bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human carriage of ESBL/pAmpC-producing
Escherichia coli
and
Klebsiella pneumoniae
in relation to the consumption of raw or undercooked vegetables, fruits, and fresh herbs
Authors: Meijs A. P. , Rozwandowicz M. , Hengeveld P. D. , Dierikx C. M. , de Greeff S. C. , van Duijkeren E. , van Dissel J. T. 
Published: January 2024

ABSTRACT

We investigated to what extent the consumption of raw or undercooked vegetables, fruits, and fresh herbs influences carriage rates of ESBL/pAmpC-producing
Escherichia coli
and
Klebsiella pneumoniae
(ESBL-E/K) in the general population. We assessed long-term carriage and changes in ESBL-E/K prevalence over time, by comparing the results to findings in the same population 5 years earlier. Between July and December 2021, participants sent in two fecal samples and questionnaires, 3 months apart. Food frequency questionnaires were sent on a monthly basis. Fecal samples were cultured and screened for ESBL-E/K, and phenotypically positive isolates were sequenced. Multivariable logistic regression models were established to assess the association between the consumption of fresh produce and ESBL-E/K carriage. The ESBL-E/K prevalence was 7.6% [41/537; 95% confidence interval (CI): 5.7–10.2] in the first sampling round and 7.0% (34/489; 95% CI: 5.0–9.6) in the second. Multivariable models did not result in statistical significance for any of the selected fruit and vegetable types. Trends for increased carriage rates were observed for the consumption of raspberry and blueberry in the summer period. ESBL-E/K prevalence was comparable with the prevalence in the same cohort 5 years earlier (7.5%; 95% CI: 5.6–10.1%). In six persons (1.2%) a genetically highly homologous ESBL-E/K was found. In conclusion, the contribution of the consumption of raw fruits, vegetables, and herbs to ESBL-E/K carriage in humans in the Netherlands is probably low. Despite COVID-19 containment measures (e.g., travel restrictions, social distancing, and hygiene) the ESBL-E/K prevalence was similar to 5 years earlier. Furthermore, indications for long-term carriage were found.

IMPORTANCE
ESBL-producing bacteria are resistant against important classes of antibiotics, including penicillins and cephalosporines, which complicates treatment of infections. Food is one of the main routes of transmission for carriage of these bacteria in the general population. Although fruits, vegetables, and herbs are generally less frequently contaminated with ESBL-producing bacteria compared to meat, exposure might be higher since these products are often eaten raw or undercooked. This research showed that the contribution of the consumption of raw or undercooked fresh produce to ESBL-E/K carriage in the general Dutch population was low. No specific types of fruit or vegetables could be identified that gave a higher risk of carriage. In addition, we demonstrated the presence of genetically highly homologous ESBL-E/K in six persons after a period of 5 years, indicative for long-term carriage.
Heterotrophic bacteria in drinking water: evaluating antibiotic resistance and the presence of virulence genes
Authors: Molale-Tom Lesego G. , Olanrewaju Oluwaseyi S. , Kritzinger Rinaldo K. , Fri Justine , Bezuidenhout Cornelius C. 
Published: January 2024

ABSTRACT

Heterotrophic bacteria, impacting those with infections or compromised immunity, pose heightened health risks when resistant to antibiotics. This study investigates heterotrophic plate count bacteria in water from North West-C (NWC) and North West-G (NWG) facilities, revealing prevalent β-hemolysis (NWC 82.5%, NWG 86.7%), enzyme production (98%), and antibiotic resistance, especially in NWC. NWG exhibits variations in hemolysin (
P
= 0.013), lipase (
P
= 0.009), and DNase activity (
P
= 0.006). Antibiotics, including ciprofloxacin, persist throughout treatment, with high resistance to β-lactams and trimethoprim (47%–100%), predominantly in NWC. Multiple antibiotic resistance index indicates that 90% of values exceed 0.20, signifying isolates from high antibiotic usage sources. Whole genome sequencing reveals diverse antibiotic resistance genes in heterotrophic strains, emphasizing their prevalence and health risks in water.

