bluuebunny/crossref_metadata_2025 huggingface dataset:
Cyclic isogenies of elliptic curves over fixed quadratic fields
Authors: Banwait Barinder , Najman Filip , Padurariu Oana
Published: August 2023

Building on Mazur’s 1978 work on prime degree isogenies, Kenku determined in 1981 all possible cyclic isogenies of elliptic curves over

Q

\mathbb {Q}

. Although more than 40 years have passed, the determination of cyclic isogenies of elliptic curves over a single other number field has hitherto not been realised.

In this paper we develop a procedure to assist in establishing such a determination for a given quadratic field. Executing this procedure on all quadratic fields

Q

(

d

)

\mathbb {Q}(\sqrt {d})

with

|

d

|

>

10
4

|d| > 10^4

we obtain, conditional on the Generalised Riemann Hypothesis, the determination of cyclic isogenies of elliptic curves over

19
19

quadratic fields, including

Q

(

213

)

\mathbb {Q}(\sqrt {213})

and

Q

(

−
2289

)

\mathbb {Q}(\sqrt {-2289})

. To make this procedure work, we determine all of the finitely many quadratic points on the modular curves

X
0

(
125
)

X_0(125)

and

X
0

(
169
)

X_0(169)

, which may be of independent interest.
Flow by 𝜎_{𝑘} curvature to the Orlicz Christoffel-Minkowski problem
Authors: Yi Caihong
Published: August 2023

In this paper, we consider the anisotropic curvature flow of smooth, origin-symmetric, uniformly convex hypersurfaces in

R

n
+
1

\mathbb {R}^{n+1}

. The flow exists for all time and converges smoothly to a solution of the even Orlicz Christoffel-Minkowski problem. Our proof also gives an approach to the solution of the

L
p

L_p

Christoffel-Minkowski problem.
Crossed homomorphisms and low dimensional representations of mapping class groups of surfaces
Authors: Kasahara Yasushi
Published: August 2023

We continue the study of low dimensional linear representations of mapping class groups of surfaces initiated by Franks–Handel [Proc. Amer. Math. So. 141 (2013), pp. 2951–2962] and Korkmaz [Low-dimensional linear representations of mapping class groups, preprint, arXiv:1104.4816v2 (2011)]. We consider

(
2
g
+
1
)

(2g+1)

-dimensional complex linear representations of the pure mapping class groups of compact orientable surfaces of genus

g
g

. We give a complete classification of such representations for

g
≥
7

g \geq 7

up to conjugation, in terms of certain twisted

1
1

-cohomology groups of the mapping class groups. A new ingredient is to use the computation of a related twisted

1
1

-cohomology group by Morita [Ann. Inst. Fourier (Grenoble) 39 (1989), pp. 777–810]. The classification result implies in particular that there are no irreducible linear representations of dimension

2
g
+
1

2g+1

for

g
≥
7

g \geq 7

, which marks a contrast with the case

g
=
2

g=2

.
Membrane binding of endocytic myosin-1s is inhibited by a class of ankyrin repeat proteins
Authors: Willet Alaina H. , Chen Jun-Song , Ren Liping , Gould Kathleen L.
Published: August 2023

Ank1 binds the myosin-1 (Myo1) and prevents its membrane and endocytic patch localization. Structural predications suggest that the (Ank1) ankyrin repeats bind the Myo1 motor while the Ank1 acidic C-terminus masks positive charges necessary for Myo1 membrane association. This regulatory mechanism appears to be evolutionarily conserved.
Accumulation of squalene in filamentous fungi Trichoderma virens PS1-7 in the presence of butenafine hydrochloride, squalene epoxidase inhibitor: biosynthesis of 13C-enriched squalene
Authors: Zhang Wen , Sunami Kazu , Liu Shuo , Zhuang Zihan , Sakihama Yasuko , Zhou Da-Yang , Suzuki Takeyuki , Murai Yuta , Hashimoto Makoto , Hashidoko Yasuyuki
Published: August 2023

Squalene is a triterpenoid compound and widely used in various industries such as medicine and cosmetics due to its strong antioxidant and anticancer properties. The purpose of this study is to increase the accumulation of squalene in filamentous fungi using exogeneous butenafine hydrochloride, which is an inhibitor for squalene epoxidase. The detailed settings achieved that the filamentous fungi, Trichoderma virens PS1-7, produced squalene up to 429.93 ± 51.60 mg/L after culturing for 7 days in the medium consisting of potato infusion with glucose at pH 4.0, in the presence of 200 µm butenafine. On the other hand, no squalene accumulation was observed without butenafine. This result indicated that squalene was biosynthesized in the filamentous fungi PS1-7, which can be used as a novel source of squalene. In addition, we successfully obtained highly 13C-enriched squalene by using [U-13C6]-glucose as a carbon source replacing normal glucose.
Enhanced overexpression of secreted enzymes by discrete repeat promoters in Streptomyces lividans
Authors: Yang Lingli , Hatanaka Tadashi
Published: August 2023

