bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes of flomoxef versus cefmetazole in hospitalized patients with urinary tract infections: Combined retrospective analyses of two real-world databases andin vitrodata
Authors: Niimura Takahiro , Goda Mitsuhiro , Nakano Satoshi , Kajihara Toshiki , Yahara Koji , Hirabayashi Aki , Miyata Koji , Ikai Marie , Shinohara Motoko , Minato Yusuke , Suzuki Masato , Ishizawa Keisuke
Published: July 2024

Background

Flomoxef is active against extended-spectrum beta-lactamase (ESBL)-producing bacteria, but its clinical effectiveness has not been compared with cefmetazole. This study aimed to compare the utility of the two drugs in treating urinary tract infection (UTI) by integratingin vitrodata with a retrospective analysis of two real-world databases.

Methods

The susceptibility rates of third-generation cephalosporin-resistantEscherichia coliandKlebsiella pneumoniaeto flomoxef and cefmetazole were compared using comprehensive national antimicrobial resistance surveillance data. Combinational antimicrobial activities against an ESBL-producing multidrug-resistant bacterial strain were tested by diagonal measurement of n-way drug interactions (DiaMOND), an innovative method to assess antimicrobial interactionsin vitro. The effectiveness of the two drugs in treating UTIs was compared using hospital stay duration as the primary outcome obtained from the Japan Medical Data Center (JMDC) Claims Database.

Results

Third-generation cephalosporin-resistantE. coliandK. pneumoniae, including ESBL-producing strains, were similarly susceptible to flomoxef and cefmetazole.In vitroassessment of combinational antimicrobial activities against an ESBL-producing multidrug-resistant strain revealed that both drugs showed similar antimicrobial interaction patterns.

JMDC Claims data analysis showed that the median time of hospital stay duration was 11 days (95% confidence interval [CI]: 11–11) in the cefmetazole group and 4 days (95% CI: 3– 5) in the flomoxef group, significantly shorter in the latter (log-rank test, P < 0.001). In addition, the flomoxef group had a significantly lower frequency of adverse events such asClostridioides difficileinfection.

Conclusions

Flomoxef exhibits effectiveness that is comparable to cefmetazole in treating UTI without major concerns about adverse events such asC. difficileinfection or renal impairment. This evidence endorses flomoxef as a viable treatment option for UTIs in locales with high prevalence of ESBL-prodcing strains.

Key Points

An oxacephem antimicrobial agent, flomoxef, exhibited effectiveness comparable to cefmetazole in the treatment of urinary tract infections and was superior in terms of safety.
Factors associated with Alzheimer's Disease Dementia prevalence in the United States: A county-level spatial machine learning analysis
Authors: Mollalo Abolfazl , Grekousis George , Benitez Andreana , Florez Hermes , Neelon Brian , Lenert Leslie A , Alekseyenko Alexander
Published: July 2024

Background: In recent years, a growing body of literature has examined the impact of neighborhood characteristics on Alzheimer's disease (AD) dementia. However, spatial variability of the most influential variables and their relative importance to AD dementia prevalence remain underexplored. Methods: We compiled various widely recognized factors to examine spatial heterogeneity and associations with AD dementia prevalence utilizing non-linear geographically weighted random forest approach. Results: The model outperformed conventional ones, with an out-of-bag R2 of 74.8%. Key findings showed the normalized difference vegetation index as the most influential environmental factor in 15.1% of US counties, lack of leisure time physical activity in 12.7%, binge drinking in 9.1%, and mobile homes as the main socioeconomic factor in 13.3% of US counties. Discussion: Spatial machine learning analyses suggest that AD dementia prevalence could be impacted by county-specific targeted interventions that improve green space, reduce air pollution and support greater access to physical activity.
Epigenome-wide association study for dilated cardiomyopathy in left ventricular heart tissue identifies putative gene sets associated with cardiac development and early indicators of cardiac risk
Authors: Tan Konstanze , Tay Darwin , Tan Wilson , Ng Hong Kiat , Wong Eleanor , Morley Michael P , Singhera Gurpreet K , Jain Pritesh R , Tai Fei Li , Hanson Paul J , Cappola Thomas P , Margulies Kenneth B , Foo Roger , Loh Marie
Published: July 2024

Background

Methylation changes linked to dilated cardiomyopathy (DCM) affect cardiac gene expression. We investigate DCM mechanisms regulated by CpG methylation using multi-omics and causal analyses in the largest cohort of left ventricular tissues available.

Methods

We mapped DNA methylation at ∼850,000 CpG sites, performed array-based genotyping and RNA sequencing in left-ventricular tissue samples from failing and non-failing hearts across two independent DCM cohorts (discovery n=329, replication n=85). Summary data-based Mendelian Randomization (SMR) was applied to explore the causal contribution of sentinel CpGs to DCM. Fine-mapping of regions surrounding sentinel CpGs revealed additional signals for cardiovascular disease risk factors. Coordinated changes across multiple CpG sites were examined using weighted gene correlation network analysis (WGCNA).

