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.

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.

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.

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.

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.

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.

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.

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.

Effectiveness of mobile health intervention for non alcoholic fatty liver disease- A meta analysis of randomized controlled trials.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Lifestyle modification is the mainstay of management, however, most patients find it difficult to significantly modify their lifestyle. Mobile health is an innovative healthcare system that has an established role in treating chronic diseases like asthma, cancer and cardiovascular disease. Hence, we conducted an updated meta analysis to evaluate the efficacy of mobile health intervention (mHI) for NAFLD. METHODS: Literature search of five electronic databases was performed from the inception of the paper till 15th May, 2024. Studies were included if they met the inclusion criteria; Randomized controlled trials evaluating use of mHI along with standard care in comparison to standard care only for patients with NAFLD over 18 years. Primary outcomes of interest included changes in weight, body mass index (BMI), and liver markers from baseline to post intervention. Risk of bias was evaluated using the Cochrane bias assessment tool while the Mantel-Haenszel Random-effects model on Review manager was used to pool outcomes. RESULTS: Outcomes were pooled from 7 RCTs comprising a total of 621 participants. There was a significant decrease in weight (P < 0.0001), aspartate aminotransferase (AST) (P = 0.002) and alkaline aminotransferase (ALT) (P = 0.0009) from baseline to follow-up in the intervention group as compared to the control group. However, the reduction in BMI was found to be non-significant (P = 0.64). CONCLUSION: Our meta analysis reports that mHI plays an important role in significantly reducing weight and liver markers in patients with NAFLD. Considering that the improvement of these factors plays a key role in the management of the disease, mHI could be the key towards paving better outcomes for patients with NAFLD.

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.

Evaluation of Quantamatrix dRASTTM system for rapid antimicrobial susceptibility testing of bacterial isolates from positive blood cultures, in comparison with commercial Micronaut broth microdilution system.

Antimicrobial susceptibility testing (AST) from blood culture (BC) may take several days, limiting the eventual impact on antimicrobial stewardship. Hence, rapid AST systems represent a valuable support in shorting the time-to-response. In this work, the Quantamatrix dRASTTM system (dRAST) was evaluated for rapid AST on 100 monomicrobial BCs (50 Gram-negatives and 50 Gram-positives), including several isolates with clinically relevant resistance mechanisms. AST results were provided in 6-hours, on average. Compared to Micronaut (Merlin) system based on broth microdilution, dRAST exhibited an overall categorical agreement of 92.5 %, essential agreement of 89.0 %, and mean bias of 15.9 %. Category overestimation (potentially leading to unnecessary high-dosage treatment or to exclude active agents) and category underestimation (potentially leading to underdosing or using ineffective agents) were observed in 4.3 % and 3.1 % of cases, respectively. Even though several issues were reported, results confirmed the potential contribution of dRAST to shorten the BCs clinical microbiology workflow and management.

A feasible approach for azo-dye (methyl orange) degradation by textile effluent isolate Serratia marcescens ED1 strain for water sustainability: AST identification, degradation optimization and pathway hypothesis.

Methyl orange (MO) is a dye commonly used in the textile industry that harms aquatic life, soil and human health due to its potential as an environmental pollutant. The present study describes the dye degradation ability of Serratia marcescens strain ED1 isolated from textile effluent and characterized by 16S rRNA gene sequence analysis. The laccase property of bacterial isolate was confirmed qualitatively. The effects of various factors (pH, temperature, incubation time, and dye concentration) were evaluated using Response Surface Methodology (RSM). The maximum dye (MO) degradation was 81.02 % achieved at 37 °C temperature and 7.0 pH with 200 mg/L dye concentration after 48 h of incubation. The beef extract, ammonium nitrate and fructose supplementation showed better response during bioremediation among the different carbon and nitrogen sources. The degree of pathogenicity was confirmed through the simple plate-based method, and an antibiotic resistance profile was used to check the low-risk rate of antibiotic resistance. However, the fate and extinct of degraded MO products were analysed through UV-Vis spectroscopy, FT-IR, and GC-MS analysis to confirm the biodegradation potential of the bacterial strain ED1 and intermediate metabolites were identified to propose metabolic pathway. The phytotoxicity study on Vigna radiata L. seeds confirmed nontoxic effect of degraded MO metabolites and indicates promising degradation potential of S. marcescens strain ED1 to successfully remediate MO dye ecologically sustainably.

Nutraceutical composition (yeast ß-glucan, prebiotics, minerals, and silymarin) predicts improvement of sleep quality and metabolic parameters: A randomized pilot study.

