Notes

Empowering Materials Processing and Performance through Data and Artificial intelligence.
Escherichia coli is the most commonly identified human pathogen and a prominent microorganism of the gut microbiota. Acquired resistance to antibiotics in this species is driven mainly by horizontal gene transfer and plasmid acquisition. Currently, the main concern is the acquisition of extended-spectrum β-lactamases of the CTX-M type in E. coli, a worldwide-observed phenomenon. Plasmids encoding CTX-M enzymes have different scaffolds and conjugate at different frequencies. Here, we show that the conjugation rates of several plasmid types encoding broad-spectrum β-lactamases are increased when the E. coli donor strain is exposed to subinhibitory concentrations of diverse orally given antibiotics, including fluoroquinolones, such as ciprofloxacin and levofloxacin, but also trimethoprim and nitrofurantoin. This study provides insights into underlying mechanisms leading to increased plasmid conjugation frequency in relation to DNA synthesis inhibitor-type antibiotics, involving reactive oxygen species (ROS) production and probably increased expression of genes involved in the SOS response. Furthermore, we show that some antioxidant molecules currently approved for unrelated clinical uses, such as edaravone, p-coumaric acid, and N-acetylcysteine, may antagonize the ability of antibiotics to increase plasmid conjugation rates. These results suggest that several antioxidative molecules might be used in combination with these "inducer" antibiotics to mitigate the unwanted increased resistance plasmid dissemination.Leishmaniasis and Chagas are among the most significant neglected tropical diseases. Due to several drawbacks with the current chemotherapy, developing new antikinetoplastid drugs has become an urgent issue. In the present work, a bioassay-guided investigation of the root bark of Maytenus chiapensis on Leishmania amazonensis and Trypanosoma cruzi led to the identification of two DA-friedo-nor-oleanane triterpenoids (celastroloids), 20β-hydroxy-tingenone (celastroloid 5) and 3-O-methyl-6-oxo-tingenol (celastroloid 8), as promising antikinetoplastid leads. They displayed higher potency on L. amazonensis promastigotes (50% inhibitory concentrations [IC50s], 0.44 and 1.12 μM, respectively), intracellular amastigotes (IC50s, 0.83 and 1.91 μM, respectively), and T. cruzi epimastigote stage (IC50s, 2.61 and 3.41 μM, respectively) than reference drugs miltefosine and benznidazole. This potency was coupled with an excellent selectivity index on murine macrophages. Mechanism of action studies, including mitochondrial membrane potential (Δψm) and ATP-level analysis, revealed that celastroloids could induce apoptotic cell death in L. Selleckchem TP0427736 amazonensis triggered by the mitochondria. In addition, the structure-activity relationship is discussed. These findings strongly underline the potential of celastroloids as lead compounds to develop novel antikinetoplastid drugs.Candida auris is an emerging pathogen that has rapidly spread to many countries on multiple continents. Invasive infections caused by this species are associated with significant mortality, and treatment options are limited due to antifungal resistance. Ibrexafungerp is the first-in-class member of the triterpenoids, which inhibit the production of (1,3)-β-d-glucan and can be administered orally. We evaluated the in vitro activity and in vivo efficacy of ibrexafungerp against C. auris Antifungal susceptibility was tested by broth microdilution against 54 C. auris isolates. Neutropenic mice were intravenously infected with a clinical isolate, and a 7-day treatment course was begun 24 h postinoculation with vehicle control, ibrexafungerp (20, 30, and 40 mg/kg orally twice daily), fluconazole (20 mg/kg orally once daily), or caspofungin (10 mg/kg intraperitoneally once daily). Fungal burden was assessed by colony counts in the kidneys on day 8 and on day 21 or as mice became moribund in the survival arm. Ibrexafungerp demonstrated consistent activity, with MICs ranging between 0.25 and 2 μg/ml against all isolates. Marked improvements in survival were observed in mice treated with the higher doses of ibrexafungerp and caspofungin. Similarly, reductions in kidney fungal burden were also observed in these groups. No improvements in survival or reductions in fungal burden were observed with fluconazole, consistent with the in vitro resistance of the isolate used to establish infection to this azole. These results demonstrate that ibrexafungerp is effective in vivo against C. auris even when the start of therapy is delayed.OXA-48-type β-lactamases are now routinely encountered in bacterial infections caused by carbapenem-resistant Enterobacterales These enzymes are of high and growing clinical significance due to the importance of carbapenems in treatment of health care-associated infections by Gram-negative bacteria, the wide and increasing dissemination of OXA-48 enzymes on plasmids, and the challenges posed by their detection. OXA-48 confers resistance to penicillin (which is efficiently hydrolyzed) and carbapenem antibiotics (which is more slowly broken down). In addition to the parent enzyme, a growing array of variants of OXA-48 is now emerging. The spectrum of activity of these variants varies, with some hydrolyzing expanded-spectrum oxyimino-cephalosporins. The growth in importance and diversity of the OXA-48 group has motivated increasing numbers of studies that aim to elucidate the relationship between structure and specificity and establish the mechanistic basis for β-lactam turnover in this enzyme family. In this review, we collate recently published structural, kinetic, and mechanistic information on the interactions between clinically relevant β-lactam antibiotics and inhibitors and OXA-48 β-lactamases. Collectively, these studies are starting to form a detailed picture of the underlying bases for the differences in β-lactam specificity between OXA-48 variants and the consequent differences in resistance phenotype. We focus specifically on aspects of carbapenemase and cephalosporinase activities of OXA-48 β-lactamases and discuss β-lactamase inhibitor development in this context. Throughout the review, we also outline key open research questions for future investigation.Diabetic foot ulcers are notoriously difficult to heal, with ulcers often becoming chronic, in many cases leading to amputation despite weeks or months of antibiotic therapy in addition to debridement and offloading. Alternative wound biofilm management options, such as topical rather than systemic delivery of antimicrobials, have been investigated by clinicians in order to improve treatment outcomes. Here, we collected blood and tissue from six subjects with diabetic foot infections, measured the concentrations of antibiotics in the samples after treatment, and compared the microbiota within the tissue before treatment and after 7 days of antibiotic therapy. We used an in vitro model of polymicrobial biofilm infection inoculated with isolates from the tissue we collected to simulate different methods of antibiotic administration by simulated systemic therapy or topical release from calcium sulfate beads. We saw no difference in biofilm bioburden in the models after simulated systemic therapy (representative of antibiotics used in the clinic), but we did see reductions in bioburden of between 5 and 8 logs in five of the six biofilms that we tested with topical release of antibiotics via calcium sulfate beads. Yeast is insensitive to antibiotics and was a component of the sixth biofilm. These data support further studies of the topical release of antibiotics from calcium sulfate beads in diabetic foot infections to combat the aggregate issues of infectious organisms taking the biofilm mode of growth, compromised immune involvement, and poor systemic delivery of antibiotics via the bloodstream to the site of infection in patients with diabetes.GSK3640254 is a next-generation maturation inhibitor that would likely be combined with standard antiretroviral agents to form a regimen of ≥2 fully active classes. This phase I, open-label, 2-period, 1-way study assessed potential pharmacokinetic (PK) interactions between GSK3640254 and tenofovir alafenamide/emtricitabine (TAF/FTC; including the metabolite tenofovir [TFV]) in healthy volunteers. Eligible participants received TAF/FTC 25/200 mg once daily (QD) on days 1 through 21 with a moderate-fat meal; GSK3640254 200 mg QD was added on days 15 through 21. Geometric least-squares mean ratios (GMRs) and 90% confidence intervals (CIs) were derived using linear mixed-effect models. Adverse events (AEs) and laboratory, electrocardiogram, and vital sign parameters were monitored. Sixteen participants, all male, received treatment; one withdrew because of treatment-related grade 1 urticaria. After TAF/FTC + GSK3640254 coadministration, TAF steady-state area under the plasma concentration-time curve from time zero to the end of the dosing interval and maximum observed concentration were 11% and 13% lower than when TAF/FTC was administered alone, with GMRs (90% CI) of 0.886 (0.75 to 1.04) and 0.874 (0.68 to 1.12), respectively. Steady-state PK of TFV and FTC was similar when TAF/FTC was administered alone or with GSK3640254. No clinically significant trends in tolerability or safety were observed. GSK3640254 200 mg QD did not meaningfully affect the steady-state PK of TAF, TFV, or FTC in healthy participants under fed conditions and was not associated with major tolerability or safety findings. These data support the further investigation of GSK3640254 for coadministration with TAF/FTC for the treatment of HIV. (This study has been registered at ClinicalTrials.gov under identifier NCT03836729.).
Telehealth became the most practical option for general practice consultations in Aotearoa New Zealand (NZ) as a result of the national lockdowns in response to the COVID-19 pandemic. What is the consumer experience of access to telehealth and how do consumers and providers perceive this mode of care delivery going forward?

