outcomes in those who received iRT. Multivariate analysis validated AST/ALT ratio as an independent prognostic factor. For AST/ALT ratios between 0.67-1.7, both ICIs-nonRT and iRT yielded similar treatment outcomes; with AST/ALT ratios greater than 1.7, iRT could be a more favorable treatment option (P=0.038). Conversely, for ratios less than 0.67, ICIs-nonRT could be a more favorable treatment option (P=0.073). Conclusions: The pre-treatment AST/ALT ratio demonstrates potential as a prognostic marker for treatment outcomes in NSCLC patients receiving either ICIs-nonRT or iRT. This finding could help guide clinicians in selecting more effective treatment protocols, thereby enhancing patient prognosis.

Strong associations between fasting lipids and glucose concentrations and ALT levels strengthened with increasing ALT quantiles.

BACKGROUND: A persistent redox state and excessive reactive species involved in carbohydrate and lipid metabolism lead to oxidative damage in the liver, however, how fasting plasma concentrations of lipids and glucose are associated with fasting blood levels of alanine transaminase (ALT) and aspartate transaminase (AST) remains to be evaluated in large-scale population. METHODS: A cross-sectional study with 182,971 residents aged 18 to 92 years; multidimensional stratified analyses including quantile linear regression analysis and sex stratification were adopted to improve the quality of the evidence. RESULTS: The associations between the concentrations of non-HDL-C and triglyceride and ALT levels were positive, stronger in males in each quantile of ALT levels and the coefficients expanded with increasing ALT levels at slopes of 3.610 and 5.678 in males and 2.977 and 5.165 in females, respectively. The associations between the HDL-C concentrations and ALT levels were negative, also stronger in males in each quantile and the coefficients expanded with increasing ALT levels at slopes of -7.839 in females and - 5.797 in males. The associations between glucose concentrations and ALT levels were positive, but stronger in females in each quantile and the coefficients expanded with increasing ALT levels at slopes of 1.736 in males and 2.177 in females, respectively. Similar pattern consist of relatively weaker coefficients and slops were observed between concentrations of non-HDL-C, triglyceride and glucose and AST levels. The associations between albumin concentration and concentrations of blood lipids and glucose were relatively steady across all quantiles. CONCLUSIONS: The dose dependent effect between blood concentrations of lipids and glucose and liver function changes suggests that excessive carbohydrate and lipid metabolism may cause subclinical liver damage. Long term sustained primary and secondary inflammatory factors produced in the liver might be transmitted to adjacent organs, such as the heart, kidneys, and lungs, to cause and/or exacerbate pathological changes in these visceral organs.

Retrospective Study on the Features and Outcomes of a Tuscany COVID-19 Hospitalized Patients Cohort: Preliminary Results.

Background: A few months after the COVID-19 pandemic onset, knowledge of SARS-CoV-2 infection and outcomes and treatments blew up. This paper aimed to evaluate the features of a Tuscany COVID-19 hospitalized cohort and to identify risk factors for COVID-19 severity. Methods: This retrospective observational COVID-19 cohort study (1 March 2020-1 March 2021) was conducted on patients ≥ 18 years old, admitted to Tuscany Hospital, and subjected to follow-up within 12 months after discharge. Patients were enrolled at Pisana, Senese and Careggi University Hospitals, and South East, North West, and Center Local Hospitals. Results: 2888 patients (M = 58.5%, mean age = 66.2 years) were enrolled, of whom 14.3% (N = 413) were admitted to an intensive care unit. Smokers were 25%, and overweight and obese 65%. The most used drugs were corticosteroids, antacids, antibiotics, and antithrombotics, all antiviral drugs, with slight differences between 2020 and 2021. A strong association was found between outcomes of evolution towards critical COVID-19 (non-invasive mechanical ventilation (NIV) and/or admission to intensive care) and smoking (RR = 4.91), ex-smoking (RR = 3.48), overweight (RR = 1.30), obese subjects (RR = 1.62), comorbidities (aRR = 1.38). The alteration of liver enzymes (aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyl transpeptidase) was associated with NIV (aOR = 2.28). Conclusions: Our cohort, characterized by patients with a mean age of 66.2 years, showed 65% of patients were overweight and obese. Smoking/ex-smoking, overweight/obesity, and other comorbidities were associated with COVID-19 adverse outcomes. The findings also demonstrated that alterations in liver enzymes were associated with worse outcomes.

Evaluation of the Vitek® Reveal™ system for rapid antimicrobial susceptibility testing of Gram-negative pathogens, including ESBL, CRE and CRAB, from positive blood cultures.

