bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Signature of Insulin Resistance and Risk of Alzheimer’s Disease
Authors: Gutierrez-Tordera Laia , Panisello Laura , García-Gonzalez Pablo , Ruiz Agustín , Cantero José Luis , Rojas-Criollo Melina , Mursil Muhammad , Atienza Mercedes , Novau-Ferré Nil , Mateu-Fabregat Javier , Mostafa Hamza , Puig Domènec , Folch Jaume , Rashwan Hatem , Marquié Marta , Boada Mercè , Papandreou Christopher , Bulló Mònica 
Published: November 2024

Abstract

Background
Substantial evidence supports the relationship between peripheral insulin resistance (IR) and the development of Alzheimer’s disease (AD)-dementia. However, the mechanisms explaining these associations are only partly understood. We aimed to identify a metabolic signature of IR associated with the progression from mild cognitive impairment (MCI) to AD-dementia.

Methods
This is a case-control study on 400 MCI subjects, free of type 2 diabetes, within the ACE cohort, including individuals ATN + and ATN−. After a median of 2.1 years of follow-up, 142 subjects converted to AD-dementia. IR was assessed using the homeostasis model assessment for insulin resistance (HOMA-IR). A targeted multiplatform approach profiled over 600 plasma metabolites. Elastic net penalized linear regression with 10-fold cross-validation was employed to select those metabolites associated with HOMA-IR. The prediction ability of the signature was assessed using support vector machine and performance metrics. The metabolic signature was associated with AD-dementia risk using a multivariable Cox regression model. Using counterfactual-based mediation analysis, we investigated the mediation role of the metabolic signature between HOMA-IR and AD-dementia. The metabolic pathways in which the metabolites were involved were identified using MetaboAnalyst.

Results
The metabolic signature comprised 18 metabolites correlated with HOMA-IR. After adjustments by confounders, the signature was associated with increased AD-dementia risk (HR = 1.234; 95% CI = 1.019–1.494; p &lt; .05). The metabolic signature mediated 35% of the total effect of HOMA-IR on AD-dementia risk. Significant metabolic pathways were related to glycerophospholipid and tyrosine metabolism.

Conclusions
We have identified a blood-based metabolic signature that reflects IR and may enhance our understanding of the biological mechanisms through which IR affects AD-dementia.
A performance measure framework for ecosystem-based management
Authors: Haugen Janne B , Link Jason S , Fulton Elizabeth A , Dickey-Collas Mark , Brainard Rusty E , Bundy Alida 
Published: November 2024

Abstract
Effective management of ocean resources is crucial for achieving desired ecological, economic, and social outcomes. Marine ecosystem-based management (EBM) offers a comprehensive approach to achieve these goals, yet its implementation has been challenging and its effectiveness has been unclear. Therefore, we need performance measures to assess the effectiveness of EBM strategies. We developed a semi-quantitative assessment framework using existing indicators and performance measures from the business and project management world (e.g. Key Performance Indicators; KPIs), national and regional economic and social wellbeing performance measures (e.g. GDP, food security), and ecosystem status assessments (e.g. overfishing, biodiversity) to evaluate the success and performance of EBM outcomes. The framework consists of four main categories: (1) sector performance; (2) marine ecosystem status; (3) management and tradeoffs; and (4) human dimensions, each flexible enough to accommodate suitable indicators and reference points. We show how the framework responds to real case studies from Southern New England, the Gulf of Maine, and the Hawaiian Islands, USA; the Baltic Sea; and the Red Sea, Saudi Arabia. The main observation from these performance measures is that higher scores in the management and tradeoffs consideration correlate with higher scores in the marine ecosystem status. Additionally, higher human dimensions scores tend to lead to higher sectoral performance scores. Although it is not certain that one leads to the other, this suggests that EBM is functioning as intended. The framework results show that there are many possible indicators, performance targets, and associated desired directionalities that can be combined to form possible performance measures across combined ocean-use sectors to inform EBM. The challenge lies in using these different operational indicators to assess the strengths and weaknesses of EBM approaches.
30+ Years of European Social Dialogue: What Way Forward After the EPSU-Case?
Authors: Copeland Paul , ter Haar Beryl 
Published: November 2024

Abstract
For 30+ years the European Social Dialogue (ESD) has been an important part of European Union law-making in the field of social policy, which makes it a good moment to look back, but mostly to look forward. The latter, especially after the rulings in the EPSU-case, which were criticised as meaning the end of the European Social Dialogue. The aim of our contribution is therefore to interrogate and assess the future of the ESD through an empirically grounded analyses of ESD and its dynamic relationship to the evolutionary process of European integration. Our conclusion is that in terms of input and output legitimacy, the ESD can improve, especially by building coalitions, and by improving the quality of their output by applying the Better Regulation principles to their agreements. Both activities would lead to the further maturing of their autonomy and might lead to a greater respect for horizontal subsidiarity by the Commission.
Longitudinal analysis of blood pressure control and influencing factors among 32 701 primary care hypertensive patients with or without diabetes: a prospective cohort study in Jianye District, China
Authors: Zhang Xia , Jiang Na , Zhang Ming , Ni Xiaoyan , Fan Lijun , Du Wei , Xue Hui 
Published: November 2024

Abstract

Background
We aimed to explore the variation in blood pressure (BP) control in primary care hypertensive patients with or without diabetes, and investigate potential factors associated with inadequate BP control during follow-up.