Results

We identified 194 epigenome-wide significant CpGs associated with DCM (discovery P<5.96E-08), enriched in active chromatin states in heart tissue. Amongst these, 183 sentinel CpGs significantly influenced the expression of 849 proximal genes (±1Mb). SMR suggested the causal contribution of two sentinel CpGs to DCM and 36 sentinel CpGs to the expression of 43 unique proximal genes (P<0.05). Colocalization analyses indicated that a single causal variant may underlie the methylation-gene expression relationship for three sentinel CpGs. Fine-mapping revealed additional signals linked to cardiovascular traits including hsCRP and blood pressure. Co-methylation modules were enriched in genes related to cardiac physiological and pathological processes and their corresponding transcriptional regulators.

Conclusions

Using the largest series of left ventricular tissue to date, this study investigates the causal role of cardiac methylation changes in DCM and suggests targets for experimental studies to probe DCM pathogenesis.
Prkra dimer senses double-stranded RNAs to dictate global translation efficiency
Authors: Lu Tong , Ma Pengcheng , Chen Aijun , Fang Hailing , Xu Jianlin , Wang Mingyu , Su Ling , Wang Sen , Zhang Yizhuang , Wang Jiasheng , Yang Boya , Shi De-Li , Zhou Yong , Gong Qianqian , Liu Xiangguo , Mao Bingyu , Shao Ming
Published: July 2024

Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, are recognized by interferon-induced protein kinase R (PKR) to trigger an integrated stress response, characterized by the inhibition of global translation. However, the interferon system is inactive in pluripotent cells, thus the mechanism underlying dsRNA sensing and translational control is unclear. In this study, we utilized early zebrafish embryos as a model of pluripotent cells and discovered a PKR-independent blockage of translation initiation induced by dsRNA stimulation. Prkra dimer was identified as the genuine dsRNA sensor. Upon binding to dsRNAs, the dimerized dsRNA binding domain 3 becomes activated to sequester the eIF2 complexes from the translation machinery, leading to a hindrance in global protein synthesis. This distinctive embryonic stress response restricts RNA virus SVCV replication in zebrafish embryos but is also conserved in early mouse embryos and embryonic stem cells. Therefore, the Prkra-mediated dsRNA sensing and translation blocking mechanism potentially represents a common strategy for reestablishing physiological homeostasis in response to environmental stresses.
The catheterized bladder environment induces dysregulation of macrophage polarization exacerbating bacterial UTI
Authors: Marrufo Armando M. , Molina Jonathan J. , Gager Chris , Andersen Marissa J. , LaBella Alyssa A. , Lucas Elizabeth R. , Wongso Ellsa , Urmi Tamanna , Arias-Parbul Kassandra , Webster Railyn , Stuckey Peter V. , Kohler Kurt N. , Donahue Deborah , Ploplis Victoria A. , Flick Matthew J. , Castellino Francis J. , Santiago-Tirado Felipe H. , Flores-Mireles Ana L.
Published: July 2024

Urinary catheterization causes bladder damage, predisposing hosts to catheter-associated urinary tract infections (CAUTIs). CAUTI pathogenesis is mediated by bladder damage-induced inflammation, resulting in accumulation and deposition of the blood-clotting protein fibrinogen (Fg) and its matrix form fibrin, which are exploited by uropathogens as biofilm platforms to establish infection. Catheter-induced inflammation also results in robust immune cell recruitment, including macrophages (Mϕs). A fundamental knowledge gap is understanding the mechanisms by which the catheterized-bladder environment suppresses the Mϕ antimicrobial response, allowing uropathogen persistence. Here, we found that Fg and fibrin differentially modulate M1 and M2 Mϕ polarization, respectively. We unveiled that fibrin accumulation in catheterized mice induced an anti-inflammatory M2-like Mϕ phenotype, correlating with pathogen persistence. Even GM-CSF treatment of wildtype mice to promote M1 polarization was not sufficient to reduce bacterial burden and dissemination, indicating that the catheterized-bladder environment provides mixed signals, dysregulating Mϕ polarization, hindering its antimicrobial response against uropathogens.
Additive and partially dominant effects from genomic variation contribute to rice heterosis
Authors: Dan Zhiwu , Chen Yunping , Zhou Wei , Xu Yanghong , Huang Junran , Chen Yi , Meng Jizhou , Yao Guoxin , Huang Wenchao
Published: July 2024

Background

The molecular mechanisms of heterosis remain debated due to discrepancies in factors such as species, phenotypes, hybrid populations, developmental stages or growth environments.

Results

Here, we screened heterosis-associated genes and metabolites from molecular differences in rice inbred lines and found that the phenylpropanoid biosynthesis was involved in heterosis. The main inheritance patterns of the heterosis-associated molecules were additive and partially dominant effects, namely, at the mid-parent levels and between the parental and mid-parent levels. The additive and partially dominant effects contributed to heterosis of 17 agronomic traits in rice, including grain yield and plant height across developmental stages, and to heterosis of F1hybrids from different populations and growth environments in both rice and maize. Furthermore, the two inheritance patterns were associated with parental genomic variants, which were correlated with heterosis of agronomic traits.