IMPORTANCE
This study’s findings are a stark reminder of a significant health concern: our water sources harbor antibiotic-resistant heterotrophic bacteria, which can potentially cause illness, especially in individuals with weakened immune systems or underlying infections. Antibiotic resistance among these bacteria is deeply concerning, as it threatens the effectiveness of antibiotics, critical for treating various infections. Moreover, detecting virulence factors in a notable proportion of these bacteria highlights their elevated risk to public health. This research underscores the immediate need for enhanced water treatment processes, rigorous water quality monitoring, and the development of strategies to combat antibiotic resistance in the environment. Safeguarding the safety of our drinking water is imperative to protect public health and mitigate the spread of antibiotic-resistant infections, making these findings a compelling call to action for policymakers and public health authorities alike.
Single-cell analysis reveals that cryptic prophage protease LfgB protects
Escherichia coli
during oxidative stress by cleaving antitoxin MqsA
Authors: Fernández-García Laura , Gao Xinyu , Kirigo Joy , Song Sooyeon , Battisti Michael E. , Garcia-Contreras Rodolfo , Tomas Maria , Guo Yunxue , Wang Xiaoxue , Wood Thomas K. 
Published: January 2024

ABSTRACT

Although toxin/antitoxin (TA) systems are ubiquitous, beyond phage inhibition and mobile element stabilization, their role in host metabolism is obscure. One of the best-characterized TA systems is MqsR/MqsA of
Escherichia coli
, which has been linked previously to protecting gastrointestinal species during the stress it encounters from the bile salt deoxycholate as it colonizes humans. However, some recent whole-population studies have challenged the role of toxins such as MqsR in bacterial physiology since the
mqsRA
locus is induced over a hundred-fold during stress, but a phenotype was not found upon its deletion. Here, we investigate further the role of MqsR/MqsA by utilizing single cells and demonstrate that upon oxidative stress, the TA system MqsR/MqsA has a heterogeneous effect on the transcriptome of single cells. Furthermore, we discovered that MqsR activation leads to induction of the poorly characterized
yfjXY ypjJ yfjZF
operon of cryptic prophage CP4-57. Moreover, deletion of
yfjY
makes the cells sensitive to H
2
O
2
, acid, and heat stress, and this phenotype was complemented. Hence, we recommend
yfjY
be renamed to
lfgB
(
l
ess
f
atality
g
ene
B
). Critically, MqsA represses
lfgB
by binding the operon promoter, and LfgB is a protease that degrades MqsA to derepress
rpoS
and facilitate the stress response. Therefore, the MqsR/MqsA TA system facilitates the stress response through cryptic phage protease LfgB.

IMPORTANCE
The roles of toxin/antitoxin systems in cell physiology are few and include phage inhibition and stabilization of genetic elements; yet, to date, there are no single-transcriptome studies for toxin/antitoxin systems and few insights for prokaryotes from this novel technique. Therefore, our results with this technique are important since we discover and characterize a cryptic prophage protease that is regulated by the MqsR/MqsA toxin/antitoxin system in order to regulate the host response to oxidative stress.
Early parenteral nutrition is associated with improved growth in very low birth weight infants: a retrospective study
Authors: Shen René Liang , Ritz Christian , Li Yanqi , Sangild Per Torp , Jiang Ping-Ping 
Published: January 2024

ObjectiveTo assess the association between early initiation of parenteral nutrition (PN) and body growth in preterm infants with very low birth weight (VLBW).DesignCausal inference analysis with confounders preselected by causal diagram based on the NeoNutriNet cohort containing data of infants born between 2011 and 2014 from 13 hospitals from 5 continents.PatientsNeonates with birth weight ≤1500 g.InterventionsPN initiated within the first day of life (early PN) versus within day 2–5 (delayed PN).Main outcome measuresThe primary outcome was body weight z-scores at postmenstrual age (PMA) 36 weeks or early discharge or death, whichever comes first (WT z-score END). Secondary outcomes included WT z-scores at week 1 and 4 of life (WT z-scores CA1 and CA4), corresponding growth velocities (GVs), mortality and incidence of necrotising enterocolitis (NEC), and duration and episodes of antibiotic treatment.ResultsIn total, 2151 infants were included in this study and 2008 infants were in the primary outcome analysis. Significant associations of early PN were found with WT z-score END (adjusted mean difference, 0.14 (95% CI 0.05 to 0.23)), CA4 (β, 0.09 (0.04 to 0.14)) and CA1 (0.04 (0.01 to 0.08)), and GV PMA 36 weeks (1.02 (0.46 to 1.58)) and CA4 (1.03 (0.56 to 1.49), all p<0.001), but not with GV CA1 (p>0.05). No significant associations with mortality, incidence of NEC or antibiotic use was found (all p>0.05).ConclusionsFor VLBW infants, PN initiated within the first day of life is associated with improved in-hospital growth.
Life outcomes after paediatric kidney transplantation: a qualitative, biographical study in long-term survivors
Authors: Ritschl Valentin , Stamm Tanja , Selzer Axana , Boesendorfer Anna , Eibensteiner Fabian , Kaltenegger Lukas , Mosor Erika , Omara Maisa , Vachuda Natalie , Sperl Lisa , Masel Eva K , Aufricht Christoph , Boehm Michael 
Published: January 2024

