bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study
Authors: Novy Emmanuel , Abdul-Aziz Mohd H. , Cheng Vesa , Burrows Fay , Buscher Hergen , Corley Amanda , Diehl Arne , Gilder Eileen , Levkovich Bianca J. , McGuinness Shay , Ordonez Jenny , Parke Rachael , Parker Suzanne , Pellegrino Vincent , Reynolds Claire , Rudham Sam , Wallis Steven C. , Welch Susan A. , Fraser John F. , Shekar Kiran , Roberts Jason A. 
Published: December 2023

ABSTRACT

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC
0-24
/MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose.
Recombinant
Pseudomonas
growing on non-natural fluorinated substrates shows stress but overall tolerance to cytoplasmically released fluoride anion
Authors: Dodge Anthony G. , Thoma Calvin J. , O’Connor Madeline R. , Wackett Lawrence P. 
Published: December 2023

ABSTRACT

Microbial response to toxic fluoride anion has traditionally been studied by adding inorganic fluoride salts to growth media. Fluoride is known to spontaneously transit the membrane as hydrogen fluoride (HF) and manifests significant toxicity in the cytoplasm. The present study investigated how microbes respond to high levels of HF generated directly in the cytoplasm to better understand potential limits of microbial defluorination of organofluorine compounds. For that purpose,
Pseudomonas putida
ATCC 12633 was engineered to express a defluorinase enzyme from
Delftia acidovorans
strain B that had high activity in producing growth-supporting alcohols from organofluorinated compounds of xenobiotic origin. Genome annotation predicted the growth of
P. putida
ATCC 12633 on all possible chiral products from 2-fluoropropionic acid and α-fluorophenylacetic acid when defluroinases are expressed. The defluorinase was shown to have complete enantioselectivity for (
S
)-fluoro substrates via experimental and computational modeling methods. The bacterium grew to a high turbidity with stoichiometric release of fluoride from the (
S
)-enantiomers into the medium. The highest yield of fluoride obtained was 50 mM with 2-fluoropropionic acid as the growth substrate. The growth yield was significantly lowered by 41% with α-fluorophenylacetic acid or 2-fluoropropionic acid compared to (
S
)-mandelic acid or D-lactic acid, respectively. Fluoride stress was also indicated by longer lag phases, slower growth, and cell morphology changes on fluorinated substrates or the cognate alcohols with NaF in the medium. In total, these studies show the potential for engineering bacterial defluorination of non-natural substrates within limits posed by fluoride stress.

IMPORTANCE

Society uses thousands of organofluorine compounds, sometimes denoted per- and polyfluoroalkyl substances (PFAS), in hundreds of products, but recent studies have shown some to manifest human and environmental health effects. As a class, they are recalcitrant to biodegradation, partly due to the paucity of fluorinated natural products to which microbes have been exposed. Another limit to PFAS biodegradation is the intracellular toxicity of fluoride anion generated from C-F bond cleavage. The present study identified a broader substrate specificity in an enzyme originally studied for its activity on the natural product fluoroacetate. A recombinant
Pseudomonas
expressing this enzyme was used here as a model system to better understand the limits and effects of a high level of intracellular fluoride generation. A fluoride stress response has evolved in bacteria and has been described in
Pseudomonas
spp. The present study is highly relevant to organofluorine compound degradation or engineered biosynthesis in which fluoride anion is a substrate.
Bile acid fitness determinants of a
Bacteroides fragilis
isolate from a human pouchitis patient
Authors: Fiebig Aretha , Schnizlein Matthew K. , Pena-Rivera Selymar , Trigodet Florian , Dubey Abhishek Anil , Hennessy Miette K. , Basu Anindita , Pott Sebastian , Dalal Sushila , Rubin David , Sogin Mitchell L. , Eren A. Murat , Chang Eugene B. , Crosson Sean 
Published: December 2023

