bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability of meropenem in portable elastomeric infusion devices: which protocol should be implemented in clinical practice?
Authors: Esteban-Cartelle Beatriz , Serrano Dolores R. , Pérez Menéndez-Conde Covadonga , Vicente-Oliveros Noelia , Álvarez-Díaz Ana , Fortún Abete Jesús , Martín-Dávila Pilar 
Published: December 2023

ABSTRACT
Meropenem has an excellent activity against gram-positive and gram-negative bacteria, including multi-resistant microorganisms. Even though meropenem is a great candidate for outpatient parenteral antimicrobial therapy (OPAT), its physicochemical stability is a major challenge. This work aimed to demonstrate the suitability of including meropenem in OPAT by elucidating its physicochemical stability in a range of commonly prescribed concentrations within portable elastomeric infusion devices. Physical and chemical stability were evaluated at two concentrations commonly used in clinical practice (2 mg/mL and 25 mg/mL), and three temperatures (2–8°C, 25°C, and 32°C) using Accufuser portable elastomeric infusion devices. Drug adsorption onto portable elastomeric infusion devices was also determined at the end of the experiment. Meropenem stability significantly decreased at higher temperatures and when higher drug solution concentrations were used. Meropenem solutions at 2 mg/mL kept the drug content above 95% over 24 h at 2–8°C, but just for 8 h at 25°C. Nevertheless, solutions containing 25 mg/mL of meropenem showed a dramatic decrease in chemical stability after 8 h 2–8°C and just after 4 h at 25°C or 32°C. However, physical stability was kept favorable during this period. The drug adsorption on the material of the elastomeric infusion device was below 1%, indicating the suitability of the chosen device. We propose several administration protocols for meropenem in portable elastomeric infusion devices in clinical practice, according to the results obtained in our study. The results obtained in this study open up a possibility of administering meropenem in an OPAT setting despite its short stability.

IMPORTANCE
Although outpatient parenteral antibiotic therapy can be a good approach to treating infections, a lack of data regarding antibiotic stability in portable elastomeric infusion devices restricts its safe and effective use. Actually, meropenem is used for prolonged periods above 24 h, and it is not physicochemically stable, which can compromise efficacy and toxicity. This work is of high importance to show the clinicians the real shelf life of meropenem when administered in portable elastomeric infusion devices. We propose several administration protocols for meropenem in portable elastomeric infusion devices in clinical practice, according to the stability drug results obtained in our study.
The type III secretion system facilitates systemic infections of
Pseudomonas aeruginosa
in the clinic
Authors: Wu Tiantian , Zhang Zhenchuan , Li Tong , Dong Xu , Wu Dan , Zhu Lixia , Xu Kaijin , Zhang Ying 
Published: December 2023

ABSTRACT

Pseudomonas aeruginosa
is a major opportunistic pathogen that can cause severe systemic infections. Here, we found that the type III secretion system effector ExoU was the main determinant of pathogenicity of a highly virulent clinical isolate strain, BSI_S5, of
P. aeruginosa
, which caused severe bloodstream infections and belongs to ST463/O4. Deletion of
exoU
showed significantly attenuated cytotoxicity and virulence
in vivo
, while deletion of two other unique genes from strain BSI_S5,
chr_1696
and
chr_4238
, which encodes type I secretion system permease/ATPase or polysaccharide biosynthesis protein, respectively, caused no apparent loss of toxicity compared to the parent strain, and complementation of the
ΔexoU
mutant restored its virulence. The presence of ExoU-induced lung lesions and the mucosal damage of gallbladder in mice, and the replication of the
ΔexoU
mutant was hindered
in vivo
compared with the parent strain. We show here for the first time that a clinical isolate with intact
exoU
harbored a mutation of T→G substitution in the adjacent specific Pseudomonas chaperone for ExoU (
spcU
), which caused phenylalanine to valine change at amino acid 94 of SpcU, resulting in significant loss of cytotoxicity. This finding suggests that intact
exoU
is not sufficient for cytotoxicity, but a functional downstream SpcU is required for ExoU secretion and cytotoxicity. Finally, we found that BSI_S5 harbored two types of insertion sequences adjacent to
exoU
, suggesting the potential of
exoU
to be transferred to other strains. Our study opens an avenue for further mechanistic study of
P. aeruginosa
systemic infections regarding its high pathogenicity and clinical spread.

