bluuebunny/crossref_metadata_2025 huggingface dataset:
11–20 MeV Alvarez Drift Tube Linac for low energy proton accelerator
Authors: Teotia Vikas , Malhotra Sanjay , Kumar Prashant , Mishra Elina , Meshram Sumit , Chimurkar Rajesh
Published: June 2023

Bhabha Atomic Research Centre is developing Low Energy High
Intensity Proton Accelerator (LEHIPA) as a pre-injector for proposed
Accelerator Driven Sub-Critical Reactor Systems (ADSS). Drift Tube
Linac is one of the two major accelerating structures of LEHIPA, the
other being the Radio Frequency Quadrupole (RFQ). Like all particle
accelerating structures, DTL needs multi-disciplinary expertise for
design, production, qualification, and installation. This paper
describes the comprehensive design, production, qualification, and
installation of the ∼ 11–20 MeV section of DTL. It details the
design of all sub-components which form part of the DTL RF
cavity. Several novel concepts were implemented in course of this
development. Important among them are DT-DTL alignment, referencing
methodology, robust vacuum design and hermetically sealed DTs. This
paper is a comprehensive coverage of design, development and
installation aspects of Alvarez DTL. At present, the DTL is ready
for beam commissioning.
Quadrupole magnet design, manufacturing and the acceptance tests for METU-defocusing beamline
Authors: Demirköz M.B. , Avaroğlu A. , Seçkin C. , Bülbül B. , Tüysüz C. , Kılıç U. , Uslu P. , Milanese A. , Thonet P.A. , Deferne G. , Petrone C.
Published: June 2023

Middle East Technical University Defocusing Beam Line (METU-DBL) performs the Single Event Effects (SEEs) radiation tests with protons in the range of 15 MeV to 30 MeV kinetic energy at Turkish Atomic Energy Authority Proton Accelerator Facility (TENMAK NÜKEN-PAF) for space and nuclear applications. The most critical beam transfer elements in the METU-DBL are three quadrupole magnets, which are used for defocusing the beam like optical lenses. The first two quadrupole magnets were purchased commercially, and the third quadrupole magnet was designed by the METU-DBL project team and manufactured by Sönmez Transformer Inc. in Turkey. Electronic, mechanic and magnetic capability tests of this custom-designed magnet were conducted both at TUBITAK and CERN facilities. After passing the acceptance tests, the magnet was certified by CERN and then installed to METU-DBL as a third quadrupole magnet. In this paper, we present details of the design, production and performed tests of the quadrupole magnet.
Dimers, webs, and local systems
Authors: Douglas Daniel , Kenyon Richard , Shi Haolin
Published: June 2023

For a planar bipartite graph

G

\mathcal {G}

equipped with an

S
L

n

\mathrm {SL}_n

-local system, we show that the determinant of the associated Kasteleyn matrix counts “

n
n

-multiwebs” (generalizations of

n
n

-webs) in

G

\mathcal {G}

, weighted by their web-traces. We use this fact to study random

n
n

-multiwebs in graphs on some simple surfaces.
𝑅=𝑇 theorems for weight one modular forms
Authors: Berger Tobias , Klosin Krzysztof
Published: June 2023

We prove modularity of certain residually reducible ordinary 2-dimensional

p
p

-adic Galois representations with determinant a finite order odd character

χ
\chi

. For certain non-quadratic

χ
\chi

we prove an

R
=
T

R=T

result for

T
T

the weight 1 specialisation of the cuspidal Hida Hecke algebra acting on non-classical weight 1 forms. Under the additional assumption that no two cuspidal Hida families congruent to an Eisenstein series cross in weight 1 we show that

T
T

is reduced. For quadratic

χ
\chi

we prove that the quotient of

R
R

corresponding to deformations split at

p
p

is isomorphic to the Hecke algebra acting on classical CM weight 1 modular forms.
Fashion or function? Relaxed selection and stasis are key features of the evolution of stripes, bands and collars in Sceloporus lizards (Squamata: Phrynosomatidae)
Authors: Cavagnaro John , Ossip-Drahos Alison G , Martins Emília P
Published: June 2023

Dorsal markings are common, and can function in predator evasion, as sexual signals, or be the remnants of developmental or physiological processes. We used phylogenetic comparative analyses to test whether black dorsal markings (stripes, bands or collars) on Sceloporus lizards reflect responses to different selective pressures over evolutionary time, or whether these markings have been linked in an integrated phenotype. We found that longitudinal striping evolved in small-bodied, terrestrial and egg-laying species, consistent with an antipredator function, especially when sexual selection was weak. Transverse bands evolved more slowly, and primarily in arboreal species, where they may enhance crypsis. Evolutionary shifts in collars were strongly linked to sexual size dimorphism, suggesting a function as sexual signals, and were tightly linked to parity mode. In two viviparous lineages, collars have been retained without loss for more than 12 Myr. Future studies are needed to determine whether this stasis is due to hormone transfer between females and their offspring or to other underlying physiological mechanisms. Our findings emphasize relaxed selection and stasis as important forces shaping the evolution of animal colours and signals.
Recentering power: conceptualizing counterpublics and defensive publics
Authors: Jackson Sarah J , Kreiss Daniel
Published: June 2023