ABSTRACT

Bacteroides fragilis
comprises 1%–5% of the gut microbiota in healthy humans but can expand to >50% of the population in ulcerative colitis (UC) patients experiencing inflammation. The mechanisms underlying such microbial blooms are poorly understood, but the gut of UC patients has physicochemical features that differ from healthy patients and likely impact microbial physiology. For example, levels of the secondary bile acid deoxycholate (DC) are highly reduced in the ileoanal J-pouch of UC colectomy patients. We isolated a
B. fragilis
strain from a UC patient with pouch inflammation (i.e., pouchitis) and developed it as a genetic model system to identify genes and pathways that are regulated by DC and that impact
B. fragilis
fitness in DC and crude bile. Treatment of
B. fragilis
with a physiologically relevant concentration of DC reduced cell growth and remodeled transcription of one-quarter of the genome. DC strongly induced expression of chaperones and select transcriptional regulators and efflux systems, and down-regulated protein synthesis genes. Using a barcoded collection of ≈50,000 unique insertional mutants, we further defined
B. fragilis
genes that contribute to fitness in media containing DC or crude bile. Genes impacting cell envelope functions including cardiolipin synthesis, cell surface glycosylation, and systems implicated in sodium-dependent bioenergetics were major bile acid fitness factors. As expected, there was limited overlap between transcriptionally regulated genes and genes that impacted fitness in bile when disrupted. Our study provides a genome-scale view of a
B. fragilis
bile response and genetic determinants of its fitness in DC and crude bile.

IMPORTANCE

The Gram-negative bacterium
Bacteroides fragilis
is a common member of the human gut microbiota that colonizes multiple host niches and can influence human physiology through a variety of mechanisms. Identification of genes that enable
B. fragilis
to grow across a range of host environments has been impeded in part by the relatively limited genetic tractability of this species. We have developed a high-throughput genetic resource for a
B. fragilis
strain isolated from a UC pouchitis patient. Bile acids limit microbial growth and are altered in abundance in UC pouches, where
B. fragilis
often blooms. Using this resource, we uncovered pathways and processes that impact
B. fragilis
fitness in bile and that may contribute to population expansions during bouts of gut inflammation.
Can antimicrobial blue light contribute to resistance development? Genome-wide analysis revealed aBL-protective genes in
Escherichia coli
Authors: Kruszewska-Naczk Beata , Grinholc Mariusz , Waleron Krzysztof , Bandow Julia Elisabeth , Rapacka-Zdończyk Aleksandra 
Published: December 2023

ABSTRACT
Antimicrobial blue light (aBL) is a promising non-antibiotic approach to fighting multidrug-resistant bacteria. However, the complete mechanism of aBL action is not fully understood yet. This study contributes to a better understanding that the response to aBL depends on many factors and that it is hardly possible to identify a predominant mechanism underlying microbial sensitivity to photoinactivation. The results of this study provide insights into genetic changes that may lead to bacterial survival at higher aBL doses, giving rise to aBL-resistant strains. To our best knowledge, this is the first study concerning genome-wide mutant testing of aBL. We managed to identify 64 single-gene mutants that lacked certain protective genes expressing aBL-increased sensitivity.

IMPORTANCE
Increasing antibiotic resistance and the lack of new antibiotic-like compounds to combat bacterial resistance are significant problems of modern medicine. The development of new alternative therapeutic strategies is extremely important. Antimicrobial blue light (aBL) is an innovative approach to combat multidrug-resistant microorganisms. aBL has a multitarget mode of action; however, the full mechanism of aBL antibacterial action requires further investigation. In addition, the potential risk of resistance development to this treatment should be considered.
Pharmacokinetic/pharmacodynamic analysis of ceftazidime/avibactam and fosfomycin combinations in an
in vitro
hollow fiber infection model against multidrug-resistant
Escherichia coli
Authors: Kroemer Niklas , Amann Lisa F. , Farooq Aneeq , Pfaffendorf Christoph , Martens Miklas , Decousser Jean-Winoc , Grégoire Nicolas , Nordmann Patrice , Wicha Sebastian G. 
Published: December 2023