IMPORTANCE

The identification of decisive virulence-associated genes in highly pathogenic
P. aeruginosa
isolates in the clinic is essential for diagnosis and the start of appropriate treatment. Over the past decades,
P. aeruginosa
ST463 has spread rapidly in East China and is highly resistant to β-lactams. Given the poor clinical outcome caused by this phenotype, detailed information regarding its decisive virulence genes and factors affecting virulence expression needs to be deciphered. Here, we demonstrate that the T3SS effector ExoU has toxic effects on mammalian cells and is required for virulence in the murine bloodstream infection model. Moreover, a functional downstream SpcU is required for ExoU secretion and cytotoxicity. This work highlights the potential role of ExoU in the pathogenesis of disease and provides a new perspective for further research on the development of new antimicrobials with antivirulence ability.
First trimester “clean catch” urine and vaginal swab sample distinct microbiological niches
Authors: Sung Juliana , Larsen Peter , Halverson Thomas M. , Waters Thaddeus P. , Goodman Jean R. , Wolfe Alan J. 
Published: December 2023

ABSTRACT

Untreated asymptomatic bacteriuria (ASB) has been associated with adverse pregnancy outcomes. Thus, routine screening by standard urine culture (SUC) and treatment of ASB are currently recommended for all pregnant women. However, SUC often misses microbes detected by expanded quantitative urine culture methods (EQUC) and 16S rRNA gene (amplicon) sequencing. The existence of these microbes (urinary microbiome) challenges the current approach to ASB screening in pregnancy as it is limited by two assumptions: (i) the female bladder is naturally sterile and (ii) SUC identifies all clinically relevant uropathogens. To determine the uniqueness or similarity between urinary and vaginal microbiomes, we performed a prospective observational institutional review board (IRB)-approved cohort study of pregnant women with a singleton pregnancy <14 weeks undergoing routine ASB screening. Consented subjects provided paired midstream voided urine and vaginal swab samples, which were assessed by EQUC and amplicon sequencing. The similarity was determined by Spearman’s correlation; statistical significance was calculated using bootstrap analysis with 1,000 random samples and a significance threshold of
P
value < 0.001. We used the Bayes theorem to quantify how well the vaginal microbiome could be used as a proxy for a patient’s urinary microbiome and vice versa. Our findings provide evidence that EQUC and amplicon sequencing reveal similar views of urinary and vaginal microbiomes in first trimester pregnant women. However, while vaginal and urinary microbial compositions were significantly correlated for the same individual, they were by no means equivalent. The first trimester urinary and vaginal microbiomes are distinct enough to preclude their use as proxies of each other.

IMPORTANCE
Untreated asymptomatic bacteriuria (ASB) has been associated with adverse pregnancy outcomes, including pyelonephritis, preterm labor, and low birth weight infants. Thus, routine screening by standard urine culture (SUC) and treatment of ASB are currently recommended for all pregnant women. For this purpose, some researchers claim that vaginal swabs and urine samples can be used as proxies for each other. Because SUC often misses microbes, we used two more sensitive, recently validated detection methods to compare the composition of the urinary and vaginal microbiomes of pregnant females in their first trimester. Both methods yielded similar results. Vaginal and urinary microbial compositions for the same individual were significantly correlated; however, they were not equivalent. We argue that first trimester urinary and vaginal microbiomes are distinct enough to preclude their use as proxies for each other.
Uncovering the diversity and distribution of biosynthetic gene clusters of prochlorosins and other putative RiPPs in marine
Synechococcus
strains
Authors: Arias-Orozco Patricia , Zhou Lu , Yi Yunhai , Cebrián Rubén , Kuipers Oscar P. 
Published: December 2023

