Survey based assessment of the quality of reporting guidelines of carotid artery stenosis.

BACKGROUND: No evaluation of the quality of different carotid guidelines using validated scales has been performed to date. The present study aims to analyze three carotid stenosis guidelines, apprizing their quality and reporting using validated tools. METHODS: A survey-based assessment of the quality of the European Society for Vascular Surgery (ESVS) 2023, European Stroke Organisation (ESO) 2021, and the Society for Vascular Surgery (SVS) 2021 carotid stenosis guidelines, was performed by 43 vascular surgeons, cardiologists, neurologist or interventional radiologists using two validated appraisal tools for quality and reporting guidelines, the AGREE II instrument and the RIGHT statement. RESULTS: Using the AGREE II tool, the ESVS, SVS, and ESO guidelines had overall quality scores of 87.3%, 79.4%, and 82.9%, respectively (p=0.001) The ESVS and ESO had better scores in the scope and purpose domain, and the SVS in the clarity of presentation domain. In the RIGHT statement, the ESVS, SVS, and ESO guidelines had overall quality scores of 84.0.7%, 74.3%, and 79.0%, respectively (p=0.001). All three guidelines stood out for their methodology for search of evidence and formulating evidence-based recommendations. On the contrary, were negatively evaluated mostly in the cost and resource implications in formulating the recommendations. CONCLUSION: The 2023 ESVS carotid stenosis guideline was the best evaluated among the three guidelines, with scores over 5% higher than the other two guidelines. Efforts should be made by guideline writing committees to take the AGREE II and RIGHT statements into account in the development of future guidelines to produce high-quality recommendations.

Nutritional Strategies for Optimizing Health, Sports Performance, and Recovery for Female Athletes and Other Physically Active Women: A Systematic Review.

CONTEXT: Despite the progress toward gender equality in events like the Olympic Games and other institutionalized competitions, and the rising number of women engaging in physical exercise programs, scientific studies focused on establishing specific nutritional recommendations for female athletes and other physically active women are scarce. OBJECTIVE: This systematic review aimed to compile the scientific evidence available for addressing the question "What dietary strategies, including dietary and supplementation approaches, can improve sports performance, recovery, and health status in female athletes and other physically active women?" DATA SOURCES: The Pubmed, Web of Science, and Scopus databases were searched. DATA EXTRACTION: The review process involved a comprehensive search strategy using keywords connected by Boolean connectors. Data extracted from the selected studies included information on the number of participants and their characteristics related to sport practice, age, and menstrual function. DATA ANALYSIS: A total of 71 studies were included in this review: 17 focused on the analysis of dietary manipulation, and 54 focused on the effects of dietary supplementation. The total sample size was 1654 participants (32.5% categorized as competitive athletes, 30.7% as highly/moderately trained, and 37.2% as physically active/recreational athletes). The risk of bias was considered moderate, mainly for reasons such as a lack of access to the study protocol, insufficient description of how the hormonal phase during the menstrual cycle was controlled for, inadequate dietary control during the intervention, or a lack of blinding of the researchers. CONCLUSION: Diets with high carbohydrate (CHO) content enhance performance in activities that induce muscle glycogen depletion. In addition, pre-exercise meals with a high glycemic index or rich in CHOs increase CHO metabolism. Ingestion of 5-6 protein meals interspersed throughout the day, with each intake exceeding 25 g of protein favors anabolism of muscle proteins. Dietary supplements taken to enhance performance, such as caffeine, nitric oxide precursors, ß-alanine, and certain sport foods supplements (such as CHOs, proteins, or their combination, and micronutrients in cases of nutritional deficiencies), may positively influence sports performance and/or the health status of female athletes and other physically active women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD480674.

Does curcumin improve liver enzymes levels in nonalcoholic fatty liver disease? A systematic review, meta-analysis, and meta-regression.