In this manuscript we consider the inconsistent ways the concept of “counterpublics” has been taken up in the field to make the claim that considerations of social power must be recentered in the theorization of publics. To do this we provide an in-depth genealogy of the concept of counterpublics, analyze its use by critical scholars, and then consider its application in empirical studies of digital networks and right-wing publics. We argue that scholars studying digital and far-right publics in particular must take the critical analysis of power seriously. Through this lens, we show that classifying right-wing movements as “defensive” is more theoretically and empirically accurate. In doing so, we conceptualize public spheres as indelible outgrowths of social structures, even as they work to transform them in turn, and provide a framework for scholars to understand public spheres through the lens of history, social differentiation, relations, resources, and access.
Multimodality imaging in marantic endocarditis associated with cancer: a multicentric cohort study
Authors: Deharo François , Arregle Florent , Bohbot Yohann , Tribouilloy Christophe , Cosyns Bernard , Donal Erwan , Di Lena Chloe , Selton Suty Christine , Bourg Corentin , Hubert Sandrine , Casalta Jean-Paul , Philip Mary , Martel Helene , Gouriet Frederique , Habib Gilbert
Published: June 2023

Aims

We aimed to assess the role of multimodality imaging (MMI) in the diagnosis of marantic endocarditis (ME) associated with cancers and to describe the clinical characteristics, management, and outcome of these patients.

Methods and results

In a retrospective multicentric study including four tertiary centres for the treatment of endocarditis in France and Belgium, patients with a diagnosis of ME were included. Demographic, MMI [echocardiography, computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)], and management data were collected. Long-term mortality was analysed. Between November 2011 and August 2021, 47 patients with a diagnosis of ME were included. Mean age was 65 ± 11 years. ME occurred in 43 cases (91%) on native valves. Vegetations were detected by echocardiography in all cases and in 12 cases (26%) by CT. No patient had an increased cardiac 18F-FDG valve uptake. The most common cardiac valve involved was aortic (34 cases, 73%). Twenty-two patients (46%) had a known cancer before ME, and 25 cases (54%) were diagnosed thanks to multimodality imaging. 18FDG PET/CT was performed in 30 patients (64%) and allowed a new diagnosis of cancer in 14 patients (30%). Systemic embolism was frequent (40 patients, 85% of cases). Forty-one patients (87%) were treated medically with anticoagulation therapy. One-year mortality was 55% (26 patients).

Conclusion

ME remains associated with a high risk of complications and death.
Validation and comparison of cardiovascular risk prediction equations in Chinese patients with Type 2 diabetes
Authors: Liang Jingyuan , Li Qianqian , Fu Zhangping , Liu Xiaofei , Shen Peng , Sun Yexiang , Zhang Jingyi , Lu Ping , Lin Hongbo , Tang Xun , Gao Pei
Published: June 2023

Aims

For patients with diabetes, the European guidelines updated the cardiovascular disease (CVD) risk prediction recommendations using diabetes-specific models with age-specific cut-offs, whereas American guidelines still advise models derived from the general population. We aimed to compare the performance of four cardiovascular risk models in diabetes populations.

Methods and results

Patients with diabetes from the CHERRY study, an electronic health records-based cohort study in China, were identified. Five-year CVD risk was calculated using original and recalibrated diabetes-specific models [Action in Diabetes and Vascular disease: PreterAx and diamicroN-MR Controlled Evaluation (ADVANCE) and the Hong Kong cardiovascular risk model (HK)] and general population-based models [Pooled Cohort Equations (PCE) and Prediction for Atherosclerotic cardiovascular disease Risk in China (China-PAR)]. During a median 5.8-year follow-up, 46 558 patients had 2605 CVD events. C-statistics were 0.711 [95% confidence interval: 0.693–0.729] for ADVANCE and 0.701 (0.683–0.719) for HK in men, and 0.742 (0.725–0.759) and 0.732 (0.718–0.747) in women. C-statistics were worse in two general population-based models. Recalibrated ADVANCE underestimated risk by 1.2% and 16.8% in men and women, whereas PCE underestimated risk by 41.9% and 24.2% in men and women. With the age-specific cut-offs, the overlap of the high-risk patients selected by every model pair ranged from only 22.6% to 51.2%. When utilizing the fixed cut-off at 5%, the recalibrated ADVANCE selected similar high-risk patients in men (7400) as compared to the age-specific cut-offs (7102), whereas age-specific cut-offs exhibited a reduction in the selection of high-risk patients in women (2646 under age-specific cut-offs vs. 3647 under fixed cut-off).

Conclusion

Diabetes-specific CVD risk prediction models showed better discrimination for patients with diabetes. High-risk patients selected by different models varied significantly. Age-specific cut-offs selected fewer patients at high CVD risk especially in women.
My journey with yeast
Authors: Abbas Charles
Published: June 2023

Advances in yeast biotechnology rely on the application of knowledge gained using modern biotechnological tools to harness the metabolic repertoire of various yeast genera that have been studied in detail. In my work, I have attempted to combine knowledge gained from academic research with industrial knowhow in practical cost-effective ways to scale-up commercial yeast fermentations from one hundred thousand to greater than one million liters. Among the processes I scaled up and/or optimized to production scale include biofuels, chemicals, food, and feed additives. During a long industrial career that spanned over three decades, I leveraged what was often very challenging work with many academic, government, and industrial scientists engaging them in collaborative research to ensure a successful outcome. Many of these collaborators responded in kind and are part of this narrative. In many ways, my journey was also theirs. However, I acquired the scientific foundation or starting point much earlier during my undergraduate studies learning from great professors that helped me understand the complexity of science while convincing me of the value of pursuing research as a career.
Hidden lesions: a case of burnt remains
Authors: Moghaddam Negahnaz , Campana Lorenzo , Abegg Claudine , Vilarino Raquel , Voland Christelle , Dedouit Fabrice , Genet Pia , Fracasso Tony
Published: June 2023