Conclusions

Our study systematically integrates parental genetic variation and highlights the predominant effects of additive and partially dominant in rice heterosis.
Dual expansion routes likely underlie the present-day population structure in aParnassiusbutterfly across the Japanese Archipelago
Authors: Tamura Hideyuki , Noda Tomoaki , Hayashi Mikiko , Fujii Yuko , Iwata Noriko , Yokota Yuko , Murata Masanori , Tatematsu Chisato , Naka Hideshi , Tera Akio , Ono Katsumi , Yokoi Kakeru , Kato Takanori , Okamoto Tomoko , Tsuchida Koji
Published: July 2024

The Japanese Archipelago, comprising a series of isolated yet interconnected islands, had been geographically separated from the Eurasian continent. The linear topography presents a unique biogeographic context for dispersing organisms from the continent. In this study, we utilized mitochondrial DNA (mtDNA) and single nucleotide polymorphism (SNP) variation to elucidate the dispersal history of the Japanese clouded butterflyParnassius glacialisacross the Japanese Archipelago, including North Island (Hokkaido), Main Island (Honshu) and Shikoku Island. Our analysis of mtDNA (COI, COII) at 1192 base pairs (bps) revealed 49 haplotypes and identified three distinct haplotype groups in the network. These groups correspond geographically to East Japan, West Japan, and Chugoku-Shikoku. The Chugoku-Shikoku group is the most ancient lineage. Interestingly, the Chugoku-Shikoku lineage showed a closer network connection to the East Japan lineage than the geographically proximate West Japan lineage. Divergence time estimates suggest that the Chugoku-Shikoku lineage diverged from the continentalP. glacialisapproximately 3.05 million years ago (MYA). Subsequently, from the Chugoku-Shikoku lineage, the East Japan and West Japan lineages diverged around 1.05 MYA, with the subsequent divergence between the East and West Japan lineages occurring at approximately 0.62 MYA. Based on the 3067 SNP genotypes, population structure analysis revealed five distinct genetic structures within the Japanese Archipelago, indicating geographical differentiation. From the analyses by mtDNA and SNP variations, four primary genetic barriers were identified: between Hokkaido and Honshu, between East and Central Japan, within the Kansai region, and within the Chugoku region. The former three lines corresponded to the Blakiston Line, the Itoigawa-Shizuoka Tectonic Line, and Lake Biwa, respectively. These findings suggest thatP. glacialisdiverged from the continentalP. glacialisand expanded its range across the Japanese Archipelago via the North and South routes, establishing its current distribution.
Evidence for infection ofEucalyptus camaldulensiswith aLeifsoniabacterium in Australia and Syria using high throughput sequencing
Authors: Randles J.W. , Hanold D. , Baumann U. , Borneman A.
Published: July 2024

A biotic hypothesis for the eucalypt disease of unknown aetiolgy, Mundulla Yellows (MY), was tested by seeking non-host nucleic acids in affectedEucalyptus camaldulensistrees using high throughput sequencing (HTS). Ten contigs were selected from a pool of nucleic acids unique to diseased trees, and oligonucleotide probes were prepared for specific dot-blot hybridisation assay of these contigs. One of the contigs was found to be associated with a few MY-affected trees collected in South Australia and Western Australia, as well as with similarly affectedE. camaldulensistrees growing in Syria. The probes for this contig represented opposite polarities of the contig, and both hybridised with the same positive samples even after alkali treatment confirming that the contig that they represented was dsDNA. This contig, comprising 766 nt, showed 95% similarity to whole genome shotgun sequence ofLeifsonia xyli. This preliminary microbiome analysis of MY affected trees provides the first evidence that aLeifsoniaspecies may infect eucalypts and that it should be further studied as a potential agent of MY.
Awareness of Intimate Partner Violence among Faith-Based Leaders of Migrant and Refugee Background in New South Wales, Australia
Authors: Kayesa Naomi K. , Ogunsiji Olayide
Published: July 2024

Purpose

Intimate Partner Violence (IPV) is a family violence issue requiring public health system interventions. Migrants and refugees experiencing IPV often rely on their Faith-Based Leaders (FBLs). However, the role of FBLs is under-reported. This study aims to report findings on awareness to IPV among FBLs of migrant and refugee backgrounds.

Methods

This qualitative study engaged 12 FBLs in face-to-face interviews. Thematic analysis revealed three themes namely: Awareness and understanding of IPV; Being the first point of call; Awareness of available services for IPV.

Results

All FBLs described IPV as relational and identified the different IPV types. Sexual violence did not resonate as IPV by eleven participants. Explanations for being the first point of contact centered around victims’ quest for a win-win outcome and in-accessibility of formal services.

Conclusions

IPV specific training, collaboration between FBLs and formal services working with victims of IPV is essential in supporting IPV victims.
Cost per episode of diarrhea and respiratory syncytial virus (RSV) in 128 low- and middle-income countries: how well do disease-specific and WHO-CHOICE estimates align?
Authors: Li Xiao , Bilcke Joke , Asare Ernest O. , Wenger Catherine , Kwon Jiye , Bont Louis , Beutels Philippe , Pitzer Virginia E.
Published: July 2024

Objective

Non-disease-specific WHO-CHOICE unit costs are often used in cost and cost-effectiveness studies in the absence of country-specific data. This study aims to compare reported country-specific disease costs and the corresponding WHO-CHOICE estimates. We use generically defined “diarrhea” (including rotavirus diarrhea) and pathogen-specific “respiratory syncytial virus (RSV)” disease as examples.

Methods

We updated systematic reviews for both diseases in low-income (LICs), lower-middle-income (LMICs) and upper-middle-income (UMICs) countries. Diarrheal (including a sub-analysis of rotavirus-specific) and RSV-specific outpatient and inpatient costs per episode were extracted and compared with WHO-CHOICE estimates in the same countries. If a consistent pattern of under- or over-estimation was identified, we quantified the magnitude of the discrepancy. All costs were updated to 2022 international dollar values.