ABSTRACT

Picocyanobacteria can synthesize a distinctive class of lanthipeptides referred to as prochlorosins. They are classified within the Nif11 family and are subject to post-translational modifications by a solitary promiscuous enzyme from the ProcM group. Their biological function is unknown but highly speculated upon. In this study, we conducted a comprehensive genome mining investigation of the
Synechococcus
and
Prochlorococcus
genomes to elucidate the genomic landscape associated with the biosynthetic gene clusters (BGCs) harboring prochlorosin genes. Our mining study led to a substantial expansion of the known prochlorosin repertoire identified in 15 picocyanobacterial genomes. We also identified a range of tailoring enzymes and gene families proximal to the
procA
/
syncA
genes. The recombination-related proteins we detected were of particular interest, as they may have a critical role in generating the diversity observed within this peptide family. Interestingly, we identified novel LAP/YcaO BGCs in
Synechococcus
that had not been previously described. These BGCs hold the potential to generate prochlorosins with secondary modifications and introduce new putative azol(in)e-containing ribosomally synthesized and post-translationally modified peptides precursors. Our investigation offers an in-depth analysis of the vast prochlorosin family.

IMPORTANCE

Genome mining studies have revealed the remarkable combinatorial diversity of ribosomally synthesized and post-translationally modified peptides (RiPPs) in marine bacteria, including prochlorosins. However, mining strategies also prove valuable in investigating the genomic landscape of associated genes within biosynthetic gene cluster (BGC) specific to targeted RiPPs of interest. Our study contributes to the enrichment of knowledge regarding prochlorosin diversity. It offers insights into potential mechanisms involved in their biosynthesis and modification, such as hyper-modification, which may give rise to active lantibiotics. Additionally, our study uncovers putative novel promiscuous post-translational enzymes, thereby expanding the chemical space explored within the
Synechococcus
genus. Moreover, this research extends the applications of mining techniques beyond the discovery of new RiPP-like clusters, allowing for a deeper understanding of genomics and diversity. Furthermore, it holds the potential to reveal previously unknown functions within the intriguing RiPP families, particularly in the case of prochlorosins.
Non-Catalytic Domains of DNA Polymerase λ: Influence on Enzyme Activity and Its Regulation
Authors: Maltseva E. A. , Rechkunova N. I. , Lavrik O. I. 
Published: December 2023

Abstract
DNA polymerase λ (Polλ) belongs to the same structural X-family as DNA polymerase β, the main polymerase of base excision repair. The role of Polλ in this process remains not fully understood. A significant difference between the two DNA polymerases is the presence of an extended non-catalytic N-terminal region in the Polλ structure. The influence of this region on the interaction of Polλ with DNA and multifunctional proteins, poly(ADP-ribose)polymerase 1 (PARP1) and replication protein A (RPA), was studied in detail for the first time. The data obtained suggest that non-catalytic Polλ domains play a suppressor role both in relation to the polymerase activity of the enzyme and in interaction with DNA and PARP1.
Predicting the risk of glaucoma-related adverse events following secondary intraocular lens implantation in paediatric eyes: a 3-year study
Authors: Chen Hui , Xu Chaoqun , Jin Ling , Wang Zhenyu , Xu Jingmin , Zou Yingshi , Jin Guangming , Luo Lixia , Lin Haotian , Chen Weirong , Zheng Danying , Liu Yizhi , Liu Zhenzhen 
Published: December 2023

AimsTo establish and evaluate predictive models for glaucoma-related adverse events (GRAEs) following secondary intraocular lens (IOL) implantation in paediatric eyes.Methods205 children (356 aphakic eyes) receiving secondary IOL implantation at Zhongshan Ophthalmic Center with a 3-year follow-up were enrolled. Cox proportional hazard model was used to identify predictors of GRAEs and developed nomograms. Model performance was evaluated with time-dependent receiver operating characteristic (ROC) curves, decision curve analysis, Kaplan-Meier curves and validated internally through C-statistics and calibration plot of the bootstrap samples.ResultsOlder age at secondary IOL implantation (HR=1.5, 95% CI: 1.03 to 2.19), transient intraocular hypertension (HR=9.06, 95% CI: 2.97 to 27.67) and ciliary sulcus implantation (HR=14.55, 95% CI: 2.11 to 100.57) were identified as risk factors for GRAEs (all p<0.05). Two nomograms were established. At postoperatively 1, 2 and 3 years, model 1 achieved area under the ROC curves (AUCs) of 0.747 (95% CI: 0.776 to 0.935), 0.765 (95% CI: 0.804 to 0.936) and 0.748 (95% CI: 0.736 to 0.918), and the AUCs of model 2 were 0.881 (95% CI: 0.836 to 0.926), 0.895 (95% CI: 0.852 to 0.938) and 0.848 (95% CI: 0.752 to 0.945). Both models demonstrated fine clinical net benefit and performance in the interval validation. The Kaplan-Meier curves showing two distinct risk groups were well discriminated and robust in both models. An online risk calculator was constructed.ConclusionTwo nomograms could sensitively and accurately identify children at high risk of GRAEs after secondary IOL implantation to help early identification and timely intervention.
Comorbid status in patients with osteomyelitis is associated with long-term incidence of extremity amputation
Authors: Schmidt Brian M , Keeney-Bonthrone Toby P , Hawes Armani M , Karmakar Monika , Frydrych Lynn M , Cinti Sandro K , Pop-Busui Rodica , Delano Matthew J 
Published: December 2023