The aim of this meta-analysis is to investigate the sources of heterogeneity in randomized clinical trials examining the effects of curcumin supplementation on liver aminotransferases in subjects with nonalcoholic fatty liver disease (NAFLD). We conducted a systematic search of the PubMed, SCOPUS, and Web of Science databases for randomized clinical trials and identified 15 studies (n = 835 subjects). We used random-effects models with DerSimonian-Laird methods to analyze the serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Our results indicate that curcumin did not affect serum alanine aminotransferase, but it did reduce aspartate aminotransferase levels. Notably, both outcomes showed high heterogeneity (p < 0.01). Subgroup analysis revealed that adding piperine to curcumin did not benefit aminotransferase levels in NAFLD patients. Additionally, we found a negative correlation between the duration of the intervention and the relative (mg/kg/day) curcumin dose with the reduction in liver aminotransferases. In summary, the sources of heterogeneity identified in our study are likely attributed to the duration of the intervention and the relative dose of curcumin. Consequently, longer trials utilizing high doses of curcumin could diminish the positive impact of curcumin in reducing serum levels of aminotransferases in patients with NAFLD.

Impact of multidrug resistance on the virulence and fitness of Pseudomonas aeruginosa: a microbiological and clinical perspective.

Pseudomonas aeruginosa is one of the most common nosocomial pathogens and part of the top emergent species associated with antimicrobial resistance that has become one of the greatest threat to public health in the twenty-first century. This bacterium is provided with a wide set of virulence factors that contribute to pathogenesis in acute and chronic infections. This review aims to summarize the impact of multidrug resistance on the virulence and fitness of P. aeruginosa. Although it is generally assumed that acquisition of resistant determinants is associated with a fitness cost, several studies support that resistance mutations may not be associated with a decrease in virulence and/or that certain compensatory mutations may allow multidrug resistance strains to recover their initial fitness. We discuss the interplay between resistance profiles and virulence from a microbiological perspective but also the clinical consequences in outcomes and the economic impact.

Risk factors and clinical impact of multidrug resistance in healthcare-associated bacteremic urinary tract infections: a post-hoc analysis of a multicenter prospective cohort in Spain.

INTRODUCTION: The global burden associated with antimicrobial resistance is of increasing concern. The aim of this study was to evaluate risk factors associated with multidrug-resistant (MDR) infection and its clinical impact in a cohort of patients with healthcare-associated (HCA) bacteremic urinary tract infections (BUTI). METHODS: This is a post-hoc analysis a prospective multicenter study of patients with HCA-BUTI (ITUBRAS-2). The primary outcome was MDR profile. Secondary outcomes were clinical response (at 48-72h and at hospital discharge) and length of hospital stay from onset of BUTI. Logistic regression was used to evaluate variables associated with MDR profile and clinical response. Length of hospital stay was evaluated using multivariate median regression. RESULTS: 443 episodes were included, of which 271 (61.17%) were classified as expressing an MDR profile. In univariate analysis, MDR profile was associated with E. coli episodes (OR 3.13, 95% CI 2.11-4.69, p<0.001) and the extensively drug-resistant (XDR) pattern with P. aeruginosa etiology (OR 7.84, 95% CI 2.37-25.95; p=0.001). MDR was independently associated with prior use of fluoroquinolones (aOR 2.43; 95% CI 1.25-4.69), cephalosporins (aOR 2.14; 95% CI 1.35-3.41) and imipenem or meropenem (aOR 2.08; 95% CI 1.03-4.20) but not with prior ertapenem. In terms of outcomes, MDR profile was not associated with lower frequency of clinical cure, but with longer hospital stay. CONCLUSIONS: MDR profile was independently associated with prior use of fluoroquinolones, cephalosporins, imipenem and meropenem, but not with prior ertapenem. MDR-BUTI episodes were not associated with worse clinical cure, although was independently associated with longer duration of hospital stay.

In vitro activity of cefiderocol in Pseudomonas aeruginosa isolates from people with cystic fibrosis recovered during three multicentre studies in Spain.

OBJECTIVES: Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and comparators in a collection of 154 P. aeruginosa isolates recovered from pwCF during three multicentre studies performed in 17 Spanish hospitals in 2013, 2017 and 2021. METHODS: ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed. RESULTS: Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis). CONCLUSIONS: Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent ß-lactam/ß-lactamase inhibitor combinations.

Physical and Psychosocial Benefits of Sports Participation Among Children and Adolescents with Chronic Diseases: A Systematic Review.