ABSTRACT

Rational combination therapy offers a valuable option to increase efficacy and prevent emergence of resistance. Therefore, this study provides a translational pharmacokinetic/pharmacodynamic analysis of the synergy of /avibactam and fosfomycin in a clinical
Escherichia coli
strain expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Detailed static time-kill experiments primed dynamic hollow fiber studies mimicking mono- and combination therapies with doses of ceftazidime/avibactam ranging from 0.06/0.015 to 2/0.5 g every 8 h (q8h) and doses of fosfomycin ranging from 0.125 to 6 g q8h. The drug effects and interactions were quantitatively evaluated by pharmacokinetic/pharmacodynamic modeling using semi-mechanistic and subpopulation synergy. A pharmacokinetic/pharmacodynamic model describing the effects of ceftazidime, avibactam, and fosfomycin and their synergy was developed from the static time-kill experiments and hollow fiber studies. Simulations revealed that combined doses as low as 0.5-g q8h fosfomycin and 0.25-/0.06-g q8h ceftazidime/avibactam lead to suppression of the bacterial count. Conversely, in monotherapy, substantially higher doses by a factor of 12 for fosfomycin (6 g q8h) or by a factor of 6 for ceftazidime/avibactam (1.5/0.375 g q8h) were needed to achieve a comparable killing over 72 h. The combination of ceftazidime/avibactam and fosfomycin was therefore shown to be highly synergistic and suppressed the emergence of resistances. Clinical evaluations of potential dose reductions or the possibility to treat strains with high-level resistance with this combination are warranted.

IMPORTANCE

Mechanistic understanding of pharmacodynamic interactions is key for the development of rational antibiotic combination therapies to increase efficacy and suppress the development of resistances. Potent tools to provide those insights into pharmacodynamic drug interactions are semi-mechanistic modeling and simulation techniques. This study uses those techniques to provide a detailed understanding with regard to the direction and strength of the synergy of ceftazidime-avibactam and ceftazidime-fosfomycin in a clinical
Escherichia coli
isolate expressing extended spectrum beta-lactamase (CTX-M-15 and TEM-4) and carbapenemase (OXA-244) genes. Enhanced killing effects in combination were identified as a driver of the synergy and were translated from static time-kill experiments into the dynamic hollow fiber infection model. These findings in combination with a suppression of the emergence of resistance in combination emphasize a potential clinical benefit with regard to increased efficacy or to allow for dose reductions with maintained effect sizes to avoid toxicity.
The Role of the Grass Snake Natrix natrix (Reptilia, Colubridae) in the Transfer of Polyunsaturated Fatty Acids from Aquatic to Terrestrial Ecosystems to Land
Authors: Dgebuadze Yu. Yu. , Neymark L. A. , Bashinskiy I. V. , Sushchik N. N. , Rudchenko A. E. , Gladyshev M. I. 
Published: December 2023

Abstract
As a result of analyses of fatty acid (FA) composition in the grass snake Natrix natrix and its food objects, tadpoles and metamorphs of two amphibian species: the moor frog Rana arvalis and the Pallas spadefoot toad Pelobates vespertinus, it was shown for the first time that the high total content of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids in the biomass of the snakes indicates its important role in the transfer of these essential substances from aquatic ecosystems to land. It was found that, since food sources of DHA in terrestrial ecosystems are absent, its high level in R. arvalis metamorps and grass snakes may be provided only by synthesis from biochemical precursors contained in food of aquatic origin.
Multimodal treatment of oligometastatic non-small cell lung cancer
Authors: Graça Luís Lourenço , Pego Alice , Lareiro Susana , Pancas Rita 
Published: December 2023

The management of patients with oligometastatic non-small cell lung cancer has undergone significant improvement in recent years. The combination of increase in sensitivity of diagnostic tests, development in systemic therapies, surgical techniques and radiotherapy allowing radical ablative treatment of metastases have significantly influenced the treatment of advanced lung cancer, mainly in the patients in which these treatment modalities converge.We report a rare case of a young patient with an oligometastatic lung adenocarcinoma with a single synchronous brain metastasis, who underwent aggressive locoregional and systemic therapies and is still in annual follow-up with excellent quality of life and progression-free survival of 164 months.
What are best practices for involving family caregivers in interventions aimed at responsive behaviour stemming from unmet needs of people with dementia in nursing homes: a scoping review
Authors: Tasseron-Dries Petra E M , Smaling Hanneke J A , Nakanishi Miharu , Achterberg Wilco P , van der Steen Jenny T 
Published: December 2023