One of the many challenging cases that forensic pathologists, anthropologists, and forensic imaging experts have to face are burnt human remains. Perpetrators frequently attempt to hide/destroy evidence and make the body unidentifiable by exposing it to fire. We present a case of a partially burnt body found in an apartment after an explosion. First, multidetector computed tomography (MDCT) images and the following autopsy revealed several lesions on the cranium. Forensic anthropologists were involved in order to specify the aetiology of the lesions observed on the cranium. Through an interdisciplinary approach bringing together MDCT scans, 3D surface scans, and anthropological analysis, it was possible to answer the questions raised during the autopsy. Analyses demonstrated that there were signs of blunt force trauma on the cranium vault that the perpetrator likely attempted to hide by exposing the body to fire. This case demonstrates the importance of close collaboration between forensic anthropologists, imaging experts, and forensic pathologists. This multidisciplinary approach allows for a better, more complete reconstitution of forensic cases.

Key points
Dosage-sensitivity shapes how genes transcriptionally respond to allopolyploidy and homoeologous exchange in resynthesized Brassica napus
Authors: Bird Kevin A , Pires J Chris , VanBuren Robert , Xiong Zhiyong , Edger Patrick P
Published: June 2023

The gene balance hypothesis proposes that selection acts on the dosage (i.e. copy number) of genes within dosage-sensitive portions of networks, pathways, and protein complexes to maintain balanced stoichiometry of interacting proteins, because perturbations to stoichiometric balance can result in reduced fitness. This selection has been called dosage balance selection. Dosage balance selection is also hypothesized to constrain expression responses to dosage changes, making dosage-sensitive genes (those encoding members of interacting proteins) experience more similar expression changes. In allopolyploids, where whole-genome duplication involves hybridization of diverged lineages, organisms often experience homoeologous exchanges that recombine, duplicate, and delete homoeologous regions of the genome and alter the expression of homoeologous gene pairs. Although the gene balance hypothesis makes predictions about the expression response to homoeologous exchanges, they have not been empirically tested. We used genomic and transcriptomic data from 6 resynthesized, isogenic Brassica napus lines over 10 generations to identify homoeologous exchanges, analyzed expression responses, and tested for patterns of genomic imbalance. Groups of dosage-sensitive genes had less variable expression responses to homoeologous exchanges than dosage-insensitive genes, a sign that their relative dosage is constrained. This difference was absent for homoeologous pairs whose expression was biased toward the B. napus A subgenome. Finally, the expression response to homoeologous exchanges was more variable than the response to whole-genome duplication, suggesting homoeologous exchanges create genomic imbalance. These findings expand our knowledge of the impact of dosage balance selection on genome evolution and potentially connect patterns in polyploid genomes over time, from homoeolog expression bias to duplicate gene retention.
O03 Penicillin and cephalosporin cross-reactivity: a single-centre UK study
Authors: Duke Eve , Abdelkader Zainab , Mooney Hannah , Byrne Fiona , Mistry Anoop , Denman Sarah
Published: June 2023

Background

Penicillin allergy (PenA) labels limit antimicrobial options, and concerns about cross-reactivity between penicillin and cephalosporins can further restrict prescribing. Alternative therapies are associated with reduced efficacy, poorer safety profiles and increased healthcare costs. Emerging literature suggests the incidence of cross-reactivity between penicillins and cephalosporins may be lower than historically reported rates of 2–10%. Furthermore, there is a lack of real-time data evaluating the percentage of patients with PenA who tolerate a cephalosporin.

Objectives

To determine the percentage of patients with a PenA label who tolerated cephalosporins in a secondary care setting.

Methods

Patients prescribed a cephalosporin from 01 January 2016 to 31 December 2020 at Leeds Teaching Hospitals NHS Trust (LTHT) were identified using the inpatient electronic prescribing system. 1613 with a PenA label were extracted for analysis. The team reviewed and clarified whether each patient (i) had a PenA label that was a potential hypersensitivity reaction, intolerance, or unknown/undocumented label and (ii) tolerated a cephalosporin. Tolerance was defined as receiving ≥1 dose without adverse effects or subsequent cephalosporin allergy label. We recorded if allergy or intolerance was a documented reason for stopping the cephalosporin.

Results

There were 1279 patients with a PenA label that received a cephalosporin. 555 (43%) had documentation in-keeping with a potential IgE-mediated allergic reaction to penicillins, 177 (14%) were deemed to have an intolerance and 547 (43%) had an unknown or undocumented label. 1263 (98.7%) patients tolerated a cephalosporin. Six (0.5%) patients stopped due to intolerance. One patient asked to stop therapy due to ‘changes’ in the skin. Nine (0.7%) patients developed possible allergic symptoms to cephalosporin; 4 patients developed a rash, 2 patients developed facial or lip swelling (without airway compromise), 1 patient developed hypotension, 1 patient developed difficulty breathing and 1 patient developed chest pain, breathlessness and itching. Of the 9 patients that had reactions; 5 had documented PenA labels that were classified as potential hypersensitivity reactions. Four patients had unknown or undocumented reactions to penicillins. Eight patients received a 2nd-generation cephalosporin (cefuroxime) and 1 received a 3rd generation (cefotaxime).