Streptomyces lividans is an efficient host for extracellular overproduction of recombinant proteins. To enhance the overexpression strength of S. lividans, we designed several kinds of expression plasmids with different positioning of repeat promoters. The effect of repeat promoters was evaluated by measuring the accumulated amounts of a stable transglutaminase or an unstable carboxypeptidase that was secreted into the medium. Successive tandem positions of repeat promoters upstream of the normal promoter did not enhance the expression of transglutaminase. Discrete positions of repeat promoters both upstream and downstream of the normal promoter enhanced the expression of transglutaminase to 2-fold, and the downstream ones also enhanced the expression of carboxypeptidase to 1.7-fold. On the other hand, there were still some constructs of plasmids with discrete repeat promoters that did not promote the expression of the target enzymes, indicating the complexity of the mechanisms of repeat promoters working on gene expression.
Prediction of pathogenic single amino acid substitutions using molecular fragment descriptors
Authors: Zadorozhny Anton , Smirnov Anton , Filimonov Dmitry , Lagunin Alexey
Published: August 2023

Motivation

Next Generation Sequencing technologies make it possible to detect rare genetic variants in individual patients. Currently, more than a dozen software and web services have been created to predict the pathogenicity of variants related with changing of amino acid residues. Despite considerable efforts in this area, at the moment there is no ideal method to classify pathogenic and harmless variants, and the assessment of the pathogenicity is often contradictory. In this article, we propose to use peptides structural formulas of proteins as an amino acid residues substitutions description, rather than a single-letter code. This allowed us to investigate the effectiveness of chemoinformatics approach to assess the pathogenicity of variants associated with amino acid substitutions.

Results

The structure-activity relationships analysis relying on protein-specific data and atom centric substructural multilevel neighborhoods of atoms (MNA) descriptors of molecular fragments appeared to be suitable for predicting the pathogenic effect of single amino acid variants. MNA-based Naïve Bayes classifier algorithm, ClinVar and humsavar data were used for the creation of structure-activity relationships models for 10 proteins. The performance of the models was compared with 11 different predicting tools: 8 individual (SIFT 4G, Polyphen2 HDIV, MutationAssessor, PROVEAN, FATHMM, MVP, LIST-S2, MutPred) and 3 consensus (M-CAP, MetaSVM, MetaLR). The accuracy of MNA-based method varies for the proteins (AUC: 0.631–0.993; MCC: 0.191–0.891). It was similar for both the results of comparisons with the other individual predictors and third-party protein-specific predictors. For several proteins (BRCA1, BRCA2, COL1A2, and RYR1), the performance of the MNA-based method was outstanding, capable of capturing the pathogenic effect of structural changes in amino acid substitutions.

Availability and implementation

The datasets are available as supplemental data at Bioinformatics online. A python script to convert amino acid and nucleotide sequences from single-letter codes to SD files is available at https://github.com/SmirnygaTotoshka/SequenceToSDF. The authors provide trial licenses for MultiPASS software to interested readers upon request.
Block Aligner: an adaptive SIMD-accelerated aligner for sequences and position-specific scoring matrices
Authors: Liu Daniel , Steinegger Martin
Published: August 2023

Motivation

Efficiently aligning sequences is a fundamental problem in bioinformatics. Many recent algorithms for computing alignments through Smith–Waterman–Gotoh dynamic programming (DP) exploit Single Instruction Multiple Data (SIMD) operations on modern CPUs for speed. However, these advances have largely ignored difficulties associated with efficiently handling complex scoring matrices or large gaps (insertions or deletions).

Results

We propose a new SIMD-accelerated algorithm called Block Aligner for aligning nucleotide and protein sequences against other sequences or position-specific scoring matrices. We introduce a new paradigm that uses blocks in the DP matrix that greedily shift, grow, and shrink. This approach allows regions of the DP matrix to be adaptively computed. Our algorithm reaches over 5–10 times faster than some previous methods while incurring an error rate of less than 3% on protein and long read datasets, despite large gaps and low sequence identities.

Availability and implementation

Our algorithm is implemented for global, local, and X-drop alignments. It is available as a Rust library (with C bindings) at https://github.com/Daniel-Liu-c0deb0t/block-aligner.
Salting-Out Assisted Liquid–Liquid Microextraction and Reverse-Phase Chromatographic Quantification of Two Neonicotinoid Insecticides from Fruits and Vegetables
Authors: Akram Sumia , Sultana Bushra , Aasi Muhammad Rafique , Mushtaq Muhammad , Liu Rui Hai
Published: August 2023

The present monograph describes the salting-out assisted liquid–liquid microextraction (SALLME) and reverse-phase high-performance liquid chromatography with diode array detector (RP-HPLC-DAD) based quantification of two frequently applied neonicotinoid insecticides, i.e., acetamiprid (ACE) and imidacloprid (IMD), from selected tropical fruits (citrus and guava) and vegetables (tomato, okra and cauliflower). The SALLME conditions like pH, liquid/solid ratio and salt ratio (NaCl/Na2SO4) were varied over a wide range of conditions for the enhanced recovery of IMD and ACE from spiked quality control (low, high and medium) of fruits and vegetables. Meanwhile, RP-HPLC-DAD quantification of IMD and ACE was found to be linear over 1–100 μg/L with the coefficient of determination (R2) value ≥0.997 and slope of the calibration curve (sensitivity) ≥2.3 × 104 peak area unit (μAu). The analysis of selected fruits and vegetables after 0 (1 h), 1, 3, 7, 10 and 14 days of foliar application revealed the presence of IMD and ACE residues in okra and guava higher than maximum residual limits set by the Codex Alimentarius Commission until the third day of spray. Overall, the SALLME-RP-HPLC-DAD was found to be a rapid, selective and expedient choice for the routine analysis of neonicotinoids in environmental and food commodities.
Hypertriglyceridemia-Associated Pancreatitis: New Concepts and Potential Mechanisms
Authors: Hansen Signe E J , Varbo Anette , Nordestgaard Børge G , Langsted Anne
Published: August 2023