ObjectivesThis study aimed to determine best practices for involving family caregivers in interventions aimed at preventing and reducing responsive behaviour stemming from unmet needs, including pain.DesignScoping review, reported according to the Preferred Reporting Items for Systematic Reviews, Meta-Analyses extension for Scoping Reviews reporting guideline.Data sourcesPubMed, Embase, Emcare, Web of Science, COCHRANE Library, PsycINFO, Academic Search Premier and Cinahl searched up to 23 July 2023.Eligibility criteriaStudies reporting on family involvement in interventions for nursing home residents with dementia were included.Data extraction and synthesisTwo researchers independently extracted the data, followed by a content analysis.ResultsOf the 1486 records screened, 20 studies were included. Family caregivers were involved in interventions aimed at planning care, life review (eg, documentation of life experiences of their relative), and selecting activities for their relative. Family caregivers preferred an active role in developing optimal care for their relative. Drivers of success and barriers to family involvement centred around three themes: (1) communication between all involved; (2) prerequisites (organisational and other conditions) and (3) personal circumstances (family’s coping and skills).ConclusionBest practices for involving family caregivers in interventions aimed at addressing responsive behaviour in residents with dementia concerned those interventions in which family caregivers were given an important role in managing responsive behaviour. This means that, in order to achieve an active role of family caregivers in the whole care process, their needs must be taken into account.Trial registration numberThe protocol of the review was regisered at OSF;https://osf.io/twcfq
Effect of preinitiated glucose-insulin-potassium strategy for patients with undergoing planned percutaneous coronary intervention: a systematic review and meta-analysis
Authors: Liu Huiruo , Liu Rugang , Yang Zeyu , Xu Feng , Li Chuanbao 
Published: December 2023

ObjectivesWhether the glucose-insulin-potassium (GIK) should be used as an adjuvant therapy for ischaemic myocardial disease remains controversial nowadays reperfusion era. This meta-analysis aimed to assess the effects of preinitiated GIK for patients undergoing planned percutaneous coronary intervention (PCI).DesignSystematic review and meta-analysis.Data sourcesPubMed, Web of science, MEDLINE, Embase, Cochrane Library and ClinicalTrials.gov were searched through 27 November 2022.Eligibility criteriaOnly randomised controlled trials involving participants preinitiated with GIK or placebo before planned PCI were included.Data extraction and synthesisTwo independent reviewers used standardised methods to search, screen and code included trials. Risk of bias was assessed with the Cochrane tool. Pooled analysis was conducted using random or effects models according to the heterogeneity. Subgroup analyses were carried out for dosage of GIK and if with ongoing myocardial ischaemia.Results13 randomised controlled trials (RCTs) including 3754 participants were evaluated. We found patients preconditioned with GIK before PCI showed a significant increase in Thrombolysis in Myocardial Infarction 3 flow events after angioplasty (OR 1.59, 95% CI 1.03 to 2.46, p=0.04), also revealed improved in-hospital left ventricular ejection fraction (weighed mean difference, WMD 1.62, 95% CI 0.21 to 3.03, p=0.02) and myocardial salvage index (WMD 0.09, 95% CI 0.01 to 0.16, p=0.03). Nevertheless, no benefit was observed in all-cause mortality neither on 30-day (OR 0.81, 95% CI 0.59 to 1.11, p=0.18) nor 6 months (OR 1.02, 95% CI 0.42 to 2.46, p=0.97). Furthermore, GIK intervention was associated with higher occurrences of complications such as phlebitis (OR 10.13, 95% CI 1.74 to 59.00, p=0.01) and hypoglycaemia (OR 10.43, 95% CI 1.32 to 82.29, p=0.03), but not hyperkalaemia (OR 9.36, 95% CI 0.50 to 175.27, p=0.13), liquid overload (OR 1.02, 95% CI 0.25 to 4.13, p=0.98) or in-hospital heart failure (OR 0.42, 95% CI 0.06 to 2.96, p=0.39).ConclusionsOur study shows preconditioning GIK exhibits myocardial reperfusion and cardiac function benefits for patients planning to receive PCI intervention, while also some complications such as phlebitis and hypoglycaemia accompany.PROSPERO registration numberCRD42022326334.
Factors associated with COVID-19 vaccine uptake among people with type 2 diabetes in Kenya and Tanzania: a mixed-methods study
Authors: Binyaruka Peter , Mtenga Sally M , Mashasi Irene , Karugu Caroline H , Mohamed Shukri F , Asiki Gershim , Mair Frances S , Gray Cindy M 
Published: December 2023