Conclusions

The rate of potential hypersensitivity reaction following administration of a cephalosporin in patients with any PenA label at LTHT was 0.7%. The incidence of cephalosporin allergy is estimated to be 1–3% of the general population (with/without PenA label). We conclude that, for patients with a history of unverified, non-anaphylactic PenA label, any cephalosporin could be administered without an increased risk of hypersensitivity reaction.
P18 Value of pneumococcal PCR in respiratory samples for exclusion of pneumococcal pneumonia
Authors: Van Herendael Bruno , Van Lint Philippe , Hoet Katrien , Willems Philippe , Van Goethem Sam
Published: June 2023

Background

Streptococcus pneumoniae is the main aetiological agent in bacterial pneumonia, making it an essential component of respiratory multiplex PCR panels. Despite its relevance, PCR test results are difficult to interpret due to frequent non-pathogenic colonization on the mucosal surface of the upper airways.

Methods

A retrospective study was conducted for lytA-gene results as target for S. pneumoniae in hospitalized patients that were diagnosed with pneumonia and on which a respiratory multiplex PCR panel was performed. Patients were classified as probable, possible or unlikely of having a pneumococcal pneumonia.

Results

No difference in semi-quantitative Ct-values could be observed between the different groups. Sensitivity of 71.4% and specificity of 89.6% was found, corresponding with a negative predictive value and positive predictive value of 97.6% and 34.2%, respectively, when considering probable versus possible/unlikely.

Conclusions

We conclude that a negative qPCR for the lytA-gene is a good marker for the inability to culture S. pneumoniae in a respiratory sample and is possibly sufficient to exclude S. pneumoniae as a causative agent, due to which we can regard it as a relevant addition to a syndromic multiplex PCR panel.
P19 Nurse evaluation of a local antibiotic IV to oral switch (IVOS) prompt tool
Authors: Bowler Sue , Clarkson Annette
Published: June 2023

Background

Early IVOS has numerous benefits for our patients, our planet, and our nurses.1,2 Importantly, a multisite qualitative study concluded that encouraging the prompt transition from IV to oral antibiotics was perceived favourably by nurses as an antibiotic stewardship nursing role.3 In November 2022, the UK Health Security Agency published the national IVOS criteria;1 these formed the basis of our revised local IVOS prompt tool. The aim of the project was to evaluate nurses’ initial responses to a local IVOS prompt tool.

Objectives

To evaluate if prompting for IVOS is currently viewed as a nursing role; to evaluate how confident nurses feel using the local IVOS prompt tool and its suitability for nursing clinical practice; to consider the need for trust-wide nurse engagement and training and to make recommendations to inform antimicrobial stewardship (AMS) nursing practice.

Methods

The local IVOS prompt tool was shown to nurses between November 2022 and March 2023, using a problem-based learning approach to gather nursing views. Nurses were asked to provide anonymous feedback via a short questionnaire, using a five-point Likert scale.

Results

Ninety-eight nurses participated and completed the questionnaire with the following mean scores obtained. Prompting for IVOS was recognized as a nursing role (4.2/5.0); generally, nurses felt confident to use the IVOS tool during the problem-based learning activity (4.1/5.0) and on the ward to assess their patients (4.2/5.0). Qualitative feedback received included ‘time constraints- another tool [to complete] when there are already many’. It was deemed that the IVOS tool would be best placed in the clinic room (where IV antibiotics are prepared), as reference aid rather than as an assessment tool requiring formal completion.

Conclusions

Nurses consider IVOS to be within their scope of professional practice and felt confident to use the tool to assess for early switch within an educational and practice setting. Application of the tool in clinical practice is a focus for trust-wide nurse engagement, education and future AMS nursing research.
P21 Promoting antimicrobial stewardship and sustainability utilizing a ‘Go Green’ IV to oral switch (IVOST) policy and electronic prescribing prompts in antimicrobials with high oral bioavailability
Authors: Rodger R , Thompson S , Robertson A , Pender C , Ray G , Chisholm L
Published: June 2023

Background

Antimicrobial stewardship (AS) is crucial in reducing antimicrobial resistance (AMR) and the sustainability impact of inappropriate antimicrobial use.1 Promotion of the oral route and IV to oral switch (IVOST) are key AS initiatives providing benefits for patients, staff and the environment including reduced risk of line infections and AMR, reduced workload and costs, reduced plastic waste and improved sustainability.2 A recent quality improvement (QI) initiative to promote oral metronidazole (bioavailability > 90%) in eligible surgical patients at the Royal Alexandra Hospital (RAH) resulted in a change in prescribing behaviour and a 45% median reduction in IV metronidazole use.3

Objectives

To scale and spread promotion of the oral route in antimicrobials with high oral bioavailability with the aim of reducing collective IV use by 20% by February 2023 at RAH.

Methods

A QI approach was used to promote the oral route where appropriate in the following agents: metronidazole, levofloxacin, fluconazole, ciprofloxacin, co-trimoxazole, clindamycin, linezolid and rifampicin. Techniques included the following: ‘Go Green IVOST’ posters in key ward areas highlighting benefits of the oral route; targeted pharmacist and pharmacy technician prospective audit and feedback using the electronic prescribing system; presentations to ward and pharmacy teams; staff champions and electronic IVOST prompts displayed when prescribing and administering the targeted agents IV. To measure improvement, oral and IV usage data were measured at baseline and for 24 months post change. Data were displayed on run charts to determine if the QI target was achieved.