Background

Triglycerides are a major source of energy, while high plasma triglycerides are a risk factor for various diseases and premature death. Severely elevated plasma triglycerides are a well-established cause of acute pancreatitis with high mortality, likely due to the presence of elevated levels of chylomicrons and large very low-density lipoproteins in plasma. As markedly elevated levels of these very large lipoproteins are not generally found in mild to moderate hypertriglyceridemia, this was previously not regarded as a cause or marker of increased risk of acute pancreatitis. However, mild to moderate hypertriglyceridemia may identify individuals who at a later timepoint develop severe hypertriglyceridemia and acute pancreatitis.

Content

We describe measurement of plasma triglycerides and studies on plasma triglycerides and risk of acute pancreatitis. Further, we summarize current European and American guidelines for the prevention of acute pancreatitis and, finally, the potential for future prevention of acute pancreatitis through lowering of plasma triglycerides.

Recent observational and genetic studies indicate that mild to moderate hypertriglyceridemia is causally related to increased risk of acute pancreatitis, most likely as a marker of future severe hypertriglyceridemia. Current guidelines do not mention individuals with mild to moderate hypertriglyceridemia, even though newer evidence suggests an unmet medical need. Treatment could include plasma triglyceride-lowering therapy targeting the pathway for lipoprotein lipase as the main triglyceride degrading enzyme in plasma. Angiopoietin-like 3 and apolipoproteinC-III are inhibitors of lipoprotein lipase, and blocking of these 2 inhibitors is showing promising results in relation to marked triglyceride-lowering and could perhaps be used to prevent acute pancreatitis in the future.
Pulmonary valve replacement in a large and tortuous right ventricle outflow tract with a 32 mm Myval valve under local anaesthesia: challenges and technical considerations: a case report
Authors: Houeijeh Ali , Sudre Arnaud , Juthier Francis , Godart François
Published: August 2023

Background

Pulmonary valve replacement in patients with congenital heart diseases and heart failure is challenging.

Case summary

Here, we describe a case of a patient who had surgical fallot repair with chronic heart failure. Investigations found severe biventricular dysfunction and enlargement due to chronic pulmonary regurgitation. The right ventricle outflow tract was tortuous and large with a diameter of 35 mm. Percutaneous pulmonary valve implantation (PPVI) was done after a challenging pre-stenting. A 32 mm Myval valve over-sized to 35 mm was used for PPVI, which yielded a good result.

Discussion

A 32 mm Myval valve is effective at extending the possibilities of PPVI in a large and tortuous right ventricle outflow tract not accessible for the other valves.
Short-term recurrence of takotsubo syndrome with phenotypic variation: a case report
Authors: Saito Takafumi , Natsumeda Makoto , Sakagami Takato , Murakami Tsutomu , Takagi Shunsuke , Ikari Yuji
Published: August 2023

Background

Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome characterized as an uncommon left ventricular (LV) cardiomyopathy. Recurrence of TTS is rare, estimated to be 1–6%. We report a rare case of TTS that occurred three times in 2 months but manifested various phenotypes.

Case summary

A 68-year-old woman was admitted to our hospital with acute-onset chest pain and hypertension. The coronary angiography findings were normal, although left ventriculography revealed inferior wall hypokinesis, leading to a mid-ventricular TTS diagnosis. She was discharged on Day 3 after her symptoms improved and vitals stabilized. The patient’s condition remained uneventful until 2-week post-discharge, when acute chest pain and hypertension recurred. She was admitted again with the same diagnosis. However, LV morphology revealed an apical ballooning pattern, with inferior LV wall hypokinesis. She was discharged on Day 7 after her symptoms and electrocardiography findings improved but was readmitted again 2 weeks later after acute chest pain and hypertension recurred. Left ventriculography performed a third time demonstrated mid-ventricular TTS. The patient was prescribed additional medications and discharged on Day 12. Her electrocardiography findings normalized, and the patient remained asymptomatic without recurrence 4 months after the initial presentation.

Discussion

Recurrence and phenotypic change of TTS are rare. Some cases have been reported but occurring months to years after initial diagnosis. Combined treatment with β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists may be more effective to prevent the recurrence than monotherapies.
Faction, Connection and Politics in the Civil Wars: Pembrokeshire, 1640–1649
Authors: Bowen Lloyd
Published: August 2023

This article considers the roles of faction and connections between centre and periphery as structuring elements of local politics during the civil wars of the mid-seventeenth century. It explores these issues through an examination of Pembrokeshire in south-west Wales. Using a considerable amount of previously unexamined printed and manuscript material, it argues that established but largely ignored factional alignments informed a good deal of the political manoeuvring in the county during and after the first civil war, and that these connected to and were complicated by evolving associations with rival political coalitions at Westminster. The article pays close attention to the connections between figures among the Pembrokeshire gentry and MPs and power-brokers in Westminster. It argues that establishing fruitful links with the political centre was vital to the success of an Independent group in the county following the war’s cessation and, conversely, the isolation and ultimate defeat of the Presbyterian party. The article throws new light on the origins of John Poyer’s 1648 rebellion, which initiated the ‘Second Civil War’. It rejects the established narrative which characterises Poyer’s revolt as borne from apolitical self-interest, arguing instead that it was the final act in a factional struggle that was at least a decade old. The piece contends that gentry faction has largely been written out of recent civil war history, but that scholars should be more attentive to its potential for influencing (although not conditioning) political and ideological alignments in the provinces.
Assessing the shooting distance of lead-free ammunition regardless of composition using Laser Induced Breakdown Spectroscopy
Authors: Doña-Fernández Alicia , Rodriguez-Pascual Jose Antonio , de Andres-Gimeno Israel , Gutiérrez-Redomero Esperanza , Valtuille-Fernández Eduardo , Gomez-Laina Francisco Javier
Published: August 2023