Results

Out of 1975 new records identified, 23 new cost studies were included. Including previous reviews, we retained 31 diarrhea and 16 RSV studies for comparison. WHO-CHOICE based direct medical costs were similar for diarrheal disease including rotavirus diarrhea, but lower for RSV-related disease. We estimated the cost per episode of diarrhea and RSV in 128 countries. RSV outpatient cost were adjusted by multiplying WHO-CHOICE costs by 6.89 (95% uncertainty interval: 5.58-8.58) in LICs and LMICs and 5.87 (4.95-6.96) in UMICs; RSV inpatient costs were multiplied by 1.43 (1.01-2.01) and 1.36 (0.82-2.27), respectively.

Conclusion

WHO-CHOICE based costs should be used cautiously. They aligned well with studies for diarrheal disease, but underestimate costs of RSV-related disease. More country- and disease-specific cost data are needed, especially for RSV in LICs.
End-to-end Stroke imaging analysis, using reservoir computing-based effective connectivity, and interpretable Artificial intelligence.
Authors: Ciezobka Wojciech , Falco-Roget Joan , Koba Cemal , Crimi Alessandro
Published: July 2024

In this paper, we propose a reservoir computing-based and directed graph analysis pipeline. The goal of this pipeline is to define an efficient brain representation for connectivity in stroke data derived from magnetic resonance imaging. Ultimately, this representation is used within a directed graph convolutional architecture and investigated with explainable artificial intelligence (AI) tools. Stroke is one of the leading causes of mortality and morbidity worldwide, and it demands precise diagnostic tools for timely intervention and improved patient outcomes. Neuroimaging data, with their rich structural and functional information, provide a fertile ground for biomarker discovery. However, the complexity and variability of information flow in the brain requires advanced analysis, especially if we consider the case of disrupted networks as those given by the brain connectome of stroke patients. To address the needs given by this complex scenario we proposed an end-to-end pipeline. This pipeline begins with reservoir computing causality, to define effective connectivity of the brain. This allows directed graph network representations which have not been fully investigated so far by graph convolutional network classifiers. Indeed, the pipeline subsequently incorporates a classification module to categorize the effective connectivity (directed graphs) of brain networks of patients versus matched healthy control. The classification led to an area under the curve of 0.69 with the given heterogeneous dataset. Thanks to explainable tools, an interpretation of disrupted networks across the brain networks was possible. This elucidates the effective connectivity biomarker's contribution to stroke classification, fostering insights into disease mechanisms and treatment responses. This transparent analytical framework not only enhances clinical interpretability but also instills confidence in decision-making processes, crucial for translating research findings into clinical practice. Our proposed machine learning pipeline showcases the potential of reservoir computing to define causality and therefore directed graph networks, which can in turn be used in a directed graph classifier and explainable analysis of neuroimaging data. This complex analysis aims at improving stroke patient stratification, and can potentially be used with other brain diseases.
Long-term consequences of drug usage on the gut microbiome
Authors: Aasmets Oliver , Taba Nele , Krigul Kertu Liis , Andreson Reidar ,   Estonian Biobank Research Team, Org Elin
Published: July 2024

Medication usage is a significant contributor to the inter-individual variability in the gut microbiome. However, drugs are often used long-term and repeatedly, a notion yet unaccounted for in microbiome studies, which might lead to underestimating the extent of drug effects. Recently, we and others showed that not only the usage of antibiotics and antidepressants at the time of sampling but also past consumption is associated with the gut microbiome. This effect can be “additive” - the more a drug is used, the stronger the effect on the microbiome. Here, by utilizing electronic health records and the Estonian Microbiome cohort metagenomics dataset (n=2,509), we systematically evaluate the long-term effects of antibiotics and human-targeted medications on the gut microbiome. We show that the past usage of medications is associated with the gut microbiome, and for example, the effects of antibiotics, psycholeptics, antidepressants, proton pump inhibitors, and beta-blockers are detectable several years after usage. Furthermore, by analyzing a subcohort (n=328) with microbiome measured repeatedly, we show that similar changes in the gut microbiome occur after treatment initiation, possibly indicating causal effects.
New job, new habits? A Multilevel Interrupted Time Series analysis of diet, physical activity and sleep changes among young adults starting work for the first time
Authors: Oxenham Alena F , Braune Tanya , van Sluijs Esther , Fairbrother Hannah , Martin Adam , Winpenny Eleanor M
Published: July 2024

Background

The workplace is an important determinant of health that people are exposed to for the first-time during adolescence/early adulthood. This study investigates how diet, physical activity, and sleep change as people aged 16-30 years transition into work and whether this varies for different individuals and job types.

Methods

Multilevel linear regression models assessed changes in fruit and vegetable intake, sleep duration, and physical activity among 3,302 UK Household Longitudinal Study (UKHLS) participants aged 16-30 years, who started work for the first time between 2015 and 2023. In line with interrupted time series, models assessed behavioural trends in the period before starting work, the immediate effect of starting work, and changes in behaviour over time after employment. Stratified analyses examined differences by selected individual and job characteristics, adjusted for covariates. All analyses were conducted in R v.4.3.2.