Results

There was a 44% median reduction in IV defined daily doses (DDDs) in the targeted antimicrobials, surpassing the 20% target (Figure 1). There was a median 10% shift in the proportion of these agents given IV as a percentage of total (IV plus oral) use (Figure 2) The greatest reduction (60%) was in IV metronidazole where usage declined from a monthly baseline of 667 to 267 DDDs. This equates to a median reduction of 1200 IV metronidazole administrations and nearly 600 hours nursing time saved per month. IV fluconazole and IV levofloxacin usage declined from baseline by a median of 35% and 24%, respectively.

Conclusions

A QI approach to promote appropriate use of the oral route in antimicrobials with high oral bioavailability resulted in a change in prescribing behaviour and a sustained reduction in IV prescribing of these agents. This is important in terms of improved AS, patient care and safety, healthcare cost and efficiency and environmental sustainability.
P22 Fabrication methodologies for antimicrobial polypropylene surfaces with leachable and non-leachable antimicrobial agents
Authors: Alkarri Saleh , Sharma Dimple , Bergholz Teresa M , Rabnawaz Muhammad
Published: June 2023

Objectives

Develop a methodology for the fabrication of antimicrobial polypropylene (PP) surfaces with (i) leachable copper (II) chloride dihydrate (CuCl2·2H2O) and (ii) non-leachable magnesium hydroxide (Mg (OH)2) biocides.

Methods and results

Two methodologies are used to develop antimicrobial PP surfaces. One method involves melt blending and subsequent injection moulding, where the biocide additives were compounded with PP and subsequently injection moulded. The other method involves the thermal embossing of antimicrobial agents on the surface of a PP substrate. The obtained biocide-bearing PP surfaces were evaluated against Escherichia coli K-12 MG1655 for 0, 4 and 24 h to evaluate their antimicrobial properties. The injection-moulded PP bearing 5% CuCl2·2H2O showed a 6-log reduction of E. coli K-12 MG1655 after 24 h, while only 1 log reduction was observed for PP bearing 5% Mg (OH)2. The thermally embossed PP surfaces bearing CuCl2·2H2O and Mg (OH)2 particles (at a concentration of 10 mg/mL) showed 3 log and 4 log reduction, respectively, against E. coli K-12 MG1655 after 24 h.

Conclusions

The results clearly demonstrate that CuCl2·2H2O conferred antimicrobial properties to PP surfaces that were prepared by both injection moulding and thermal embossing approaches owing to the presence of leachable copper ions. In contrast, the non-leachable Mg (OH)2 imparted antimicrobial properties only to the surface prepared via the thermal embossing technique.

Significance and impact

Plastics with leachable biocides are effective antimicrobial surfaces, but their toxicity is a major concern. This study provides a fabrication methodology for non-leachable PP-based antimicrobial surfaces that are potentially safer. In addition, this strategy can be extended to many other plastic substrates.
P28 Rezafungin efficacy and safety in immunocompromised patients: sub-analyses of the Phase 3 trial in treatment of candidaemia and invasive candidiasis
Authors: Sandison Taylor , Ramos-Martinez Antonio , Kim Young Keun , Chai Louis , Slavin Monica
Published: June 2023

Background

Rezafungin (RZF) once weekly (QWk) is a next-generation echinocandin in development for treatment of candidaemia and invasive candidiasis (IC) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp. in BMT.

Objectives

The Phase 3 ReSTORE treatment trial (NCT03667690) demonstrated RZF QWk noninferiority to caspofungin (CAS) QD. This sub-analysis evaluated efficacy and safety outcomes in patients identified as immunocompromised (immuno-c) during the trial.

Methods

As previously described, adults with confirmed candidaemia and/or IC were randomized to RZF QWk (400 mg Wk1 then 200 mg QWk) or CAS QD for ≥14 days (≤4 weeks) with optional oral fluconazole stepdown for CAS. In this sub-analysis, immuno-c patients were those with prior and/or concomitant use of immunosuppressants (e.g. calcineurin inhibitors and corticosteroids) and/or medical history ongoing at screening of neutropenia, BMT, SOT, lymphoma or leukaemia.

Results

Of 187 patients (mITT population), 90 were immuno-c as defined. Results are for those with data available for analyses: Day 14 global cure—Immuno-c: RZF, 51.1% (23/45); CAS, 55.6% (25/45); –No immuno-c: RZF, 66.7% (32/48); CAS 65.3% (32/49). Day 5 mycological eradication—Immuno-c: RZF, 64.4% (29/45); CAS, 51.1% (23/45); no immuno-c: RZF, 72.9% (35/48); CAS, 71.4% (35/49). Among immuno-c, more had ≥1 AE (96.9%) and ≥1 SAE (64.6%) versus no immuno-c (79.0% and 45.0% respectively).