BACKGROUND: This study aims to identify sports interventions for children and adolescents (CaA) with chronic diseases and evaluate their impact on physical, psychological, and social well-being. The findings of this study will contribute to our understanding of the potential benefits of sports interventions for CaA with chronic diseases and inform future interventions to promote their overall health and well-being. METHODS: A systematic review was conducted in eight databases. This systematic review followed PRISMA guidelines and utilized a comprehensive search strategy to identify studies on sport-based interventions for CaA with chronic diseases. The review included randomized controlled trials and observational studies that focused on physical and psychosocial outcomes. RESULTS: We screened 10,123 titles and abstracts, reviewed the full text of 622 records, and included 52 primary studies. A total of 2352 participants were assessed with an average of 45 ± 37 participants per study. Among the included studies involving CaA with chronic diseases with an age range from 3 to 18 years, 30% (n = 15) autism spectrum disorders, 21% (n = 11) cerebral palsy, 19% (n = 10) were attention deficit hyperactivity disorder, and 17% (n = 9) obesity. Other diseases included were cancer (n = 5), asthma (n = 1) and cystic fibrosis (n = 1). Interventions involved various sports and physical activities tailored to each chronic disease. The duration and frequency of interventions varied across studies. Most studies assessed physical outcomes, including motor performance and physical fitness measures. Psychosocial outcomes were also evaluated, focusing on behavioural problems, social competencies, and health-related quality of life. CONCLUSION: Overall, sport-based interventions effectively improved physical and psychosocial outcomes in CaA with chronic diseases. Interventions are generally safe, and participants adhere to the prescribed protocols favorably. Despite that, there is little evidence that interventions are being implemented. Future studies should include interventions tailored to meet the common issues experienced by CaA with chronic conditions, providing a comprehensive understanding of the impact of sports interventions on those affected. REGISTRATION: The methodology for this review was pre-determined and registered in the PROSPERO database (registration number: CRD42023397172).

Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

OBJECTIVE: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P. aeruginosa strains using the CDC dynamic in vitro biofilm reactor (CBR), mechanism-based mathematical modelling (MBM) and genomic studies. METHODS: Two CF multidrug-resistant strains were investigated in a 168 h CBR (n = 2 biological replicates). Regimens were inhaled aztreonam (75 mg 8-hourly) and tobramycin (300 mg 12-hourly) in monotherapies and combination. The simulated pharmacokinetic profiles of aztreonam and tobramycin (t1/2 = 3 h) were based on published lung fluid concentrations in patients with CF. Total viable and resistant counts were determined for planktonic and biofilm bacteria. MBM of total and resistant bacterial counts and whole genome sequencing were completed. RESULTS: Both isolates showed reproducible bacterial regrowth and resistance amplification for the monotherapies by 168 h. The combination performed synergistically, with minimal resistant subpopulations compared to the respective monotherapies at 168 h. Mechanistic synergy appropriately described the antibacterial effects of the combination regimen in the MBM. Genomic analysis of colonies recovered from monotherapy regimens indicated noncanonical resistance mechanisms were likely responsible for treatment failure. CONCLUSION: The combination of aztreonam and tobramycin was required to suppress the regrowth and resistance of planktonic and biofilm bacteria in all biological replicates of both hypermutable multidrug-resistant P. aeruginosa CF isolates. The developed MBM could be utilised for future investigations of this promising inhaled combination.

OriPlex: Origami-enabled multiplexed detection of respiratory pathogens.

Origami biosensors leverage paper foldability to develop total analysis systems integrated in a single piece of paper. This capability can also be utilized to incorporate additional features that would be difficult to achieve with rigid substrates. In this article, we report a new design for 3D origami biosensors called OriPlex, which leverages the foldability of filter paper for the multiplexed detection of bacterial pathogens. OriPlex immunosensors detect pathogens by folding nanoparticle reservoirs containing different types of nanoprobes. This releases antibody-coated nanoparticles in a central channel where targets are captured through physical interactions. The OriPlex concept was demonstrated by detecting the respiratory pathogens Pseudomonas aeruginosa (PA) and Klebsiella pneumoniae (KP) with a limit of detection of 3.4·103 cfu mL-1 and 1.4·102 cfu mL-1, respectively, and with a turn-around time of 25 min. Remarkably, the OriPlex biosensors allowed the multiplexed detection of both pathogens spiked into real bronchial aspirate (BAS) samples at a concentration of 105 cfu mL-1 (clinical infection threshold), thus demonstrating their suitability for diagnosing lower tract respiratory infections. The results shown here pave the way for implementing OriPlex biosensors as a screening test for detecting superbugs requiring personalized antibiotics in suspected cases of nosocomial pneumonia.