Results

Sleep duration was stable over the years before and after starting work, but starting work was associated with an immediate reduction in sleep duration (β=-9.74 [95% CI: −16.81 to −2.67], min/night). Physical activity, measured in Metabolic Equivalent Tasks (MET), increased immediately after starting work (β =113.3, [95% CI: 80.49 to 146.11] MET-min/day), but subsequently decreased over time after starting work (β =−26.7, [95% CI: −40.75 to −12.66] MET-min/day/year). The increase in physical activity was greater among men, among those with no degree and among those starting lower socioeconomic classification jobs. Starting a “work from home” job had an immediate negative effect on physical activity (β =−157.81, [-313.07 to - 2.56] MET-min/day), whereas those who worked at their employer’s premises showed an initial increase (β=125.71 [95% CI: 85.79 to 165.63] MET-min/day). Starting work had little influence of fruit and vegetable consumption.

Conclusions

This is the first study to examine how diet, physical activity, and sleep behaviours in young adults change as they start employment in the UK. Starting work is associated with decreased sleep time and increased physical activity, with differences based on sociodemographic and job characteristics. Future research should consider these potential influences of the work environment when developing intervention targets to promote healthy behaviour in the workplace.
Increasing prevalence of bacteriocin carriage in a six-year hospital cohort ofE. faecium
Authors: Garretto Andrea , Dawid Suzanne , Woods Robert
Published: July 2024

Vancomycin resistant enterococci (VRE) are important pathogens in hospitalized patients, however, the factors involved in VRE colonization of hospitalized patients are not well characterized. Bacteriocins provide a competitive advantage to enterococci in experimental models of colonization, but little is known about bacteriocin content in samples derived from humans and even less is known about their dynamics in the clinical setting. To identify bacteriocins which may be relevant in the transmission of VRE, we present a systematic analysis of bacteriocin content in the genomes of 2,428 patient derivedE. faeciumisolates collected over a six-year period from a single hospital system. We used computational methods to broadly search for bacteriocin structural genes and a functional assay to look for phenotypes consistent with bacteriocin expression. We identified homology to 15 different bacteriocins with two having high presence in this clinical cohort. Bacteriocin 43 (bac43) was found in a total of 58% of isolates, increasing from 8% to 91% presence over the six-year collection period. There was little genetic variation in the bac43 structural or immunity genes across isolates. The enterocin A structural gene was found in 98% of isolates but only 0.3% of isolates had an intact enterocin A gene cluster and displayed a bacteriocin producing phenotype. This study presents a wide survey of bacteriocins from hospital isolates and identified bac43 as highly conserved, increasing in prevalence, and phenotypically functional. This makes bac43 an interesting target for future investigation for a potential role inE. faeciumtransmission.

Importance

While enterococci are a normal inhabitant of the human gut, vancomycin-resistantE. faecalisandE. faeciumare urgent public health threats responsible for hospital associated infections. Bacteriocins are ribosomally synthesized antimicrobial proteins and are commonly used by bacteria to provide a competitive advantage in polymicrobial environments. Bacteriocins have the potential be used byE. faeciumto invade and dominate the human gut leading to a greater propensity for transmission. In this work, we explore bacteriocin content in a defined clinically derived population ofE. faeciumusing both genetic and phenotypic studies. We show that one highly active bacteriocin is increasing in prevalence over time and demonstrates great potential relevance toE. faeciumtransmission.
Genetic and Lifestyle Risks for Coronary Artery Disease and Long-Term Risk of Incident Dementia Subtypes
Authors: Sittichokkananon Arisa , Garfield Victoria , Chiesa Scott T.
Published: July 2024

Background

Shared genetic and lifestyle risk factors may underlie the development of both coronary artery disease (CAD) and dementia. This study aimed to examine if an increased genetic risk for CAD is associated with long-term risk of developing all-cause, Alzheimer’s, or vascular dementia, and investigate whether the presence of healthy lifestyle behaviours in the mid-to-late life period may attenuate this risk.

Methods

A prospective cohort study of 365,782 participants free from dementia for at least 5 years post-baseline assessment was conducted within the UK Biobank study. Genetic risk was assessed using a genome-wide polygenic risk score (PRS) for CAD, and lifestyle risk using a modified version of the American Heart Association’s Life’s Essential 8 Lifestyle Risk Score (LRS). Primary outcomes were incident all-cause, Alzheimer’s, and vascular dementia diagnoses obtained from linked electronic health records. Secondary outcomes were neuroimaging phenotypes with well-established links to future dementia risk measured in 32,592 participants recalled for MRI imaging.

Results

8,870 cases of all-cause dementia were observed over a median 13.9-year follow-up. Higher genetic risk for CAD was associated with an elevated risk of all dementia subtypes (HRs = 1.08-1.16; p<0.001 for all). A higher LRS was associated with a modestly increased risk of all-cause dementia (HR = 1.06 [1.04-1.08]; p < 0.001), with this risk likely arising through increased rates of vascular dementia (HR = 1.22 [1.17-1.28]) as no evidence was found for any associations with Alzheimer’s disease (HR = 0.99 [0.95-1.02]; p = 0.535). Individuals with a combination of high genetic and high lifestyle risk scores for CAD were more than twice as likely to develop vascular dementia during long-term follow-up compared to those with low levels of both. This risk was substantially attenuated in those following healthy lifestyle behaviours at baseline, however, regardless of underlying genetic risk (e.g. HR for low vs high lifestyle risk scores = 1.43 [1.12-1.81] vs. 2.16 [1.73-2.69] respectively in individuals with high genetic risk). In a subset of individuals recalled for neuroimaging assessments, those with high genetic and lifestyle risk for CAD demonstrated a 30% greater volume of white matter hyperintensities than those with low risk, while showing little difference in grey matter or hippocampal volumes.