Conclusions

In this sub-analysis of ReSTORE, immune-c status reduced efficacy rates overall but did not change efficacy rate differences between RZF and CAS.
The effects of cystine and theanine mixture on the chronic survival rate and tumor incidence of rats after total body X-ray irradiation
Authors: Matsuu-Matsuyama Mutsumi , Shichijo Kazuko , Tsuchiya Takashi , Nakashima Masahiro
Published: June 2023

Cystine and theanine (CT), an amino acid mixture, provides the substrates cysteine and glutamic acid that promote glutathione synthesis. We previously reported that CT pre-treatment significantly improved the acute survival rate and reduced acute radiation injury of the small intestine and bone marrow of rats after 5 Gy of total body X-ray irradiation. To examine the long-term effects of CT administration after irradiation, we investigated the effects of CT pre-treatment and pre- and post-treatment on the chronic survival rate and solid tumor (spleen, skin and subcutis, and thyroid) incidence after irradiation using 7-week-old male Wistar rats. CT pre-treatment of 280 mg/kg was administered orally for 5 days before 5 Gy irradiation, and CT pre- and post-treatment was administered 5 days before and 5 days after irradiation. A 0.5% carboxymethyl cellulose solution was administered as a control. The chronic survival rate of the pre-treated rats was higher than that of the control rats at 441 days after irradiation (40 vs 8.1%, P = 0.011). However, the survival rate did not significantly differ between the pre- and post-treatment and control rats at 467 days after irradiation (33.8 vs 30.2%, P = 0.792). In addition, more solid tumors, especially subcutis sarcomas, were observed in the pre-treatment rats (26.1%, 6/23) than in the control rats (4.5%, 1/22) after irradiation. Therefore, pre-administration of CT improves the chronic survival rate after irradiation; however, the occurrence of solid tumors was not suppressed.
Assessing target localization accuracy across different soft-tissue matching protocols using end-exhalation breath-hold cone-beam computed tomography in patients with pancreatic cancer
Authors: Sasaki Makoto , Nakamura Mitsuhiro , Ashida Ryo , Nakata Manabu , Yoshimura Michio , Mizowaki Takashi
Published: June 2023

The purpose of this study was to retrospectively assess target localization accuracy across different soft-tissue matching protocols using cone-beam computed tomography (CBCT) in a large sample of patients with pancreatic cancer and to estimate the optimal margin size for each protocol. Fifty-four consecutive patients with pancreatic cancer who underwent 15-fraction volumetric modulated arc therapy under the end-exhalation breath-hold condition were enrolled. Two soft-tissue matching protocols were used according to the resectability classification, including gross tumor volume (GTV) matching for potentially resectable tumors and planning target volume (PTV) matching for borderline resectable or unresectable tumors. The tolerance of the target localization error in both matching protocols was set to 5 mm in any direction. The optimal margin size for each soft-tissue matching protocol was calculated from the systematic and random errors of the inter- and intrafraction positional variations using the van Herk formula. The inter- and intrafraction positional variations of PTV matching were smaller than those of GTV matching. The percentage of target localization errors exceeding 5 mm in the first CBCT scan of each fraction in the superior–inferior direction was 12.6 and 4.8% for GTV and PTV matching, respectively. The optimal margin sizes for GTV and PTV matching were 3.7 and 2.7, 5.4 and 4.1 and 3.9 and 3.0 mm in the anterior–posterior, superior–inferior and left–right directions, respectively. Target localization accuracy in PTV matching was higher than that in GTV matching. By setting the tolerance of the target localization error, treatment can be successful within the planned margin size.
Partial liver irradiation in rats induces the hypertrophy of nonirradiated liver lobes through hepatocyte proliferation
Authors: Adachi Takuya , Yoshida Yukari , Shibuya Kei , Sato Ken , Yamazaki Yuichi , Kakizaki Satoru , Uraoka Toshio , Takahashi Akihisa
Published: June 2023

Irradiation of the liver induces a regenerative response in the nonirradiated part of the liver. It is unclear whether this leads to actual liver enlargement. The aim of this study was to evaluate the weight of compensatory hypertrophy that occurs in nonirradiated livers and to clarify the mechanism of hypertrophy from the viewpoint of hepatocyte proliferation. The anterior liver lobes (anterior lobes) were irradiated with 60 Gy of X-rays (X60 Gy) under opening laparotomy. Body weights and liver lobe weights were measured before and at 1, 4, 8 and 12 weeks after irradiation, and serum and liver tissue samples were analyzed at each time point. The anterior lobes atrophied progressively, whereas the posterior liver lobes (posterior lobes) hypertrophied in the X-ray irradiated (X-irradiated) group. Although temporary liver damage was observed after irradiation, liver function did not decrease at any time point. Hepatocyte degeneration and loss were observed in the anterior lobes of the X-irradiated group, and significant fibrosis developed 8 weeks postirradiation. Following irradiation, the proportion of Ki-67-positive cells in the anterior lobes decreased markedly in the early postirradiation period, whereas the proportion of positive cells in the posterior lobes increased, peaking at 4 weeks postirradiation (P < 0.05). Increased tumor necrosis factor-α expression was observed only in the anterior liver lobes of the X-irradiated group at 1 and 4 weeks postirradiation. Partial liver irradiation with X60 Gy induced compensatory hypertrophy of nonirradiated liver lobes. This study suggests that liver hypertrophy after partial liver irradiation is caused by increased hepatocyte mitosis.
Antimicrobial and antivirulence saponins of Mimusops laurifolia leaves
Authors: Mostafa Hayam M A , Taha Mohamed , El-Gendy Ahmed O , Khairalla Ahmed S , abd El fattah Medhat , Raslan Mai
Published: June 2023