IntroductionOsteomyelitis is associated with significant morbidity, including amputation. There are limited data on long-term amputation rates following an osteomyelitis diagnosis. We sought to determine the incidence of amputation in patients with osteomyelitis over 2 years.Research design and methodsObservational cohort study of 1186 inpatients with osteomyelitis between 2004 and 2015 and stratified by osteomyelitis location status to evaluate the impact on amputation, mortality rates, readmission data, and inpatient days.ResultsPersons with diabetes had 3.65 times greater probability of lower extremity amputation (p<0.001), readmission (p<0.001), and longer inpatient stay (p<0.001) and had higher 2-year mortality (relative risk (RR) 1.23, p=0.0027), adjusting for risk factors. Male gender (RR 1.57, p<0.001), black race (RR 1.41, p<0.05), former smoking status (RR 1.38, p<0.01), myocardial infarction (RR 1.72, p<0.001), congestive heart failure (RR 1.56, p<0.001), peripheral vascular disease (RR 2.25, p<0.001) and renal disease (RR 1.756, p<0.001) were independently associated with amputation. Male gender (RR 1.39, p<0.01), black race (RR 1.27, p<0.05), diabetes (RR 2.77, p<0.001) and peripheral vascular disease (RR 1.59, p<0.001) had increased risk of lower, not upper, extremity amputation.ConclusionsPatients with osteomyelitis have higher rates of amputation and hospitalization. Clinicians must incorporate demographic and comorbid risk factors to protect against amputation.
Is the awarding gap at UK medical schools influenced by ethnicity and medical school attended? A retrospective cohort study
Authors: Brown Celia , Goss Charlotte , Sam Amir H 
Published: December 2023

ObjectivesTo better characterise the Awarding Gap (AG) between black, Asian and other minority ethnic (BAME) and white students in UK undergraduate medical education by examining how it affects eight minority ethnicity subgroups (Bangladeshi, black, Chinese, Indian, Pakistani, mixed, other Asian background and other ethnic background) and whether the AG varies by medical school attended.DesignRetrospective cohort study.SettingData extracted from the UK Medical Education Database on students enrolled at 33 UK medical schools in the academic years starting 2012, 2013 and 2014.Participants16 020 ‘Home’ tuition fee status students who sat the University Clinical Aptitude Test on entry to university and obtained a UK Foundation Programme (UKFP) application score on exit.Primary outcome measureUKFP Z-scores on exit from medical school.ResultsThere were significant differences in UKFP Z-scores between ethnicity subgroups. After white students, mixed ethnicity students performed best (coefficient −0.15 standard deviations [SD]) compared with white students, (95% confidence interval [CI] −0.23 to −0.08, p<0.001) and Pakistani students scored lowest (coefficient −0.53 SD, 95% CI −0.60 to −0.46, p<0.001). In pairwise comparisons of scores between all nine individual ethnicity subgroups, 15/36 were statistically significant. The AG varied considerably across medical schools. The largest gap showed the coefficient for BAME was −0.83 SD compared with white students (95% CI −1.18 to −0.49, p<0.001), while the smallest demonstrated no statistically significant difference in performance between BAME and white students (+0.05 SD, 95% CI −0.32 to 0.42, p=0.792).ConclusionsBAME students are significantly disadvantaged by the current UK medical education system. There are clear differences in medical school outcomes between students from different ethnicity subgroups, and the size of the AG also varies by medical school attended. Urgent and effective action must be taken to address the AG and achieve an equal learning environment for our future doctors.
Regional and racial disparities in major amputation rates among medicare beneficiaries with diabetes: a retrospective study in the southeastern USA
Authors: Lobo Jennifer Mason , Kang Hyojung , Brennan Meghan B , Kim Soyoun , McMurry Timothy L , Balkrishnan Rajesh , Anderson Roger , McCall Anthony , Sohn Min-Woong 
Published: December 2023