ObjectiveThe objective of this study was to analyse the narrative life stories of children with end-stage kidney disease (ESKD) and their families to determine how health professionals can effectively support these children to achieve better life outcomes.DesignQualitative narrative biographic study.SettingWe invited every long-term survivor of paediatric kidney transplants and their families at the Medical University of Vienna between 2008 and 2013 to participate in this study.ParticipantsNineteen patients (women: n=8, 42%) and 34 family members (women: n=22, 65%) were interviewed. The patients had a mean age of 7.6 (SD±5.6) years at the time of transplantation and 22.2 (SD±5.4) at the time of interview.Main outcome(s) measure(s)A qualitative narrative biographical analysis was combined with computational structured topic models using the Latent Dirichlet Allocation.ResultsThe overarching finding was the desire for normality in daily life in long-term survivors and their families but with different perceptions of what normality looks like and predominance of this aspect evolving. Different strategies were used by patients (focused on their advancement) and caregivers (normality for all family members). Siblings played a major role in supporting survivors’ social inclusion.ConclusionsThe strong desire for normality confirms recent findings of the Standardised Outcomes in Nephrology Group initiative, which proposes survival and life participation as core outcomes in children with chronic kidney disease. Our study should be a starting point for an international effort to identify typologies and stratified interventions for children with ESKD and their families, particularly siblings.
PSCK9 inhibitors reduced early recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis
Authors: Wu Li , Zhang Bo , Li Chenghao , Zhuang Zhuolin , Liu Kang , Chen Hualin , Zhu Shuanggen , Zhu Juehua , Dai Zheng , Huang Huameng , Jiang Yongjun 
Published: January 2024

BackgroundSymptomatic intracranial atherosclerotic stenosis (ICAS) is prone to cause early recurrent stroke (ERS). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels and prevent cardiovascular events. This multicentre, hospital-based prospective cohort study was designed to investigate whether PCSK9 inhibitors would prevent ERS in patients with symptomatic ICAS.MethodsFrom 1 October 2020 to 30 September 2022, consecutive patients with acute ischaemic stroke attributed to ICAS admitted within 1 week after onset were enrolled and followed up for 1 month. Patients were divided into two groups, the PCSK9 inhibitors group receiving PCSK9 inhibitors add-on therapy, and the control group receiving statins and/or ezetimibe. The primary outcome was ERS. Cox proportional hazard models and Kaplan-Meier survival curve were used to estimate the association between PCSK9 inhibitors and ERS.ResultsAt the end of follow-up, the LDL-C levels were further lowered by PCSK9 inhibitors add-on therapy (n=232, from 3.06±1.16 mmol/L to 2.12±1.19 mmol/L) than statins and/or ezetimibe treatment (n=429, from 2.91±1.05 mmol/L to 2.64±0.86 mmol/L, p<0.001). The Kaplan-Meier survival curves showed that PCSK9 inhibitors add-on therapy significantly reduced ERS (5.59%, 24/429, vs 2.16%, 5/232; log-rank test, p=0.044). The multivariate Cox regression analysis revealed that, after adjusting for confounders with a p value less than 0.05 in univariate analysis or of particular importance, the HR was 0.335 (95% CI 0.114 to 0.986, p=0.047), compared with the control group.ConclusionsIn our study, PCSK9 inhibitors add-on therapy further reduced LDL-C levels and ERS in patients with symptomatic ICAS.
Fragility of randomised controlled trials for systemic lupus erythematosus and lupus nephritis therapies
Authors: Figueroa-Parra Gabriel , Putman Michael S , Crowson Cynthia S , Duarte-García Alí 
Published: January 2024