Mimusops laurifolia is a native species restricted to the Red Sea mountains and Gulf of Aden. Its leaves contain saponins with wide range of biological activities. The presented research aimed to prepare saponins-rich extract from n-butanol fraction of M. laurifolia leaves and screen it for promising antimicrobial activities. Minimum inhibitory concentration (MIC) of the prepared saponins against Candida albicans, and their potential anti-pathogenic and antivirulence effects were determined. Different concentrations of the saponins-rich extract were investigated for their antimicrobial potential, particularly against C. albicans, using the agar well diffusion method. To assess the potential antivirulence and antipathogenic effects, we carried out molecular docking of the bioactive saponins against four key enzymes in C. albicans, which are involved in virulence and/or pathogenicity. Different concentrations of the investigated mixture showed notable antifungal activity against C. albicans with an MIC value of 6.4 μg ml−1. Docking analysis of the investigated saponins showed their affinity toward the docked enzymes, particularly saponin 1 with secreted aspartic proteinase 3 and saponin 6 with secreted aspartic proteinase 5. Thereafter, the stability of these two protein-ligand interactions was investigated using molecular dynamics (MD) simulation. The molecular interactions between saponins and the enzymes' active sites were analyzed and discussed.
#2568 LONG-READ SEQUENCING IDENTIFIES NOVEL PATHOGENIC INTRONIC VARIANTS IN GITELMAN SYNDROME
Authors: Viering Daan , Hureaux Marguerite , Neveling Kornelia , Blanchard Anne , Konrad Martin , Bindels René , Schlingmann Karl Peter , Vargas-Poussou Rosa , de Baaij Jeroen
Published: June 2023

Background and Aims

Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3, which encodes the Na+-Cl− cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield.

Method

Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants.

Results

A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C>T variant and intronic candidate variants demonstrated aberrant splicing patterns.

Conclusion

Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome, especially in patients with one pathogenic variant.
#3408 A META-ANALYSIS OF VASCULAR ACCESS OUTCOMES IN HEMODIALYSIS PATIENTS OVER 75 YEARS OF AGE
Authors: Ntemka Alexandra , Argyriou Christos , Kyriklidou Parthena , Lazaridis Miltiadis , Georgiadis Georgios
Published: June 2023

Background and Aims

The age of patients with end-stage renal disease is constantly growing, but evidence for the best vascular access for hemodialysis is scarce and controversial for elderly. A meta-analysis was performed in hemodialysis patients over 75 years old to compare the outcomes of different vascular access procedures in the sub-group of elderly ESRD patients ≥ 75 years of age.

Method

A literature search was performed using the electronic databases MEDLINE and SCOPUS up to October 2021. Twelve eligible articles fulfilled the inclusion criteria and were finally selected in the meta-analysis (Table). Three of these studies including ESRD patients >70 years of age were exceptionally included as the mean age was well above 75 years. First step analysis was focused on studies that reported the primary patency rates of autologous vs. prosthetic vascular accesses (5 studies). Second step analysis was focused on articles comparing the results of primary and secondary patency rates of distal (forearm) vs. proximal (upper arm) fistulas in elderly patients (8 studies). All these studies were retrospective cohort studies, none was randomized controlled trial.

Results

Regarding the first step analysis, primary failure rate at 24 months was in favor of AVFs (OR: 0.56, 95% CI: 0.38-0.83, p = 0.003, Fig. 1). Although several studies have shown that AVG patency is not affected by age, this meta-analysis showed patency benefit of AVF in this subgroup of elderly patients ≥75 years of age. In a second step, the 12-month primary failure rate was by far in favor of proximal AVFs (OR: 2.14, 95% CI: 1.53-2.97; p<.00001, Fig. 2). The 12-month secondary patency rate of the forearm AVFs was also inferior compared to the proximal AVF (OR: 1.76, 95% CI: 1.12-2.78; p<.01, Fig. 3) These findings favor the use of proximal AVFs as first choice access in this subgroup of elderly patients, especially when they are late referrals or have low life expectancy.

Conclusion

The question of the right access in elderly ESRD patients does not have an easy answer. The present study shows that patients ≥75 years old should not be excluded from creation of an autologous access, with proximal AVFs having better patency rates.
#3794 AUTOPHAGY PATHWAY ACTIVATION IN IMMUNE-INFLAMMATORY CELLS OF PERITONEAL DIALYSIS PATIENTS
Authors: Granata Simona , Bruschi Maurizio , Pontrelli Paola , Candiano Giovanni , Stallone Giovanni , Gesualdo Loreto , Zaza Gianluigi
Published: June 2023

Background and Aims

The better understanding of the biological pathways related to chronic kidney disease (CKD) may be useful for the identification of new therapeutic targets to improve the management of CKD patients. High-throughput technologies with innovative bioinformatics approaches for data analysis are very useful to achieve this objective.

Method

We reinterrogated our previous gene expression microarray data obtained from peripheral mononuclear cells (PBMCs) of 5 healthy subjects (HS), 9 chronic kidney disease patients with KDOQI stage II-III (CKD) and 10 CKD patients undergoing peritoneal dialysis treatment (PD). Advanced statistical and machine learning methods, including support vector machine learning and partial least squares discriminant analysis, were used for bioinformatics. Western blot and flow cytometry, then, was used to validate these results in an independent study group (10 HS, 10 CKD and 15 PD).

Results

Statistical analysis revealed that the transcriptomic profile of PD was significantly different from HS and CKD. Instead, no significant differences were observed between HS and CKD. A total of 348 genes (p<0.0001, FDR<5%) were able to differentiate PD patients from the other two study groups. Autophagy resulted one of the most up-regulated pathways in PD and the autophagy related 5 (ATG5), a gene encoding for a key protein involved in autophagic vesicle formation, was the top discriminative transcript (as demonstrated also by the VIP score). Western blot for ATG5 and LC3BII, main phagosome proteins, performed on the validation cohort, confirmed the activation of autophagy pathway only in PBMC of PD patients.