Blood culture (BC) remains the reference diagnostic tool for bloodstream infections but is hampered by long turn-around time (TAT). This study evaluated the Vitek® Reveal™ (VR) system for rapid antimicrobial susceptibility testing (AST) with 72 cases of monomicrobial BCs (55 Enterobacterales, 12 Pseudomonas aeruginosa and 5 Acinetobacter baumannii), including isolates producing carbapenemases and/or extended-spectrum ß-lactamases. VR returned AST results with a mean TAT of 5.4 h. Compared to a conventional workflow based on broth microdilution, VR exhibited essential agreement (EA) and category agreement (CA) >90 % in most cases, except with meropenem for Enterobacterales (CA, 85.5 %), piperacillin/tazobactam for P. aeruginosa (EA, 83.3 %), and trimethoprim/sulfamethoxazole for A. baumannii (CA and EA, 80 %). Bias exhibited an underestimation trend with ceftazidime/avibactam (-78.9 %) and ceftazidime (-50 %) for Enterobacterales and P. aeruginosa, respectively. Overall, VR appears an interesting tool to decrease TAT of the BC workflow, although further evaluation with some antibiotic-pathogen combinations would be warranted.

The different associations of serum gamma-glutamyl transferase and alanine aminotransferase with insulin secretion, ß-cell function, and insulin resistance in non-obese Japanese.

The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and ß-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m2. Pancreatic ß-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese.

Assessment of change in antimicrobial susceptibility pattern of bacteria causing orthopaedic infections by sequential sampling: A prospective cohort study.

Background: Management of Orthopaedic wound infections often depend on isolation of bacteria species (spp.) and its subsequent antimicrobial susceptibility testing (AST). However, the susceptibility to antibiotics may change over time in the same bacterial spp. particularly after initiation of antibiotic therapy. Repeating AST through sequential sampling can be used for the early detection of changes in antimicrobial susceptibility pattern. However, the recommendations about the optimal frequency of repeat AST for same bacterial spp. isolates from same patient to detect the changes in susceptibility patterns are still not established. Furthermore, no prospective research is available to address the crucial issue. Thus, we aimed this study to evaluate the need of repeat AST through sequential samples from the same site. Methods: AST was performed on same bacterial spp. isolates from three sequential samples using Kirby-Bauer disc diffusion method. Considering day 1 as control/baseline, changes in antimicrobial susceptibility pattern was interpreted on two sequential instances (on day 3 and day5). Changes were categorized into favorable & unfavorable and major & minor change categories. Results: The overall change in antimicrobial susceptibility pattern was 28 % on instance 1(on day3) and 36.1 % at instance 2 (on day 5). Susceptible to resistance phenotypic change was 14.9 % at instance 1 and 9.2 % at instance 2.A higher percentage change per case in antimicrobial susceptibility pattern was observed at instance 2. Predominant changes were towards the direction of favorable antimicrobial susceptibility pattern. Conclusion: The risk of change in antimicrobial susceptibility potential was over 10 % at both the instances. Furthermore, it was higher at instance 2 i.e., at day5, therefore a repeat sequential antimicrobial susceptibility testing would be recommended at later instance.

Hetero-antagonism of avibactam and sulbactam with cefiderocol in carbapenem-resistant Acinetobacter spp.

Cefiderocol, a siderophore-cephalosporine conjugate antibiotic, shows promise as a therapeutic option for carbapenem-resistant (CR) Acinetobacter infections. While resistance has already been reported in A. baumannii, combination therapies with avibactam or sulbactam reduce MICs of cefiderocol, extending its efficacy. However, careful consideration is necessary when using these combinations. In our experiments, exposure of A. baumannii and A. lwoffii to cefiderocol and sulbactam or avibactam led to the selection of cefiderocol-resistant strains. Three of those were subjected to whole genome sequencing and transcriptomic analysis. The strains all possessed synonymous and non-synonymous substitutions and short deletions. The most significant mutations affected efflux pumps, transcriptional regulators, and iron homeostasis genes. Transcriptomics showed significant alterations in expression levels of outer membrane proteins, iron homeostasis, and ß-lactamases, suggesting adaptive responses to selective pressure. This study underscores the importance of carefully assessing drug synergies, as they may inadvertently foster the selection of resistant variants and complicate the management of CR Acinetobacter infections.IMPORTANCEThe emergence of carbapenem-resistant Acinetobacter strains as a serious global health threat underscores the urgent need for effective treatment options. Although few drugs show promise against CR Acinetobacter infections, resistance to both drugs has been reported. In this study, the molecular characterization of spontaneous cefiderocol-resistant variants, a CR A. baumannii strain with antagonism to sulbactam, and an A. lwoffii strain with antagonism to avibactam, provides valuable insights into the mechanisms of resistance to cefiderocol. Some mechanisms observed are associated with mutations affecting efflux pumps, regulators, and iron homeostasis genes. These findings highlight the importance of understanding resistance mechanisms to optimize treatment options. They also emphasize the importance of early evaluation of drug synergies to address the challenges of antimicrobial resistance in Acinetobacter infections.

Dixon-based B0 self-navigation in radial stack-of-stars multi-echo gradient echo imaging.