At present, it is challenging to accurately determine firearm shooting distances in the case that lead-free ammunition is involved, largely because different manufacturers use different primer compositions. Laser-induced breakdown spectroscopy (LIBS) allows the simultaneous detection of multiple elements with high sensitivity and so may represent a solution to this problem. Previous studies have, in fact, demonstrated that LIBS can be used to determine shooting distances when working with gunshot residues from conventional ammunition based on scanning fabric surfaces. The present study confirms that the shooting distance can be ascertained using LIBS to detect copper originating from the ammunition casing and projectile but not the primer on fabric surfaces. This estimation can be performed regardless of the primer composition of lead-free ammunition.

Key points
Efficacy and Safety of Dapagliflozin in Patients With Chronic Kidney Disease Across the Spectrum of Frailty
Authors: Vart Priya , Butt Jawad H , Jongs Niels , Schechter Meir , Chertow Glenn M , Wheeler David C , Pecoits-Filho Roberto , Langkilde Anna Maria , Correa-Rotter Ricardo , Rossing Peter , McMurray John J V , Heerspink Hiddo J L
Published: August 2023

Background

A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level.

Methods

Adults with CKD, with/without type 2 diabetes, with an estimated glomerular filtration rate (eGFR) of 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5 000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was a composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD), or death from kidney or cardiovascular (CV) causes.

Results

Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4 303/4 304 (99.9%) patients: 1 162 (27.0%) in not-to-mildly frail (FI ≤0.210), 1 642 (38.2%) in moderately frail (FI 0.211–0.310), and 1 499 (34.8%) in severely frail categories (FI >0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% confidence interval {CI}]: 0.50 [0.33–0.76], 0.62 [0.45–0.85], and 0.64 [0.49–-0.83], respectively; p-interaction = 0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; p-interaction = 0.44), CV endpoint (heart failure hospitalization or CV death; p-interaction = 0.63), and all-cause mortality (p-interaction p = .42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin versus placebo in all FI categories (16.9% vs 20.1%, 26.3% vs 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately, and severely frail categories, respectively).

Conclusions

The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety.
A Genealogy of theLife History Album(1884): Gerontology, Genre, and Health Across the Life Span
Authors: Bailey Suzanne
Published: August 2023

This paper demonstrates what emerges when we undertake a literary reading of a medical text, examining its form and structure as a text. The study of what appears to be a singular publication reveals instead an under-examined moment in medical history that anticipates contemporary health investigations in modern medicine, while reflecting the limitations of medical and gerontological knowledge in the 1880s. I demonstrate this argument by conducting a Foucauldian archeology of the text, with attention to authorship and the concept of textual genre. My primary text is the Life History Album (1884), which I link to a related endeavor, G. M. Humphry’s Old Age (1889), a little-known publication that contains medical observations on the resiliency of aging bodies and anticipates ideas associated with early twentieth-century geriatrics. My investigation brings new attention to the work of Dr. Frederick Akbar Mahomed, a pioneer in the study of hypertension, whose story is part of the genealogy of the text. Inviting its creator to keep records of health throughout the life span, the Life History Album anticipates a new kind of modern subject, who participates in co-creating his or her medical and life health history, whereas Humphry’s Old Age, which draws on similar methods, is humanistic, includes literary references, and allows for contentment in older age.
Can ChatGPT pass Glycobiology?
Authors: Williams Devin Ormsby , Fadda Elisa
Published: August 2023

The release of text-generating applications based on interactive Large Language Models (LLMs) in late 2022 triggered an unprecedented and ever-growing interest worldwide. The almost instantaneous success of LLMs stimulated lively discussions in public media and in academic fora alike not only on the value and potentials of such tools in all areas of knowledge and information acquisition and distribution but also on the dangers posed by their uncontrolled and indiscriminate use. This conversation is now particularly active in the higher education sector, where LLMs are seen as a potential threat to academic integrity at all levels, from facilitating cheating by students in assignments to plagiarizing academic writing in the case of researchers and administrators. Within this framework, we are interested in testing the boundaries of the LLM ChatGPT (www.openai.com) in areas of our scientific interest and expertise and in analyzing the results from different perspectives, i.e. of a final year BSc student, of a research scientist, and of a lecturer in higher education. To this end, in this paper, we present and discuss a systematic evaluation on how ChatGPT addresses progressively complex scientific writing tasks and exam-type questions in Carbohydrate Chemistry and Glycobiology. The results of this project allowed us to gain insight on: (i) the strengths and limitations of the ChatGPT model to provide relevant and (most importantly) correct scientific information, (ii) the format(s) and complexity of the query required to obtain the desired output, and (iii) strategies to integrate LLMs in teaching and learning.
Plasmodium falciparum Malaria Is Associated With Increased Kaposi Sarcoma–Associated Herpesvirus (KSHV) Seropositivity and Higher KSHV Antibody Breadth and Magnitude: Results of a Case-Control Study From Rural Uganda
Authors: Nalwoga Angela , Sabourin Katherine R , Miley Wendell , Jackson Conner , Maktabi Mahdi , Labo Nazzarena , Mugisha Joseph , Whitby Denise , Rochford Rosemary , Newton Robert
Published: August 2023