Activity of cefiderocol and innovative ß-lactam/ß-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double ß-lactamases under high and low permeability conditions.

OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.

Transferable AmpCs in Klebsiella pneumoniae: interplay with peptidoglycan recycling, mechanisms of hyperproduction, and virulence implications.

Chromosomal and transferable AmpC ß-lactamases represent top resistance mechanisms in different gram-negatives, but knowledge regarding the latter, mostly concerning regulation and virulence-related implications, is far from being complete. To fill this gap, we used Klebsiella pneumoniae (KP) and two different plasmid-encoded AmpCs [DHA-1 (AmpR regulator linked, inducible) and CMY-2 (constitutive)] as models to perform a study in which we show that blockade of peptidoglycan recycling through AmpG permease inactivation abolished DHA-1 inducibility but did not affect CMY-2 production and neither did it alter KP pathogenic behavior. Moreover, whereas regular production of both AmpC-type enzymes did not attenuate KP virulence, when blaDHA-1 was expressed in an ampG-defective mutant, Galleria mellonella killing was significantly (but not drastically) attenuated. Spontaneous DHA-1 hyperproducer mutants were readily obtained in vitro, showing slight or insignificant virulence attenuations together with high-level resistance to ß-lactams only mildly affected by basal production (e.g., ceftazidime, ceftolozane/tazobactam). By analyzing diverse DHA-1-harboring clinical KP strains, we demonstrate that the natural selection of these hyperproducers is not exceptional (>10% of the collection), whereas mutational inactivation of the typical AmpC hyperproduction-related gene mpl was the most frequent underlying mechanism. The potential silent dissemination of this kind of strains, for which an important fitness cost-related contention barrier does not seem to exist, is envisaged as a neglected threat for most ß-lactams effectiveness, including recently introduced combinations. Analyzing whether this phenomenon is applicable to other transferable ß-lactamases and species as well as determining the levels of conferred resistance poses an essential topic to be addressed.IMPORTANCEAlthough there is solid knowledge about the regulation of transferable and especially chromosomal AmpC ß-lactamases in Enterobacterales, there are still gaps to fill, mainly related to regulatory mechanisms and virulence interplays of the former. This work addresses them using Klebsiella pneumoniae as model, delving into a barely explored conception: the acquisition of a plasmid-encoded inducible AmpC-type enzyme whose production can be increased through selection of chromosomal mutations, entailing dramatically increased resistance compared to basal expression but minor associated virulence costs. Accordingly, we demonstrate that clinical K. pneumoniae DHA-1 hyperproducer strains are not exceptional. Through this study, we warn for the first time that this phenomenon may be a neglected new threat for ß-lactams effectiveness (including some recently introduced ones) silently spreading in the clinical context, not only in K. pneumoniae but potentially also in other pathogens. These facts must be carefully considered in order to design future resistance-preventive strategies.

In vitro activity of human defensins HNP-1 and hBD-3 against multidrug-resistant ESKAPE Gram-negatives of clinical origin and selected peptidoglycan recycling-defective mutants.