PURPOSE: To develop a Dixon-based B 0 $$ {\mathrm{B}}_0 $$ self-navigation approach to estimate and correct temporal B 0 $$ {\mathrm{B}}_0 $$ variations in radial stack-of-stars gradient echo imaging for quantitative body MRI. METHODS: The proposed method estimates temporal B 0 $$ {\mathrm{B}}_0 $$ variations using a B 0 $$ {\mathrm{B}}_0 $$ self-navigator estimated by a graph-cut-based water-fat separation algorithm on the oversampled k-space center. The B 0 $$ {\mathrm{B}}_0 $$ self-navigator was employed to correct for phase differences between radial spokes (one-dimensional [1D] correction) and to perform a motion-resolved reconstruction to correct spatiotemporal pseudo-periodic B 0 $$ {\mathrm{B}}_0 $$ variations (three-dimensional [3D] correction). Numerical simulations, phantom experiments and in vivo neck scans were performed to evaluate the effects of temporal B 0 $$ {\mathrm{B}}_0 $$ variations on the field-map, proton density fat fraction (PDFF) and T 2 ∗ $$ {\mathrm{T}}_2^{\ast } $$ map, and to validate the proposed method. RESULTS: Temporal B 0 $$ {\mathrm{B}}_0 $$ variations were found to cause signal loss and phase shifts on the multi-echo images that lead to an underestimation of T 2 ∗ $$ {\mathrm{T}}_2^{\ast } $$ , while PDFF mapping was less affected. The B 0 $$ {\mathrm{B}}_0 $$ self-navigator captured slowly varying temporal B 0 $$ {\mathrm{B}}_0 $$ drifts and temporal variations caused by respiratory motion. While the 1D correction effectively corrected B 0 $$ {\mathrm{B}}_0 $$ drifts in phantom studies, it was insufficient in vivo due to 3D spatially varying temporal B 0 $$ {\mathrm{B}}_0 $$ variations with amplitudes of up to 25 Hz at 3 T near the lungs. The proposed 3D correction locally improved the correction of field-map and T 2 ∗ $$ {\mathrm{T}}_2^{\ast } $$ and reduced image artifacts. CONCLUSION: Temporal B 0 $$ {\mathrm{B}}_0 $$ variations particularly affect T 2 ∗ $$ {\mathrm{T}}_2^{\ast } $$ mapping in radial stack-of-stars imaging. The self-navigation approach can be applied without modifying the MR acquisition to correct for B 0 $$ {\mathrm{B}}_0 $$ drift and physiological motion-induced B 0 $$ {\mathrm{B}}_0 $$ variations, especially in the presence of fat.

Risk Factors for Progressive Fibrosis and Cirrhosis in Patients With Chronic Hepatitis C in India.

Background Liver cirrhosis (LC) caused by chronic hepatitis C (CHC) infection is a major global public health concern. This study will look at the risk factors for progressive fibrosis and cirrhosis in patients with persistent hepatitis C virus (HCV) infection. Methods In this cohort study, a total of 300 patients were included. We collected comprehensive diagnostic records for the entire study group of 200 people with chronic hepatitis C infection. For the comparison, 100 healthy people were recruited and assessed. FibroScan (Echosens, Paris, France) scores were used to categorize liver fibrosis stages: F0-F1 (no or mild fibrosis, <7 kPa), F2 (moderate fibrosis, 7-8.99 kPa), F3 (significant fibrosis, 9-12.49 kPa), and F4 (cirrhosis, ≥12.5 kPa). Their demographic, biochemical, and serological data were evaluated and compared. Results Most patients were males (47% females and 53% males). In the CHC group, the mean age of diagnosis was 37.68±11.57 years, whereas in the chronic hepatitis C-related liver cirrhosis (CHC-LC) group, the mean age was 48.89±12.30 years (p=0.01). Compared to normal individuals, CHC patients had higher body mass index (BMI) (22.37±1.89 versus 21.72±1.95, p=0.01), alanine aminotransferase (ALT) (36.70±7.13 versus 82.78±82.53, p=0.01), and aspartate aminotransferase (AST) (34.96±6.04 versus 80.82±91.77, p=0.01). However, compared to the patients with CHC, the patients with LC have lower platelet (PLT) count (1.51±0.78 versus 1.7±0.41, p=0.01) and higher liver enzymes (AST: 117.7±186.9 versus 80.8±91.7, p=0.01; ALT: 86.71±80.24 versus 82.78±82.53, p=0.01). On regression analysis, higher BMI, older age, low hemoglobin (Hb), and higher bilirubin, ALT, AST, and prothrombin time (PT) were associated with LC. Conclusion It is imperative to shift toward prevention and early intervention as the new approach to managing patients with HCV-related cirrhosis. Cirrhosis should be suspected in older patients with CHC who are obese and have low platelet counts with higher liver enzymes.