Background

Previously, we showed that children with asymptomatic Plasmodium falciparum (Pf) malaria infection had higher Kaposi sarcoma–associated herpesvirus (KSHV) viral load, increased risk of KSHV seropositivity, and higher KSHV antibody levels. We hypothesize that clinical malaria has an even larger association with KSHV seropositivity. In the current study, we investigated the association between clinical malaria and KSHV seropositivity and antibody levels.

Methods

Between December 2020 and March 2022, sick children (aged 5–10 years) presenting at a clinic in Uganda were enrolled in a case-control study. Pf was detected using malaria rapid diagnostic tests (RDTs) and subsequently with quantitative real-time polymerase chain reaction (qPCR). Children with malaria were categorized into 2 groups: RDT+/PfPCR+ and RDT–/PfPCR+.

Results

The seropositivity of KSHV was 60% (47/78) among Pf-uninfected children, 79% (61/77) among children who were RDT–/PfPCR+ (odds ratio [OR], 2.41 [95% confidence interval {CI}, 1.15–5.02]), and 95% (141/149) in children who were RDT+/PfPCR+ (OR, 10.52 [95% CI, 4.17–26.58]; Ptrend < .001). Furthermore, RDT+/PfPCR+ children followed by RDT–/PfPCR+ children had higher KSHV IgG and IgM antibody levels and reacted to more KSHV antigens compared to uninfected children.

Conclusions

Clinical malaria is associated with both increased KSHV seropositivity and antibody magnitude, suggesting that Pf is affecting KSHV immunity.
O02 Nitrofurantoin: what is the evidence for current guidance?
Authors: Kashouris Eleanor , Joseph Amelia , Lewis Tom
Published: August 2023

In this abstract, we review current approaches to the management of uncomplicated urinary tract infection (UTI) and begin to explore alternative approaches to antibiotic prescribing. We review clinical guidelines on the use of nitrofurantoin internationally to capture the level of variation in evidence-based guidance. We find that the evidence base has been interpreted in very different ways. UK guidelines from NICE and the Scottish Intercollegiate Guidelines Network (SIGN) are unusual in promoting short (3 day) courses of nitrofurantoin. We find little direct evidence to support this, and that this guidance has been extrapolated from studies based on other agents. ‘Short’ courses of antibiotics aim to provide optimum balance between providing effective treatment whilst reducing selective pressure driving resistance amongst colonizing microbial flora. Three days of nitrofurantoin may indeed be a useful intervention in a large group of patients. Longer courses of nitrofurantoin still demonstrate considerable rates of treatment failure. The concept of a course length in itself is limited. The variation between recommendations internationally reflects both the uncertain foundations upon which evidence-based guidelines are written, and the limits of what can be safely concluded from evidence. We join others in pointing out there may be ways of customizing duration of therapy to the patient’s response in primary care settings. There is a need for a more patient-focused approach to uncomplicated UTI, including better safety-netting and (currently lacking) guidance on best practice in the common clinical scenario of treatment failure.
O03 The effect of antibiotic selection on collateral susceptibility and evolvability of uropathogenic Escherichia coli
Authors: Hubbard Alasdair T M , James Beth , Whelan Rachel , Meehan Conor , Domingo Sananes Maria Rosa
Published: August 2023

Urinary tract infections (UTIs) are a common infection in healthy adult women and as such account for 1%–3% of all medical consultations and the second most common reason for prescribing antimicrobials in the UK. Escherichia coli is a frequent aetiological agent of uncomplicated UTIs, causing 75% of cases, associated with recurrence of infection (40%) and a major source of bacteraemia (∼40%). Trimethoprim and nitrofurantoin are currently recommended as first-line antibiotics for the treatment of uncomplicated UTIs. However, 48700 deaths in Europe in 2019 have been associated with antimicrobial-resistant UTIs and resistance to trimethoprim in community-acquired UTIs caused by E. coli is high (33.4%). With little to no antimicrobial development in recent years, new strategies are therefore required to maintain efficacy in currently available antibiotics. One such strategy is to use evolutionary principles to understand how antimicrobial resistance (AMR) to one antibiotic can affect the activity and probability of resistance development to a second antibiotic. Effect on antimicrobial activity can be assessed through collateral susceptibility, where prior resistance to one antibiotic either increases or decreases susceptibility to a second, unrelated class of antibiotic. While the probability of resistance development can be assessed by the mutant selection window (MSW), an antibiotic concentration range where AMR mutations can be selected for. This ranges from the MIC (the lowest concentration to select for resistance) to the mutant prevention concentration (MPC, the highest concentration to select for resistance). In this study, we aimed to determine the effect trimethoprim resistant derivatives of three clinical strains of uropathogenic E. coli on collateral susceptibility and MSWs to nitrofurantoin. We found that trimethoprim-resistant mutants conferred the expected decrease in susceptibility to trimethoprim and an increase in the MSW. This suggests prior selection with trimethoprim increases the probability of treatment failure and the selection of further mutations conferring high-level resistance to trimethoprim. We also observed collateral resistance to nitrofurantoin in the trimethoprim-resistant mutants. Importantly, however, there was a reduction in the MPC, and therefore a narrowing of the MSW, reducing the probability of selection of higher levels of nitrofurantoin resistance. This suggests that using nitrofurantoin after trimethoprim may reduce the probability of developing nitrofurantoin resistance compared with using nitrofurantoin first. These data provide a potential evidence base to use evolutionary principles when designing antimicrobial regimens to limit AMR development and improve treatment success.
P14 Optimization of real-time sequencing for rapid detection of bacterial species and antimicrobial resistance in blood and urine infections
Authors: Getino Maria , Stout Rebecca , Davies Frances , Jauneikaite Elita
Published: August 2023