The use of immune compounds as antimicrobial adjuvants is a classic idea recovering timeliness in the current antibiotic resistance scenario. However, the activity of certain antimicrobial peptides against ESKAPE Gram-negatives has not been sufficiently investigated. The objective of this study was to determine the activities of human defensins HNP-1 and hBD-3 alone or combined with permeabilizing/peptidoglycan-targeting agents against clinical ESKAPE Gram-negatives [Acinetobacter baumannii (AB), Enterobacter cloacae (EC), Klebsiella pneumoniae (KP), and acute/chronic Pseudomonas aeruginosa (PA)]. Lethal concentrations (LCs) of HNP-1 and hBD-3 were determined in four collections of multidrug resistant EC, AB, KP, and PA clinical strains (10-36 isolates depending on the collection). These defensins act through membrane permeabilization plus peptidoglycan building blockade, enabling that alterations in peptidoglycan recycling may increase their activity, which is why different recycling-defective mutants were also included. Combinations with physiological lysozyme and subinhibitory colistin for bactericidal activities determination, and with meropenem for minimum inhibitory concentrations (MICs), were also assessed. HNP-1 showed undetectable activity (LC > 32 mg/L for all strains). hBD-3 showed appreciable activities: LC ranges 2-16, 8-8, 8->32, and 8->32 mg/L for AB, EC, KP, and PA, being PA strains from cystic fibrosis significantly more resistant than acute origin ones. None of the peptidoglycan recycling-defective mutants showed greater susceptibility to HNP-1/hBD-3. Combination with colistin or lysozyme did not change their bactericidal power, and virtually neither did meropenem + hBD-3 compared to meropenem MICs. This is the first study comparatively analyzing the HNP-1/hBD-3 activities against the ESKAPE Gram-negatives, and demonstrates interesting bactericidal capacities of hBD-3 mostly against AB and EC. IMPORTANCE: In the current scenario of critical need for new antimicrobials against multidrug-resistant bacteria, all options must be considered, including classic ideas such as the use of purified immune compounds. However, information regarding the activity of certain human defensins against ESKAPE Gram-negatives was incomplete. This is the first study comparatively assessing the in vitro activity of two membrane-permeabilizing/peptidoglycan construction-blocking defensins (HNP-1 and hBD-3) against relevant clinical collections of ESKAPE Gram-negatives, alone or in combination with permeabilizers, additional peptidoglycan-targeting attacks, or the blockade of its recycling. Our data suggest that hBD-3 has a notable bactericidal activity against multidrug-resistant Acinetobacter baumannii and Enterobacter cloacae strains that should be considered as potential adjuvant option. Our results suggest for the first time an increased resistance of Pseudomonas aeruginosa strains from chronic infection compared to acute origin ones, and provide new clues about the predominant mode of action of hBD-3 against Gram-negatives (permeabilization rather than peptidoglycan-targeting).

In vitro activity of cefiderocol against European Pseudomonas aeruginosa and Acinetobacter spp., including isolates resistant to meropenem and recent ß-lactam/ß-lactamase inhibitor combinations.

Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. represent major threats and have few approved therapeutic options. Non-|fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and ß-lactam/ß-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 P. aeruginosa; 501 Acinetobacter spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than |ß|-|l|a|c|t|a|m|/|ß|-|l|a|c|t|a|mase| inhibitor combinations against P. aeruginosa (98.9% vs 83.3%-91.4%), and P. |aeruginosa resistant to meropenem (n = 139; 97.8% vs 12.2%-59.7%), ß-lactam/ß-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-||45.0%) or |ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against Acinetobacter spp. (92.4% and 97.0%) and meropenem-resistant Acineto|bacter |spp. (n = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- (n |= 15; 13.3%) and cefiderocol- (n = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant P. aeruginosa and Acinetobacter spp., the most common ß-||lactamase genes were metallo-ß-lactamases [30/139; blaVIM-2 (15/139)] and oxacillinases [215/227; blaOXA-23 (194/227)], respectively. Acquired ß-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant P. aeruginosa and Acinetobacter spp., and pirA-like or piuA mutations in 10/10 and 37/38, respectively. Conclusion: cefiderocol susceptibility was high against P. aeruginosa and Acinetobacter spp., including meropenem-resistant isolates and those resistant to recent ß-lactam/ß-lactamase inhibitor combinations common in first-line treatment of European non-fermenters. IMPORTANCE: This was the first study in which the in vitro activity of cefiderocol and non-licensed ß-lactam/ß-lactamase inhibitor combinations were directly compared against Pseudomonas aeruginosa and Acinetobacter spp., including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and ß-lactam/ß-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant P. aeruginosa and Acinetobacter spp. and indicate how early susceptibility testing of cefiderocol in parallel with ß-lactam/ß-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.

Nonlethal Molecular Nanomachines Potentiate Antibiotic Activity Against Gram-Negative Bacteria by Increasing Cell Permeability and Attenuating Efflux.