BackgroundPeople with type 2 diabetes (T2D) are at increased risk of poor outcomes from COVID-19. Vaccination can improve outcomes, but vaccine hesitancy remains a major challenge. We examined factors influencing COVID-19 vaccine uptake among people with T2D in two sub-Saharan Africa countries that adopted different national approaches to combat COVID-19, Kenya and Tanzania.MethodsA mixed-methods study was conducted in February-March 2022, involving a survey of 1000 adults with T2D (500 Kenya; 500 Tanzania) and 51 in-depth interviews (21 Kenya; 30 Tanzania). Determinants of COVID-19 vaccine uptake were identified using a multivariate logistic regression model, while thematic content analysis explored barriers and facilitators.ResultsCOVID-19 vaccine uptake was lower in Tanzania (26%) than in Kenya (75%), which may reflect an initial political hesitancy about vaccines in Tanzania. People with college/university education were four times more likely to be vaccinated than those with no education (Kenya AOR=4.25 (95% CI 1.00 to 18.03), Tanzania AOR=4.07 (1.03 to 16.12)); and people with health insurance were almost twice as likely to be vaccinated than those without health insurance (Kenya AOR=1.70 (1.07 to 2.70), Tanzania AOR=1.81 (1.04 to 3.13)). Vaccine uptake was higher in older people in Kenya, and among those with more comorbidities and higher socioeconomic status in Tanzania. Interviewees reported that wanting protection from severe illness promoted vaccine uptake, while conflicting information, misinformation and fear of side-effects limited uptake.ConclusionCOVID-19 vaccine uptake among people with T2D was suboptimal, particularly in Tanzania, where initial political hesitancy had a negative impact. Policy-makers must develop strategies to reduce fear and misconceptions, especially among those who are less educated, uninsured and younger.
Impact of type, intensity, frequency, duration and volume of physical activity on dementia and mild cognitive impairment in older adults: protocol for a systematic review and meta-analysis
Authors: Junger Ana Lúcia , de Sousa Romeiro Amanda Maria , Noll Matias , de Oliveira Cesar , Silveira Erika Aparecida 
Published: December 2023

IntroductionWorldwide, the prevalence of degenerative diseases such as dementia and mild cognitive impairment (MCI) is increasing with population ageing and increasing life expectancy. Both conditions share modifiable risk factors. Physical inactivity is one of these modifiable risk factors, and research points to the protective effect of physical activity on the incidence of dementia and MCI. However, this association tends to change according to type, intensity, frequency, duration and volume of physical activity. Furthermore, it remains unclear which of these characteristics offers the greatest protective effect. Therefore, this study aims to evaluate the impacts of different types, intensities, frequencies, duration and volume of physical activity on dementia and cognitive decline in older adults.Methods and analysisThe search will be carried out from October 2023, using the following databases: PubMed, Embase, Scopus, CINAHL and Web of Science. Cohort studies with a follow-up time of 1 year or longer that have investigated the incidence of dementia and/or MCI in older adults exposed to physical activity will be included. There will be no limitations on the date of publication of the studies. Studies published in English, Spanish or Portuguese will be analysed. Two researchers will independently screen the articles and extract the data. Any discrepancies will be resolved by a third reviewer. Association measures will be quantified, including OR, HR, relative risk and incidence ratio, with a 95% CI. If the data allow, a meta-analysis will be performed. To assess the methodological quality of the selected studies, the Grading of Recommendations, Assessment, Development and Evaluations instrument, and the Downs and Black instrument to assess the risk of bias, will be used.Ethics and disseminationEthical approval is not required. The results will be submitted for publication in a peer-reviewed journal.PROSPERO registration numberCRD42023400411.