Objectives

To optimize the process to obtain bacterial DNA directly from human urine and blood samples to produce high-quality genomic data using long-read Nanopore sequencer.

Methods

A total of 22 blood cultures and 24 urine samples positive for Escherichia coli or Klebsiella pneumoniae and corresponding isolates were collected from the microbiology diagnostics laboratory. DNA isolation optimization was performed testing three different sample volumes and seven DNA extraction kits. DNA concentration was quantified with Qubit fluorometer. Nanopore sequencing was performed on a MinION Mk1C device in R9.4.1 flow cells using the Rapid Barcoding Kit. Bacterial species and antimicrobial resistance (AMR) genes were determined with EPI2ME ARMA pipeline. Genomes were assembled with Flye, polished with Medaka and remaining human contigs removed with Krakentools. Bacterial isolates from the same samples were also sequenced using Illumina technology. Illumina and Nanopore assemblies were quality checked with Quast, Kraken was used to identify bacterial species, MLST for multilocus sequence typing and ABRicate with ResFinder database to detect AMR genes.

Results

A total of 72 DNA extractions from 24 urine and 22 blood samples with different kits were performed to find the optimal extraction protocol for each sample type. DNA from urine samples was isolated from 5 mL, while 1 mL was best for blood cultures. We found that the host depletion step prior to DNA extraction using MolYsis basic 5 Kit (VH-Bio) was essential. DNA from urine samples was extracted with GenElute Bacterial Genomic DNA Kit (Merck) and QIAamp Biostic bacteremia Kit (Qiagen) was best to allow successful bacterial genome sequencing for blood samples. Bacterial isolates from 11 urine and 1 blood sample (out of 54 sequenced) were successfully sequenced. In all 12 cases, the highest percentage of bacterial reads matched with the causative organism found during routine microbiology diagnostics (E. coli). A variety of clinically relevant AMR genes were detected, such as dfrA and bla  CTX-M genes, which matched the phenotypic antimicrobial susceptibility testing results. Comparison of genomic assemblies obtained through Nanopore sequencing of 10 urine samples and Illumina sequencing of the corresponding clinical isolates showed a high degree of matching, validating Nanopore sequencing as an alternative option to support diagnosis and treatment choice.

Conclusions

We have successfully optimized the protocols to extract and sequence pathogenic bacterial DNA directly from blood and urine samples. Short-read sequencing confirmed results acquired by Nanopore sequencer, endorsing long-read sequencing in clinical settings to support timely diagnosis and treatment.
P19 Burden of illness and costs among female patients with uncomplicated urinary tract infection in England
Authors: Wilcox Mark , Heaton Dave , Mulgirigama Aruni , Joshi Ashish V , Chirikov Viktor , Gibbons Daniel C , Webb David , Marston Xiaocong , Alexander Myriam , Mitrani-Gold Fanny S
Published: August 2023

Background and Objectives

Uncomplicated urinary tract infection (uUTI) is usually community-acquired. Data regarding the wider burden of illness from uUTI are scarce. We evaluated the burden of uUTI in female patients in England.

Methods

This retrospective comparative cohort study utilized linked anonymized patient data from 1 January 2017 to 29 February 2020 from the Clinical Practice Research Datalink (CPRD) and English Hospital Episode Statistics databases. All eligible patients were female, aged ≥12 years and had ≥12 months’ CPRD data available pre- and post-index (i.e. ≥24 months total). Patients with an index UTI diagnosis who had received ≥1 oral antibiotic within ±5 days of index formed the uUTI cohort; uUTI episodes were defined as 28 days from index diagnosis. Patients who had visited a primary care setting but did not have a UTI (uUTI or complicated UTI [cUTI]) diagnosis during the study period formed the control cohort and were matched to the index date of uUTI patients. Patients who were hospitalized or visited an accident and emergency department 28 days prior to index, had cUTI and/or had received IV antibiotics as initial therapy were excluded. Burden of illness (index/12 month follow-up all-cause and UTI-related healthcare resource use [HCRU] and costs) was evaluated in a 1:1 age- and Charlson Comorbidity Index (CCI) score-matched cohort.

Results

Overall, 120519 female patients with uUTI and 233670 female control patients (without uUTI) were identified and matched 1:1. Before matching, more of the uUTI cohort patients versus controls were <50 years old, had a higher mean CCI score, and were more often menopausal; region- and practice-level differences were modest (Table 1). HCRU and costs were significantly higher among uUTI patients versus matched controls, notably for primary care, specialist, and accident and emergency visits, and hospital admissions (P<0.001, Table 2). After adjusting for patient characteristics, Poisson or negative binomial models showed significant HCRU differences in primary and secondary care for uUTI patients versus matched controls (Table 3).