Conclusions

Individuals who are genetically predisposed to developing CAD also face an increased risk of developing dementia in old age. This risk is reduced in those adopting healthy lifestyle behaviours earlier in the lifespan, however, particularly in those at risk from dementia caused by underlying vascular pathology.
WITHDRAWN: Eligibility for thrombolysis and outcome in pediatric acute ischemic stroke
Authors: Briest Romain C. , Bhatia Kartik D , Miteff Christina , Cheung Andrew , Antony Jayne , Ardern-Holmes Simone , Bye Annie , Cardamone Michael , Chan Denise , Dale Russell , Farrar Michelle , Gill Deepak , Gupta Sachin , Johnson Alexandra , Kandula Tejaswi , Lawson John , Manning Nathan , McCann Karlee , McQuinn Alexander , Menezes Manoj P , Miteff Ferdinand , Pillai Sekhar , Sampaio Hugo , Smith Robert L , Subramanian Gopinath M , Teoh Hooi Ling , Troedson Christopher , Webster Richard , Wenderoth Jason , Whitley Justin , Andrews P. Ian
Published: July 2024

Withdrawal statement

The authors have withdrawn this manuscript because the manuscript has undergone considerable revision, such that this manuscript does not represent the data or interpretation as intended. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
The effect of microbial metabolites from colonic protein fermentation on bacteria-induced cytokine production in dendritic cells
Authors: Xie Zhuqing , Eriksen Danny Blichfeldt , Johnsen Peter Riber , Nielsen Dennis Sandris , Frøkiær Hanne
Published: July 2024

Scope

Compared to the well-defined immune-modulating effect of butyrate, the knowledge of other metabolites from colonic protein fermentation is limited.

Methods and results

The effect of protein-derived metabolites (valerate, branched-chain fatty acids, ammonium, phenol, p-Cresol, indole, and H2S) on cytokine production in murine bone marrow-derived dendritic cells (BMDCs) stimulated with LPS,Lactobacillus acidophilusNCFM, orStaphylococcus aureusUSA300 was investigated. The metabolites modulated the cytokine profile differently and depended on the specific microbial stimulus with short-chain fatty acids (SCFAs) exhibiting the strongest effects and no toxicity. After short-term treatment, SCFAs affected the cytokine profile similar to but weaker than butyrate, reflected by inhibition of IL-12p70 and IL-10 but enhanced IL-23 (LPS andS. aureusUSA300) and IL-1β production. Compared to valerate, butyrate exhibited a stronger and more prompt effect on cytokine gene expression without influencing reactive oxygen species (ROS) formation. Oppositely, long-term treatment with the two SCFAs resulted in similar anti-inflammatory effects, i.e. abrogation of LPS-induced IL-12 and enhancement of IL-10 and the expression of aryl hydrocarbon receptor (Ahr) and LPS-stimulated dual specificity phosphatase 1 (Dusp1).

Conclusion

Our data reveals immune-modulating effects of various protein fermentation metabolites, and valerate in specific holds activities resembling but not identical to butyrate.
Cell-scale gene-expression measurements inVibrio choleraebiofilms reveal spatiotemporal patterns underlying development
Authors: Johnson Grace E. , Fei Chenyi , Wingreen Ned S. , Bassler Bonnie L.
Published: July 2024

Bacteria commonly exist in multicellular, surface-attached communities called biofilms. Biofilms are central to ecology, medicine, and industry. TheVibrio choleraepathogen forms biofilms from single founder cells that, via cell division, mature into three-dimensional structures with distinct, yet reproducible, regional architectures. To define mechanisms underlying biofilm developmental transitions, we establish a single-molecule fluorescence in situ hybridization (smFISH) approach that enables accurate quantitation of spatiotemporal gene-expression patterns in biofilms at cell-scale resolution. smFISH analyses ofV. choleraebiofilm regulatory and structural genes demonstrate that, as biofilms mature, overall matrix gene expression decreases, and simultaneously, a pattern emerges in which matrix gene expression becomes largely confined to peripheral biofilm cells. Both quorum sensing and c-di-GMP-signaling are required to generate the proper temporal pattern of matrix gene expression. Quorum sensing autoinducer levels are uniform across the biofilm, and thus, c-di-GMP-signaling alone sets the regional matrix gene expression pattern. The smFISH strategy provides insight into mechanisms conferring particular fates to individual biofilm cells.
Exploring Harmala Alkaloids as Novel Antimalarial Agents againstPlasmodium falciparumthrough Bioinformatics Approaches
Authors: Dipto Kaushik Zaman , Shariar Raiyan , Saha Chinmoy Kumar , Huzaifa Abir , Robin Tanjin Barketullah , Patil Rajesh B. , Alam Md. Tamzidul , Rafi Md. Irfan Habib , Faruk Ashraf Zaman , Moin Abu Tayab , Zinnah Kazi Md. Ali , Hasanuzzaman Md. , Islam Tofazzal
Published: July 2024

Malaria, caused by thePlasmodium falciparum, remains a significant global health challenge, with Plasmodium falciparum accounting for approximately 50% of cases and posing a considerable threat. Despite advances in control measures, malaria continues to cause an estimated one million deaths annually. The complex lifecycle ofP. falciparum, involving both vertebrate hosts and Anopheles mosquitoes, complicates eradication efforts. The parasite’s resistance to existing antimalarial drugs, along with medication toxicity, necessitates innovative therapeutic approaches.