BACKGROUND & AIMS: The search for integrative and natural therapies that favor homeostasis to boost sleep and diet quality took place for young adult populations as a non-pharmacological strategy for long-term good quality of life. Thus, the present pilot study aims to investigate the effects of 90-day consumption of a nutraceutical composition on the neuro-immune-endocrine axis, providing better sleep quality and health improvement. METHODS: For this, from March 2021 to June 2021, twenty-two Brazilian young adult volunteers (women and men) with BMI between 18.5 and 34.9 kg/m2 were divided into three distinct supplementation groups: NSupple; NSupple plus_S, and NSupple plus. Briefly, the supplement compositions included yeast ß-glucan, prebiotics, and minerals in different concentrations associated or not with the herbal medicine silymarin. Neither nutritional nor physical activity interventions were performed during this pilot study period. The anthropometrics measures, questionnaires answer data, and harvest blood for metabolic, inflammatory, and hormonal tests were collected at baseline time (day zero-T0) and day 90 (T90) post-supplementation. RESULTS: Our results highlight that the supplementation reduced body mass index (BMI), Waist-to-height ratio (WHtR), waist circumference, AST/ALT ratio, alkaline phosphatase, and HbA1c. Post-supplementation the IL-6 and IL-10 levels and the sleep, humor, and quality of life scores were suggested to improve. Sleep quality improvement seems to predict the reduction of adiposity-related body measures. CONCLUSION: In sum, the nutraceutical supplementation might be related to anthropometric, metabolic, and endocrine parameters after 90 days reflecting on perception of humor, sleep, and life quality enhancement. However, it is important to recognize the limitation of the data presented considering that this was a pilot study. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04810572 registered on 20th February 2021.

Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer.

Background: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). Methods: In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80 mg once daily or gefitinib 250 mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Findings: Three hundred and fifty-seven patients (furmonertinib group, n = 178; gefitinib group, n = 179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25-4.04], p = 0.027), nausea/vomiting (-1.56 [95% CI -2.62 to -0.49], p = 0.004), appetite loss (-2.24 [95% CI -4.26 to -0.23], p = 0.029), diarrhoea (-3.36 [95% CI -5.19 to -1.54], p < 0.001), alopecia (-2.62 [95% CI -4.54 to -0.71], p = 0.007), and pain in other parts (-4.55 [95% CI -7.37 to -1.74], p = 0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42-0.94], p = 0.021), cognitive functioning (0.73 [95% CI 0.54-0.98], p = 0.034), nausea/vomiting (0.64 [95% CI 0.41-0.99], p = 0.042), appetite loss (0.63 [95% CI 0.43-0.92], p = 0.016), diarrhoea (0.63 [95% CI 0.46-0.85], p = 0.002), dyspnoea (0.72 [95% CI 0.53-0.98], p = 0.034), cough (0.67 [95% CI 0.44-1.00], p = 0.049), dysphagia (0.54 [95% CI 0.35-0.83], p = 0.004), and alopecia (0.62 [95% CI 0.42-0.90], p = 0.012) was longer with furmonertinib versus gefitinib. Interpretation: In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Funding: Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Modified HT-SPOTi: An Antimicrobial Susceptibility Testing to Evaluate Formulated Therapeutic Combinations Against Bacterial Growth and Viability.

Antimicrobial resistance (AMR) poses a serious threat to global health, potentially causing 10 million deaths per year globally by 2050. To tackle AMR, researchers from all around the world have generated a selection of various formulated (viz. nanoparticulate, liposomal) therapeutic combinations to be evaluated for new antimicrobial drug discovery. To meet the urgent need for accelerating new antibacterial drug development, we need rapid but reliable whole-cell assay methods and models to test formulated therapeutic combinations against several pathogens in different in vitro conditions as models of actual infections.Over the past two decades, high-throughput spot-culture growth inhibition assay (HT-SPOTi) has been demonstrated to be a gold-standard drug susceptibility method for evaluating novel chemotherapeutic entities and existing drugs against various microbes of global concern. Our modified HT-SPOTi method serves the purpose of evaluating drug combinations against Gram-positive/negative microorganisms as well as acid-fast bacilli. The newly developed and modified HT-SPOTi assay builds upon the limitations of our previously published method to incorporate antimicrobial susceptibility testing with formulated therapeutic combinations. The modified HT-SPOTi is compared with a range of other antimicrobial susceptibility testing methods and validated using a library of existing antibiotics as well as formulated therapeutic combinations. The modified HT-SPOTi assay can serve as an efficient and reliable high-throughput drug screening platform to discover new potential antimicrobial molecules, including as part of therapeutic formulations.This chapter describes the generation of drug susceptibility profile for formulated therapeutic combinations using modified HT-SPOTi in a semi-automated system.

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.

Evaluation of Vitek-2 and MicroScan ASTs directly from positive blood culture: A cost-effective 24-h reduction for Enterobacterales and staphylococci.

The reduction of antimicrobial susceptibility testing (AST) time-to-result is a central need, especially in sepsis treatment. The current automated rapid ASTs are still too expensive for many laboratories. We aimed to evaluate three pre-treatment methods for a same-day inoculation on both automated AST platforms available in our laboratory. We tested 100 Enterobacterales or staphylococci positive bottles. We obtained good results with the different methods and instruments. In particular, Vitek-2 showed good performances with Enterobacterales AST when inoculated with bacterial pellet (96.6% categorical agreement - CA-, 93.3% essential agreement - EA). Also short-term incubation colonies for staphylococci AST had acceptable CA (94.2%), even if with 77.5% EA. MicroScan system for staphylococci AST with both short-term incubation and direct blood inoculation reached >95% CA, but 92.5% and 83.6% EA, respectively. On the other hand, Enterobacterales AST showed optimal performances only with bacterial pellet inoculation (97.6% CA). In fact, direct blood inoculation showed not acceptable parameters for several molecules. Both systems allow a 24-h reduction in time-to-result, by using the same instruments of routine activity after rapid and cheap pre-treatments.

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.