Conclusions

Patients with uUTI in England had significantly higher burden of illness, consuming more resources, during index uUTI episodes and follow-up, versus matched controls.
P23 Prevalence of asymptomatic bacteriuria and associated risk factors in an adult population relevant to UK primary care: a systematic review and meta-analysis
Authors: Moore Abi , Coyle Conor , Seeley Anna , Cherrington-Walker Phoebe , Khan Maaedah , Fanshawe Thomas , Pouwels Koen , Lecky Donna , Hayward Gail , Cooper Emily
Published: August 2023

Background

The use of urine dipstick tests in people who are more likely to have asymptomatic bacteriuria (ASB) can lead to the over-diagnosis of urinary tract infection (UTI) and unnecessary antibiotic prescribing. As a result, urine dipsticks are not recommended in those over the age of 65 years, or those with a urinary catheter in UK primary care guidelines. However, due to variation in prevalence estimates for ASB and the age of some of the existing prevalence studies it is unclear whether the use of age 65 as a cut-off for dipstick testing remains appropriate.

Objectives

This systematic review aims to identify and synthesize more recent evidence around ASB prevalence and other risk factors relevant to a UK community context, in order to improve how UK primary care UTI diagnostic guidance addresses asymptomatic bacteriuria.

Methods

The protocol for this systematic review is registered with PROSPERO. Inclusion criteria are: study participants aged ≥18 years; prospective studies recruiting from a primary care relevant population; studies that measure ASB prevalence and risk factors; and studies from the Organization for Economic Co-operation and Development member countries. Exclusion criteria include: studies from inpatient hospital settings (including the emergency department); studies exclusively including people who are pregnant, who have urinary catheters, who are post renal transplant or who have structural urological abnormalities; animal studies; laboratory studies; studies published before 1990; and studies not written in English. Searches were conducted in CINAHL, Embase and Medline using MeSH and free text words adapted for each database including terms for bacteriuria AND asymptomatic disease. The Cochrane Collaboration Covidence platform is being used for the management of screening and assessment of studies. Two authors are independently completing screening, data extraction and quality assessments.

Results

The initial search identified 3891 studies. After screening, 685 are currently undergoing full text review. Overall findings will be reported in a narrative synthesis. We will describe the studies identified, including how ASB has been defined within each of the studies. If sufficient data are available we will complete a meta-analysis. Using standard meta-analysis methods we will generate forest plots showing prevalence and 95% CIs for each study. If possible, we will estimate pooled prevalence of ASB from the reported prevalence of eligible studies, by age group and gender.

Conclusions

The results of this review may highlight where new evidence around ASB prevalence and risk factors relevant to a UK primary care population is needed.
P26 Evaluating the antibacterial activity of recombinant phage-encoded lysin against drug-resistant uropathogenic Escherichia coli
Authors: Dhar Sakshi , Nain Sonia , Gupta Vaishali , Gaharwar Utkarsh , Chavan Bhakti , Das Ritam , Hanif Sarmad , Bajpai Urmi , Sikriwal Deepa , Choudhary Aasiya , Syeda Safia , Shah Sanket , Ahmed Syed
Published: August 2023

Background

Atrocious use of antibiotics has led to the emergence of MDR in uropathogenic Escherichia coli (UPEC) that poses a serious challenge in the management of urinary tract infections (UTIs). The WHO has described antibiotic resistance in uropathogens as a key pressure point in the burgeoning global antimicrobial resistance crisis. Given this grim situation, we are exploring phage-encoded lysins as plausible alternatives.

Objectives

Our study involved an in silico strategy for the discovery and characterization of lysin sequences (seq) targeting E. coli cell wall and evaluating the bactericidal activity of these recombinant lysins using in-vitro assays.

Methods

Novel lysin sequences were searched by BLAST homology and by screening E. coli prophages in the database (using PHASTER). Lysozyme-like domain was observed in 9 out of 16 lysins. Their characterization depicted modular or globular structure. Based on the physicochemical properties, 7 out of 16 lysins were selected for cloning, expression, and purification as recombinant proteins for evaluating the bactericidal activity.

Results

Among the several lysins screened, lysin seq 5 demonstrated the highest activity using in vitro assays. Using static biofilm assay, lysin seq 5 (180 μg) showed efficient reduction (>50%) in the biofilm formed by ATCC UPEC 700928 strain. As per turbidity reduction method, lysin seq 5 (50 μg) showed 37% drop in OD600nm on UPEC 700928 strain after 3 h of incubation at 37°C. Using spot on lawn assay, lysin seq 5 (20 μg) exhibited lytic activity (zone of inhibition) on five drug-resistant clinical UTI isolates, which were pretreated with an outer membrane permeabilizer (OMP), viz., EDTA (0.3 mM).

Conclusions

Lysin seq 5 exhibited antibiofilm activity against UPEC 700928 strain as well as lytic activity against drug-resistant clinical UTI isolates. Screening of additional drug-resistant clinical isolates from UTI patients is underway.
P27 Rethinking UTI diagnosis: how gold is the ‘gold standard’ and how much does antimicrobial susceptibility testing really matter?
Authors: Diggle Joanna , Nieuwland Jeroen , Hayhurst Emma
Published: August 2023

Objectives

To analyse the results provided by culture methods for UTI diagnosis and estimate its potential effectiveness for clinical decision making.