Recent research has revealed that harmine, an alkaloid produced by an endophytic gut bacterium of Anopheles mosquitoes, can impede the transmission of the malarial parasite to humans by inhibiting a crucial life stage. This study investigates harmala alkaloids, sourced from plants and bacteria such asPeganum harmala, as potential alternatives to conventional antimalarial drugs. Notably, harmine and harmaline have shown promising antimalarial activity by inhibiting the essential enzyme protein kinase 4 (PK4), which is vital for the parasite’s survival. These compounds exhibit lower toxicity, effectively inhibiting both the blood stage growth and transmission of the parasite. Using in silico methodologies, including ADME analysis, molecular docking, MD simulation, and toxicity analysis, this study identifies harmala alkaloids as potential inhibitors against crucialP. falciparumproteins. Targeting proteins essential for the parasite’s survival, similar to established drugs like pfCRT protein, lays the foundation for developing effective antimalarial treatments. The comprehensive screening of harmala alkaloid molecules opens avenues for the pharmaceutical industry to tackle challenges related to drug resistance and toxicity, offering a promising route for the biorational management of malaria.
Cryptic Cryptophytes – revision of the genusGoniomonas
Authors: Sachs Maria , Nitsche Frank , Arndt Hartmut
Published: July 2024

Cryptomonad protists are ubiquitously distributed over marine and freshwater habitats. As an exception to the coloured cryptomonads, the heterotrophic cryptomonads of the genusGoniomonashave an ancestral phylogenetic position. They lack any kind of chloroplast and most likely represent a basal group to those cryptomonad groups having obtained their chloroplast by secondary endosymbiosis. Earlier studies have shown a deep divergence between freshwater and marine clades of goniomonads that comprise large genetic distances between members within the group and also between the two groups of marine and freshwater taxa. Still, marine and freshwater species carry the same genus name, and until up to date only few species have been described. We therefore restructured goniomonad systematics based not only on a separation of marine and freshwater taxa, but, taking the large genetic distances into account, also several new genera are described. Based on morphological as well as phylogenetic data (18S rDNA sequences), this leads to the formation of the freshwater generaLimnogoniomonasn. g.,GoniomonasandAquagoniomonasn. g. and the marine generaNeptunogoniomonasn. g.,Baltigoniomonasn. g.,Marigoniomonasn. g.,Thalassogoniomonasn. g.,Poseidogoniomonasn. g. andCosmogoniomonasn. g. To give the restructuring process a stable basis, we additionally propose a neotype forGoniomonas truncata.
Construction of mirror-image RNA nanostructure for enhanced biostability and drug delivery efficiency
Authors: Zhang Ying , Dantsu Yuliya , Zhang Wen
Published: July 2024

The development of stable and efficient drug delivery systems is crucial for advancing therapeutic applications. Here, we present a novel approach involving the construction of a mirror-image RNA (L-RNA) nanostructure to enhance biostability and drug delivery efficiency. Specifically, we utilized L-RNA to create a three-way junction structure, which was then conjugated with small interfering RNA (siRNA) and chemotherapy agents for targeted drug delivery. Our findings demonstrate that this L-RNA nanostructure significantly improves therapeutic efficiency due to its enhanced stability compared to natural D-RNA. In additionally, the conjugated folic acid (FA) group dramatically enhance the specificity and endosomal escape efficiency of the nanoparticles, which benefit the combinatorial drug delivery. This work highlights the potential of mirror-image RNA nanostructures as robust platforms for drug delivery applications.
PLINDER: The protein-ligand interactions dataset and evaluation resource
Authors: Durairaj Janani , Adeshina Yusuf , Cao Zhonglin , Zhang Xuejin , Oleinikovas Vladas , Duignan Thomas , McClure Zachary , Robin Xavier , Studer Gabriel , Kovtun Daniel , Rossi Emanuele , Zhou Guoqing , Veccham Srimukh , Isert Clemens , Peng Yuxing , Sundareson Prabindh , Akdel Mehmet , Corso Gabriele , Stärk Hannes , Tauriello Gerardo , Carpenter Zachary , Bronstein Michael , Kucukbenli Emine , Schwede Torsten , Naef Luca
Published: July 2024

Protein-ligand interactions (PLI) are foundational to small molecule drug design. With computational methods striving towards experimental accuracy, there is a critical demand for a well-curated and diverse PLI dataset. Existing datasets are often limited in size and diversity, and commonly used evaluation sets suffer from training information leakage, hindering the realistic assessment of method generalization capabilities. To address these shortcomings, we present PLIN-DER, the largest and most annotated dataset to date, comprising 449,383 PLI systems, each with over 500 annotations, similarity metrics at protein, pocket, interaction and ligand levels, and paired unbound (apo) and predicted structures. We propose an approach to generate training and evaluation splits that minimizes task-specific leakage and maximizes test set quality, and compare the resulting performance of DiffDock when retrained with different kinds of splits.
Economic cost of suicide of culturally and linguistically diverse populations in Australia
Authors: Maheen Humaira , Doran Chris
Published: July 2024

Background

Suicide and self-harm pose significant global public health challenges and have substantial economic implications. Recent evidence from Australia has indicated significant variations in the prevalence of suicidal behaviours and mortality among diverse populations. Aim: This study aims to examine the economic cost of suicide among culturally and linguistically diverse (CALD) migrants in Australia.