Antibiotic resistance is a pressing public health threat. Despite rising resistance, antibiotic development, especially for Gram-negative bacteria, has stagnated. As the traditional antibiotic research and development pipeline struggles to address this growing concern, alternative solutions become imperative. Synthetic molecular nanomachines (MNMs) are molecular structures that rotate unidirectionally in a controlled manner in response to a stimulus, such as light, resulting in a mechanical action that can propel molecules to drill into cell membranes, causing rapid cell death. Due to their broad destructive capabilities, clinical translation of MNMs remains challenging. Hence, here, we explore the ability of nonlethal visible-light-activated MNMs to potentiate conventional antibiotics against Gram-negative bacteria. Nonlethal MNMs enhanced the antibacterial activity of various classes of conventional antibiotics against Gram-negative bacteria, including those typically effective only against Gram-positive strains, reducing the antibiotic concentration required for bactericidal action. Our study also revealed that MNMs bind to the negatively charged phospholipids of the bacterial inner membrane, leading to permeabilization of the cell envelope and impairment of efflux pump activity following light activation of MNMs. The combined effects of MNMs on membrane permeability and efflux pumps resulted in increased antibiotic accumulation inside the cell, reversing antibiotic resistance and attenuating its development. These results identify nonlethal MNMs as pleiotropic antibiotic enhancers or adjuvants. The combination of MNMs with traditional antibiotics is a promising strategy against multidrug-resistant Gram-negative infections. This approach can reduce the amount of antibiotics needed and slow down antibiotic resistance development, thereby preserving the effectiveness of our current antibiotics.

A randomized controlled mHealth trial that evaluates social comparison-oriented gamification to improve physical activity, sleep quantity, and quality of life in young adults.

INTRODUCTION: The integration of gamification in mHealth interventions presents a novel approach to enhance user engagement and health outcomes. This study aims to evaluate whether comparison-oriented gamification can effectively improve various aspects of health and well-being, including physical activity, sedentary behavior, sleep, and overall quality of life among young adults. METHODS: Potential 107 young adults (from 19 to 28 years old) participated in an 8-week trial. Participants were assigned to either a gamified mHealth intervention (LevantApp) with daily leaderboards and progress bars (n = 53, 26 % dropped-out), or a control condition without gamification (n = 52, 29 % dropped-out). Physical activity (number of steps, moderate and moderate-to-vigorous physical activity -MVPA-) and sleep quantity were measured objectively via accelerometry and subjectively using the International Physical Activity Questionnaire(IPAQ), Pittsburgh Sleep Quality Index(PSQI), Sedentary Behavior Questionnaire(SBQ), and Short Form Health Survey(SF-36). RESULTS: This mHealth intervention with social comparison-oriented gamification significantly improved moderate physical activity to a greater extent than the control group. Additionally, the intervention group showed improvements in the number of steps, moderate physical activity, sedentary time, emotional wellbeing, and social functioning. However, no significant group by time interaction was observed. No significant differences were observed in sleep quality or quantity. CONCLUSION: s: The LevantApp gamified mHealth intervention was effective in improving moderate physical activity, physical functioning, and role-emotional in young adults. No significant effects were found on step counts, MVPA or sleep, suggesting that while gamification can enhance specific aspects of physical activity and quality of life, its impact may vary across different outcomes.

Filling knowledge gaps related to AmpC-dependent ß-lactam resistance in Enterobacter cloacae.

Enterobacter cloacae starred different pioneer studies that enabled the development of a widely accepted model for the peptidoglycan metabolism-linked regulation of intrinsic class C cephalosporinases, highly conserved in different Gram-negatives. However, some mechanistic and fitness/virulence-related aspects of E. cloacae choromosomal AmpC-dependent resistance are not completely understood. The present study including knockout mutants, ß-lactamase cloning, gene expression analysis, characterization of resistance phenotypes, and the Galleria mellonella infection model fills these gaps demonstrating that: (i) AmpC enzyme does not show any collateral activity impacting fitness/virulence; (ii) AmpC hyperproduction mediated by ampD inactivation does not entail any biological cost; (iii) alteration of peptidoglycan recycling alone or combined with AmpC hyperproduction causes no attenuation of E. cloacae virulence in contrast to other species; (iv) derepression of E. cloacae AmpC does not follow a stepwise dynamics linked to the sequential inactivation of AmpD amidase homologues as happens in Pseudomonas aeruginosa; (v) the enigmatic additional putative AmpC-type ß-lactamase generally present in E. cloacae does not contribute to the classical cephalosporinase hyperproduction-based resistance, having a negligible impact on phenotypes even when hyperproduced from multicopy vector. This study reveals interesting particularities in the chromosomal AmpC-related behavior of E. cloacae that complete the knowledge on this top resistance mechanism.