ObjectiveWhile rates for non-traumatic lower extremity amputations (LEA) have been declining, concerns exist over disparities. Our objectives are to track major LEA (MLEA) rates over time among Medicare beneficiaries residing in a high diabetes prevalence region in the southeastern USA (the diabetes belt) and surrounding areas.MethodsWe used Medicare claims files for ~900 000 fee-for-service beneficiaries aged ≥65 years in 2006–2015 to track MLEA rates per 1000 patients with diabetes. We additionally conducted a cross-sectional analysis of data for 2015 to compare regional and racial disparities in major amputation risks after adjusting for demographic, socioeconomic, access-to-care and foot complications and other health factors. The Centers for Disease Control and Prevention defined the diabetes belt as 644 counties across Appalachian and southeastern US counties with high prevalence.ResultsMLEA rates were 3.9 per 1000 in the Belt compared with 2.8 in the surrounding counties in 2006 and decreased to 2.3 and 1.6 in 2015. Non-Hispanic black patients had 8.5 and 6.9 MLEAs per 1000 in 2006 and 4.8 and 3.5 in 2015 in the Belt and surrounding counties, respectively, while the rates were similar for non-Hispanic white patients in the two areas. Although amputation rates declined rapidly in both areas, non-Hispanic black patients in the Belt consistently had >3 times higher rates than non-Hispanic whites in the Belt. After adjusting for patient demographics, foot complications and healthcare access, non-Hispanic blacks in the Belt had about twice higher odds of MLEAs compared with non-Hispanic whites in the surrounding areas.DiscussionOur data show persistent disparities in major amputation rates between the diabetes belt and surrounding counties. Racial disparities were much larger in the Belt. Targeted policies to prevent MLEAs among non-Hispanic black patients are needed to reduce persistent disparities in the Belt.
Outsciencing the scientists: a cross-sectional mixed-methods investigation of public trust in scientists in seven European countries
Authors: Heyerdahl Leonardo W , Borzykh Yanina , Lana Benedetta , Volkmann Anna-Maria , Crusefalk Lars , Colman Elien , Tvardik Nastassia , Anthierens Sibyl , Vray Muriel , Giles-Vernick Tamara 
Published: December 2023

BackgroundIn this era of global health crises, public trust in scientists is a crucial determinant of adherence to public health recommendations. Studies of trust in scientists often link sociodemographic and other factors to such adherence but rely on assumptions about scientists and neglect scientific uncertainty. We undertook a cross-sectional mixed-methods study evaluating factors associated with public trust of scientists in Europe, investigating how and why respondents embraced certain claims in scientific debates.MethodsA survey was administered to 7000 participants across seven European countries in December 2020. Data concerning sociodemographic characteristics, trust in scientists, information source preferences, COVID-19 experiences and beliefs about pandemic origins were analysed using a multiple regression model. We employed thematic analysis to interpret open-text responses about pandemic origins and likely acceptance of treatments and vaccination.ResultsTrust in scientists was associated with multiple sociodemographic characteristics, including higher age and educational levels, left/centre political affiliation and use of certain information sources. Respondents claiming that COVID-19 was deliberately released and that 5G technology worsened COVID-19 symptoms had lower levels of trust in scientists. Explaining their positions in debates about pandemic origins, respondents trusting and not trusting scientists invoked scientific results and practices, arguing that scientists were not the most important actors in these debates.ConclusionsAlthough our quantitative analyses align with prior studies, our qualitative analyses of scientists, their practices and perceived roles are more varied than prior research presumed. Further investigation of these variations is needed to strengthen scientific literacy and trust in scientists.