Methods

We evaluated the economic impact of suicide by considering years of life lost, years of productive life lost, and overall economic costs, including direct, indirect, and intangible costs. We used data on suicide deaths in 2020 from the National Coroners Information System.

Results

The estimated annual economic cost of these suicides is $2.9 billion (in 2023 dollars). The average cost per suicide is $8.04 million for males and $9.23 million for females. The value of a statistical life year is the most significant cost driver, representing 94% of the total economic burden.

Limitation

These estimates do not capture costs associated with suicidal ideation, thoughts or self-harm attempts, which may substantially increase the economic burden.

Conclusion

This study emphasises the significant economic impacts of CALD suicide in Australia and highlights the urgent need for a comprehensive national suicide prevention program tailored for diverse populations.
Designing gram-scale resonators for precision inertial sensors
Authors: Carter Jonathan J. , Birckigt Pascal , Gerberding Oliver , Koehlenbeck Sina M.
Published: July 2024

Recent advances in glass fabrication technology have allowed for the development of high-precision inertial sensors in devices weighing of the order of grams. Gram-scale inertial sensors can be used in many applications with tight space or weight requirements. A key element of these devices’ performance is the behavior of a mechanical resonator. We present a detailed study on the design of resonators for such sensors. First, we consider how the mechanical parameters of a resonator couple with an inertial sensor’s performance. Then, we look at how to geometrically design resonators to achieve specific mechanical behavior without undergoing brittle failure. Both analytic tools and finite element analysis are used to this end. We then derive expressions that can be used to optimize the performance of an inertial sensor for a specific sensitive bandwidth. A simple geometry used throughout the field is studied as an example. However, the results are presented in a general form so that they can be easily adapted to any required geometry and use case. Ultimately, the results presented here guide the design of gram-scale inertial sensors and will improve the performance of devices that follow them.

Published by the American Physical Society
2024
Spin-dependent interactions in orbital-density-dependent functionals: Noncollinear Koopmans spectral functionals
Authors: Marrazzo Antimo , Colonna Nicola
Published: July 2024

The presence of spin-orbit coupling or noncollinear magnetic spin states can have dramatic effects on the ground-state and spectral properties of materials, in particular on the band structure. Here, we develop noncollinear Koopmans-compliant functionals based on Wannier functions and density-functional perturbation theory, targeting accurate spectral properties in the quasiparticle approximation. Our noncollinear Koopmans-compliant theory involves functionals of four-component orbital densities that can be obtained from the charge and spin-vector densities of Wannier functions. We validate our approach on four emblematic nonmagnetic and magnetic semiconductors where the effect of spin-orbit coupling goes from small to very large: the III-IV semiconductor GaAs, the transition-metal dichalcogenide WSe2, the cubic perovskite CsPbBr3, and the ferromagnetic semiconductor CrI3. The predicted band gaps are comparable in accuracy to state-of-the-art many-body perturbation theory and include spin-dependent interactions and screening effects that are missing in standard diagrammatic approaches based on the random phase approximation. While the inclusion of orbital- and spin-dependent interactions in many-body perturbation theory requires self-screening or vertex corrections, they emerge naturally in the Koopmans-functionals framework.

Published by the American Physical Society
2024
Satisfying the needs for highly qualified engineering staff in a disruptively changing aircraft industry with special care for MRO sector
Authors: Ichou Sally , Veress Árpád
Published: July 2024

Purpose

The number of passengers in the aviation sector following COVID-19 has recovered in 2023 and is 5% higher than it was in 2019. The average annual growth of air travel is predicted to be 3.2% between 2019 and 2039. This means the need for aircraft maintenance, repair and overhaul (MRO) services will also increase. Moreover, the stakeholders require lower costs, higher effectiveness/market share and sustainability. These expectations can be realized only with the identification, development and implementation of new innovations while improving and optimizing the already used processes and procedures. Since only highly qualified graduates can reach these requirements, the need for profession-specific MSc and PhD level engineers has elevated significantly. The purpose of this paper is to introduce the development and implementation of a new MRO higher educational framework program in strong cooperation with enterprises and universities.

Design/methodology/approach

The emphasis is placed on the program’s scouting, investigation, development, realization and evaluation by defining key performance indexes and aiming for the optimal solution for all participants.

Findings

The result of this study is the establishment of a new educational framework, the reinvention of the MSc curriculum and the integration of PhD-level researchers in the industry in a way that fulfills the needs and requirements of the MRO sector. In return, it will give various benefits to all parties involved.

Originality/value

The novelty of this work comes from creating a new educational MSc and PhD level framework that can push the MRO industry forward and fill the gap of missing engineers in this field. Plus, the newly developed program is highly flexible and can be used by other players in the economy after making some adaptions and modifications.