Methods

The results of all 80981 urine samples processed by the Public Health Wales laboratory in Cardiff in 2022 were collated and analysed. Prevalence and resistance data were collected and analysed using Datastore. Specific aims were as follows: (i) determine the prevalence of ‘no growth’ and ‘mixed growth’ samples, and of each individual uropathogen; (ii) determine resistance rates for each pathogen; and (iii) estimate the potential effectiveness of these culture results for making clinical decisions.

Results

Of the 80981 urine samples analysed, 22775 (28%) were negative following flow cytometry analysis and were not cultured. Of the 58206 urine samples cultured, 18656 (32%) showed no growth and 20516 (35%) showed mixed growth and were not analysed further. A total of 19034 (33%) showed growth of one or more specific pathogens. The most common uropathogen was Escherichia coli (58%), followed by Klebsiella pneumoniae (8.6%), Enterococcus spp. (7.3%) and Proteus mirabilis (4.2%). Resistance rates varied by pathogen. Resistance to nitrofurantoin in E. coli was low (2.4%) but resistance to trimethoprim amongst E. coli isolates was higher (30.5%). Klebsiella, Pseudomonas and Proteus spp. were not routinely tested for resistance to nitrofurantoin, presumably due to high levels of inherent resistance. Of the 22 P. mirabilis isolates tested, all were resistant to nitrofurantoin. Trimethoprim resistance was high for all species routinely tested. Only 24% of all samples analysed returned an antimicrobial susceptibility test (AST) result. AST results relevant to the first-choice antibiotics of nitrofurantoin or trimethoprim were obtained for only 16% and 19% of all urines tested, respectively. Overall resistance to nitrofurantoin was 2.8% and to trimethoprim 32%, representing 0.44% and 6% of total samples tested, respectively.

Conclusions

These results highlight issues with laboratory culturing. Over one-third of all samples cultured did not return a usable clinical result due to mixed growth and AST results were returned for less than one-quarter of all samples tested. The clinical utility of AST depends on the specific antibiotic and species being tested. With nitrofurantoin resistance currently so low in all species routinely tested, knowing whether there is an infection and which bacteria is causing it will have more impact than performing susceptibility testing for this antibiotic. However, for trimethoprim, resistance rates are higher and more variable, so AST has more potential clinical impact.
P29 Catheter-associated urinary tract infections, potential for diagnostic and antimicrobial stewardship
Authors: Kelly Siobháin , O’ Donnell Sinead , Powderly Ailish , Fitzpatrick Fidelma
Published: August 2023

Background and Objectives

Catheter-associated urinary tract infections (CAUTIs) are one of the most common healthcare-associated infections.1 Microbiological investigation of catheter specimens of urine (CSUs) results in a significant workload for microbiology laboratories. As bacteria cultured from CSUs often reflect colonization rather than infection, we must prudently interpret these culture results and judiciously prescribe antimicrobials in this setting. For these reasons, we felt it was important to assess if CAUTIs are being appropriately investigated and managed in our hospital.

Methods

We identified all the CSUs received in the microbiology laboratory from inpatients over a 7 day period in an 820-bed adult tertiary referral hospital. Once identified, a retrospective review of each patient’s clinical and drug charts was undertaken. The CDC definition of CAUTI was applied for the purpose of this audit.2

Results

A total of 126 CSUs from 101 patients were included. The majority of patients (n=79, 78%) had a urinary catheter introduced during their hospital admission. At the time of CSU sampling, suspicion of infection was documented in only 47 patients. Only 9% of patients who had a CSU processed met the criteria for a CAUTI.2 Fifty-six percent of patients were commenced on antibiotics, despite only 31% returning a culture positive CSU sample. CSU results were documented in only 10% of patient charts. In cases where a CAUTI was suspected, it took an average of 6.75 days for the urinary catheter to be exchanged or removed. Four patients continued to receive an antibiotic despite the organism isolated being reported as resistant.

Conclusions

Overall, we noted that there was poor documentation of both urinary catheter status and of CSU results. Our audit revealed that several patients had multiple specimens processed within the 7 day period. Most patients had no clear indication for CSU sampling. From an antimicrobial stewardship perspective, there was unnecessary and inappropriate prescribing of antimicrobials. The results of this audit show that there is potential for both diagnostic and antimicrobial stewardship in the management of CAUTIs.
Radio emission from the first quasars at z = 6–15
Authors: Latif Muhammad A , Whalen Daniel J , Mezcua Mar
Published: August 2023

Nearly 300 quasars have now been found at z > 6, including nine at z > 7. They are thought to form from the collapse of supermassive primordial stars to 104–105 M⊙ black holes at z ∼ 20–25, which then rapidly grow in the low-shear environments of rare, massive haloes fed by strong accretion flows. Sensitive new radio telescopes such as the Next-Generation Very Large Array (ngVLA) and the Square Kilometre Array (SKA) could probe the evolution of these objects at much earlier times. Here, we estimate radio flux from the first quasars at z ∼ 6–15 at 0.5–12.5 GHz. We find that SKA and ngVLA could detect a quasar like ULAS J1120+0641, a 1.35 × 109 M⊙ black hole at z = 7.1, at much earlier stages of evolution, z ∼ 14–16, with 100 h integration times in targeted searches. The advent of these new observatories, together with the JWST, Euclid, and the Roman Space Telescope, will inaugurate the era of z ≲ 15 quasar astronomy in the coming decade.