Conclusion

Our high-throughput data demonstrated, for the first time, that the autophagy pathway is activated in immune-cells of PD patients. This condition may significantly impact their immune-response and -homeostasis and, probably, it represents the last attempt of these circulating cells to avoid apoptosis.
#3940 RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS ACCORDING TO DIALYSIS MODALITY
Authors: Bitar Wisam , Helve Jaako , Haapio Mikko , Rauta Virpi , Honkanen Eero Olavi , Finne Patrik
Published: June 2023

Background and Aims

Among dialysis patients, cardiovascular events are the leading cause of death. Little is known about difference in the frequency of cardiovascular events between various dialysis modalities. Glucose load may contribute to a metabolic burden in peritoneal dialysis (PD). On the other hand, hemodialysis can cause intradialytic hypotension, cardiac stunning, and arrhythmias, which are associated with increased risk of death. We compared risk of major cardiovascular events in patients who started continuous ambulatory PD (CAPD), automated PD (APD) and home HD with in-center HD patients.

Method

We included 968 patients who entered dialysis in the Helsinki-Uusimaa healthcare district in Finland from 2004 to 2017, of whom 162 were on CAPD, 229 on APD, 145 on home HD and 432 on in-center HD at day 90 from the start of dialysis. Patients were followed up for 5 years or until the end of 2019. Major adverse cardiovascular event (MACE) was defined as acute myocardial infarction, stroke or death due to cardiovascular disease. The cumulative incidence of the first MACE was calculated by taking other causes of death into account as competing risk events and censoring at time of kidney transplantation. Cox regression was used to compare risk of MACE between dialysis modalities with adjustment for age, gender, primary renal disease, prior comorbidities (coronary heart disease, left ventricular hypertrophy, heart failure and stroke), and laboratory data (plasma albumin, phosphate and ionized calcium). Imputation was performed to replace missing values of comorbidities and laboratory data.

Results

Of all 968 patients, 195 (20%) experienced a MACE during the entire follow-up and 62 (6.4%) during the first year of follow-up. The cumulative incidence of first MACE was similar in in-center HD and CAPD patients and higher than that in APD and home HD patients (Figure 1). Without adjustments, the hazard ratio of MACE was 0.83 [95% CI 0.56–1.2] for CAPD, 0.49 [95% CI 0.31–0.77] for APD and 0.42 [95% CI 0.23–0.78] for home HD in comparison to in-center HD. After adjustment for possible confounders, the hazard ratio of MACE was 1.1 [95% CI 0.70–1.6] for CAPD, 0.88 [95% CI 0.53–1.5] for APD and 0.80 [95% CI 0.41–1.6] for home HD and not statistically significantly different in comparison to in-center HD.

Conclusion

We observed a lower risk of MACE among patients who entered APD or home hemodialysis compared to in-center hemodialysis, but after adjusting for potential confounding factors, the difference diminished and was no longer statistically significant.
#4503 ESTIMATING DELAY IN TIME TO KIDNEY FAILURE OR DEATH FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY
Authors: Mercer Alex , Carroll Kevin , Conley Leah , Hendry Bruce , Pitcher David , Gale Daniel , Barratt Jonathan
Published: June 2023

Background and Aims

Reduction in proteinuria is associated with lower risk of kidney failure (KF) in IgA nephropathy (IgAN) (Thompson et al, 2019). In phase 3 randomized controlled trials in IgAN patients, a treatment effect on proteinuria reduction is typically evaluated as a mean percent change in proteinuria from baseline at 6-9 months. In this study, we aim to estimate the delay in time to KF or death associated with treatment effects of 40% and 50% reduction of proteinuria at this timepoint.

Method

In this study, we used individual patient level data from the UK National Registry of Rare Kidney Disease (RaDaR) IgAN cohort. Adult IgAN patients (n = 535) with a urine protein-creatinine ratio ≥100 mg/mmol (0.88 g/g) ≥6 months from diagnosis (time point defined as baseline) and eGFR ≥30 mL/min at baseline (study population mean = 61 ml/min/1.73 m2 [SD 26]) were included. Predicted risk of KF (eGFR <15 mL/min, initiation of dialysis, transplantation)/doubling serum creatinine/death associated with treatment effects reducing proteinuria by 40% and 50% at 9 months were calculated from IgAN trial level analysis data (Thompson et al, 2019). Accelerated failure time modelling was used to analyse time to KF/death during follow up in the RaDaR IgAN study population, and to estimate the effect that changes in hazard ratio had on median survival time and 5-year survival rates. Weibull, Log-Logistic and Log-Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC.

Results

Treatment effects reducing proteinuria by 40% and 50% in IgAN patients predict a 59% and 67% lower risk of KF/death, respectively. A 59% reduction in risk, is estimated to extend the median time to KF/death by 6.3 years, from 8.6 years (95% CI 7.8, 9.5) to 14.9 years (95% CI 13.6, 16.4), while the corresponding extension in median time to KF/death estimate for a 67% reduction in risk is 8.5 years (from 8.6 years [95% CI 7.8, 9.5] to 17.1 years [95% CI 15.6, 18.8]) (Figure 1). Five-year KF/death free survival rate increased from 75% to 89% and 91%, for 59% and 67% reduced risk in KF/death, respectively.

Conclusion

Therapeutic interventions that reduce proteinuria and the risk of KF can confer important and clinically meaningful extensions in the time patients are alive and free from KF.