ObjectiveWe aimed to evaluate the robustness of phase III randomised controlled trials (RCTs) for SLE and lupus nephritis (LN) using the fragility index (FI), the reverse FI (RFI) and the fragility quotient (FQ).MethodsWe searched for phase III RCTs that included patients with active SLE or LN. Data on primary endpoints, total participants and the number of events for each arm were obtained. We calculated the FI score for RCTs with statistically significant results (number of patients required to change from event to non-event to make the study lose statistical significance), the RFI for RCTs without statistically significant results (number of patients required to change from non-event to event to make study gain statistical significance) and the FQ score for both (FI or RFI score divided by the sample size).ResultsWe evaluated 20 RCTs (16 SLE, four LN). The mean FI/RFI score was 13.6 (SD 6.6). There were nine RCTs with statistically significant results (seven SLE, two LN), and the mean FI score was 10.2 (SD 6.2). The lowest FI was for the ILLUMINATE-2 trial (FI=2), and the highest FI was for the BLISS-52 trial (FI=17).Twelve studies had non-statistically significant results (10 SLE, two LN) with a mean RFI score of 15.6 (SD 6.1). The lowest RFI was for the ILLUMINATE-1 trial (RFI=4), and the highest RFI was for the TULIP-1 trial (RFI=27). The lowest FQ scores were found in the ILLUMINATE trials and the highest in the Rituximab trials (EXPLORER and LUNAR), meaning that the last ones were the most robust results after accounting for sample size.ConclusionsThe evidence of therapies for patients with SLE and LN is derived mostly from fragile RCTs. Clinicians and trialists must be aware of the fragility of these RCTs for clinical decision-making and designing trials for novel therapeutics.
Severe gastrointestinal involvements in patients with adult dermatomyositis with anti-NXP2 antibody
Authors: Fu Yakai , Gu Liyang , Chen Jie , Dai Yuting , Feng Qi , Chen Zhiwei , Fan Jie , Gao Mingshi , Wang Xiaodong , Fu Qiong , Ye Shuang 
Published: January 2024

ObjectiveGastrointestinal (GI) involvements were scarcely reported in adult anti-nuclear matrix protein 2 (NXP2) dermatomyositis (NXP2+DM). In this study, we investigated the clinical, pathological and molecular features as well as treatment options of this rare yet life-threatening disease.MethodsWe retrospectively collected the data of the cohort of NXP2+DM from 2012 to 2022 in our hospital. RNA sequencing was performed in intestinal samples of perforated patients compared with healthy controls data set.ResultsA total of 56 patients with adult NXP2+DM were collected including 10 cases with GI involvements. Abdominal pain and melena were the initial manifestations for GI involvements with a median 10-month time lag after the diagnosis of NXP2+DM when myositis largely subsided. Within weeks, GI perforation occurred in 8 of 10 patients, while five patients underwent eight surgical interventions subsequently. The short-term mortality was observed in four patients. NXP2+DM with GI involvements presented with more extramuscular systemic manifestations such as interstitial lung disease and subcutaneous calcinosis. The GI pathological features encompassed vasculitis/vasculopathy with high MxA expression, intestinal smooth muscle necrosis and serosal calcinosis. Gene expression profile validated the type-I interferon activation and revealed that epithelial mesenchymal transition and focal adhesion pathway may also contribute. Finally, vedolizumab, an anti-α4β7-integrin monoclonal antibody, exhibited promising therapeutic signals which should be further investigated.ConclusionsGI involvement is a unique complication in patients with adult NXP2+DM. Timely recognition and targeted therapy may turn out to be lifesaving.
Cretaceous palaeoceanographic events of the northern South Atlantic: an overview
Authors: Koutsoukos Eduardo A. M. , Bengtson Peter 
Published: January 2024

Abstract

The break-up of Gondwana in the latest Jurassic and earliest Cretaceous and the subsequent opening and evolution of the South Atlantic Ocean as a new widening seaway linking northern and southern high latitudes, was the single most significant palaeoceanographic event during the Cretaceous with global consequences for the climate and the biotic evolution, both on land and at sea. Its main evolutionary stages are now becoming well known but, despite that, their global impact has been widely underestimated. Aiming to shed light on some of these unanswered questions, this work presents an overview of research carried out during the past decades in the Sergipe Basin in northeastern Brazil, integrating foraminiferal and ammonite biostratigraphic data, coupled with an assessment of their biogeographic patterns. Three main topics are discussed, and the key findings presented and set against their possible global impact: the opening of the Equatorial Atlantic Gateway in the late early to mid Aptian (
c.
118–119 Ma); the mid-Cretaceous dysoxic–anoxic events recorded in the northern South Atlantic (maxima in the late Aptian–earliest Albian, early Cenomanian and at the Cenomanian–Turonian boundary); and the timing of the North Atlantic–South Atlantic oceanic connection in the late Coniacian to early Santonian (
c.
85–87 Ma).
Compiler Autotuning through Multiple-phase Learning
Authors: Zhu Mingxuan , Hao Dan , Chen Junjie 
Published: January 2024