A national survey of general practice consumers and providers who used telehealth services since the national lockdowns in 2020 will be distributed. It is based on the Unified Theory of Acceptance and Use of Technology framework of technology acceptance and the access to care framework. The data will be statistically analysed to create a foundation for in-depth research on the use of telehealth services in NZ general practice services, with a specific focus on consumer experiences and health outcomes.

Ethics approval was granted by the Auckland Health Research Ethics Committee on 13/11/2020, reference AH2539. The survey will be disseminated online.
Ethics approval was granted by the Auckland Health Research Ethics Committee on 13/11/2020, reference AH2539. The survey will be disseminated online.
We sought to identify metabolic changes potentially related to rheumatoid arthritis (RA) pathogenesis occurring in the blood prior to its diagnosis.

In a US military biorepository, serum samples collected at two timepoints prior to a diagnosis of RA were identified. These were matched to controls who did not develop RA by subject age, race and time between sample collections and RA diagnosis time to stored serum samples. Relative abundances of 380 metabolites were measured using liquid chromatography-tandem mass spectrometry. We determined whether pre-RA case versus control status predicted metabolite concentration differences and differences over time (trajectories) using linear mixed models, assessing for interactions between time, pre-RA status and metabolite concentrations. We separately examined pre-RA and pre-seropositive RA cases versus matched controls and adjusted for smoking. Multiple comparison adjustment set the false discovery rate to 0.05.

291 pre-RA cases (80.8% pre seropositive RA) were matched to 292 controls, all with two serum samples (2.
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