Widely used compilers like GCC and LLVM usually have hundreds of optimizations controlled by optimization flags, which are enabled or disabled during compilation to improve the runtime performance (e.g., small execution time) of the compiler program. Due to the large number of optimization flags and their combination, it is difficult for compiler users to manually tune compiler optimization flags. In the literature, a number of autotuning techniques have been proposed, which tune optimization flags for a compiled program by comparing its actual runtime performance with different optimization flag combinations. Due to the huge search space and heavy actual runtime cost, these techniques suffer from the widely recognized efficiency problem. To reduce the heavy runtime cost, in this article we propose a lightweight learning approach that uses a small number of actual runtime performance data to predict the runtime performance of a compiled program with various optimization flag combinations. Furthermore, to reduce the search space, we design a novel particle swarm algorithm that tunes compiler optimization flags with the prediction model. To evaluate the performance of the proposed approach, CompTuner, we conduct an extensive experimental study on two popular C compilers, GCC and LLVM, with two widely used benchmarks, cBench and PolyBench. The experimental results show that CompTuner significantly outperforms the six compared techniques, including the state-of-the-art technique BOCA.
ARCTURUS
: Full Coverage Binary Similarity Analysis with Reachability-guided Emulation
Authors: Zhou Anshunkang , Hu Yikun , Xu Xiangzhe , Zhang Charles 
Published: January 2024

Binary code similarity analysis is extremely useful, since it provides rich information about an unknown binary, such as revealing its functionality and identifying reused libraries. Robust binary similarity analysis is challenging, as heavy compiler optimizations can make semantically similar binaries have gigantic syntactic differences. Unfortunately, existing semantic-based methods still suffer from either incomplete coverage or low accuracy.

In this article, we propose
ARCTURUS
, a new technique that can achieve high code coverage and high accuracy simultaneously by manipulating program execution under the guidance of code reachability. Our key insight is that the compiler must preserve program semantics (e.g., dependences between code fragments) during compilation; therefore, the code reachability, which implies the interdependence between code, is invariant across code transformations. Based on the above insight, our key idea is to leverage the stability of code reachability to manipulate the program execution such that deep code logic can also be covered in a consistent way. Experimental results show that
ARCTURUS
achieves an average precision of 87.8% with 100% block coverage, outperforming compared methods by 38.4%, on average.
ARCTURUS
takes only 0.15 second to process one function, on average, indicating that it is efficient for practical use.
Raludotatug Deruxtecan, a CDH6-Targeting Antibody–Drug Conjugate with a DNA Topoisomerase I Inhibitor DXd, Is Efficacious in Human Ovarian and Kidney Cancer Models
Authors: Suzuki Hirokazu , Nagase Shotaro , Saito Chiemi , Takatsuka Atsuko , Nagata Motoko , Honda Kokichi , Kaneda Yuki , Nishiya Yumi , Honda Tomoyo , Ishizaka Tomomichi , Nakamura Kensuke , Nakada Takashi , Abe Yuki , Agatsuma Toshinori 
Published: January 2024

AbstractCadherin-6 (CDH6) is expressed in several cancer types, but no CDH6-targeted therapy is currently clinically available. Here, we generated raludotatug deruxtecan (R-DXd; DS-6000), a novel CDH6-targeting antibody–drug conjugate with a potent DNA topoisomerase I inhibitor, and evaluated its properties, pharmacologic activities, and safety profile. In vitro pharmacologic activities and the mechanisms of action of R-DXd were assessed in serous-type ovarian cancer and renal cell carcinoma cell lines. In vivo pharmacologic activities were evaluated with several human cancer cell lines and patient-derived xenograft mouse models. The safety profile in cynomolgus monkeys was also assessed. R-DXd exhibited CDH6 expression-dependent cell growth-inhibitory activity and induced tumor regression in xenograft models. In this process, R-DXd specifically bound to CDH6, was internalized into cancer cells, and then translocated to the lysosome. The DXd released from R-DXd induced the phosphorylation of Chk1, a DNA damage marker, and cleaved caspase-3, an apoptosis marker, in cancer cells. It was also confirmed that the DXd payload had a bystander effect, passing through the cell membrane and impacting surrounding cells. The safety profile of R-DXd was favorable and the highest non-severely toxic dose was 30 mg/kg in cynomolgus monkeys. R-DXd demonstrated potent antitumor activity against CDH6-expressing tumors in mice and an acceptable safety profile in monkeys. These findings indicate the potential of R-DXd as a new treatment option for patients with CDH6-expressing serous-type ovarian cancer and renal cell carcinoma in a clinical setting.