Methods
Primary care hypertensive patients with and without diabetes were recruited in 2020 from Jianye District of Nanjing and prospectively followed up until 2023. Effective BP control was measured in terms of consistent normal readings of systolic BP &lt;140 mmHg and of diastolic BP &lt;90 mmHg based on the most recent assessment during the follow-up period. We used the negative binomial model with total person-years as an offset to evaluate whether the study population would achieve BP control after the 3-y follow-up period in terms of rate ratio (RR) and 95% CI. We further conducted subgroup analysis based on the absence or presence of clinically confirmed diabetes and BP stability at baseline.

Results
Of a total of 32 701 patients with hypertension, compared with those without comorbid diabetes and stable BP at baseline, patients with comorbid diabetes and unstable BP at baseline were less likely to have effective BP control at follow-up (adjusted RR=2.01, 95% CI 1.89 to 2.15). We observed an elevated risk of ineffective BP control at follow-up in those aged 60–70 y (1.69; 95% CI 1.56 to 1.83) or ≥70 y (1.73; 95% CI 1.59 to 1.88), females (1.09; 95% CI 1.03 to 1.16), those with a higher waist-to-height ratio (1.25; 95% CI 1.17 to 1.34), overweight/obese in terms of body mass index (1.16; 95% CI 1.09 to 1.23) or regularly consuming alcohol (1.26; 95% CI 1.16 to 1.37). Higher educational attainment indicated a reduced risk of ineffective BP control at follow-up (0.68; 95% CI 0.63 to 0.75).

Conclusions
Achieving effective BP control remains a persistent challenge, especially for patients with comorbid hypertension and diabetes. In the absence of any novel strategies for hypertension care, the existing multidisciplinary care approaches could be repurposed and integrated for effective management of the aforementioned comorbid conditions in primary care settings.
Perception, practice and associated factors of labour pain management among obstetric care providers in public health facilities in Harari Region, Ethiopia: a multicentre cross-sectional study
Authors: Wondimu Loza , Bekana Miressa , Tura Abera Kenay , Getachew Tamirat 
Published: November 2024

Abstract

Background
Although providing relief from labour pain can improve the mother's satisfaction with the birthing process and lead to better reproductive outcomes. This study aims to evaluate the perceptions, practices and related aspects of labour pain management among obstetric care providers in public health institutions in the Harari Region of Ethiopia.

Methods
A cross-sectional study was conducted in the labour and delivery wards of public health facilities in the Harari Region. Data were collected using a semi-structured and pretested self-administered questionnaire among systematically selected obstetrics care providers (OCPs). A multivariate logistic regression model was used to identify factors associated with the practice of labour pain management. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to determine the strength of associations and a p-value &lt;0.05 was considered significantly associated.

Results
Data from 234 OCPs were employed for analysis. A total of 70.9% of OCPs have positive perceptions and 69.7% practiced labour pain management in the past 4 weeks. Being a female (adjusted OR [aOR] 2.33 [95% CI 1.06 to 5.15]), having a positive perception (aOR 7.76 [95% CI 3.21 to 18.72]), being a physician (aOR 6.35 [95% CI 1.94 to 20.82]), being a midwife (aOR 5.28 [95% CI 1.78 to 15.63]) and being a highly qualified OCP (aOR 17.89 [95% CI 5.22 to 61.30]) were associated with being more likely to practice labour pain management. Positive attitude (aOR 2.77 [95% CI 1.51 to 8.72]), being a physician (aOR 6.01 [95% CI 1.23 to 29.35]) and practicing labour pain management (aOR 12.89 [95% CI 4.57 to 36.38]) were associated with labour pain management perceptions.

Conclusions
Seven of ten OCPs practiced labour pain relief methods and had a positive perception of managing labour pain. Therefore, facilitating training and improving the perceptions and attitudes of OCPs towards labour pain management should be encouraged.
Modeling and feasibility of a pharmacotherapeutic follow-up service for psychiatric patients in secondary care: a pilot study
Authors: da Silva Lima Camila , Lacerda Barreto Joslene , Denisson Maurício Viana Max , Alves Izabel Almeida 
Published: November 2024

Abstract

Background
Patients with severe mental disorders lack pharmacotherapy monitoring in public outpatient clinics in Brazil.

Objective
To test a model of pharmacotherapeutic follow-up for patients with severe mental disorders and to verify its feasibility.

Methods
The study was divided into three phases: (1) definition of a practice model for the pharmacotherapeutic follow-up service, (2) testing the model with regular consultations, and (3) evaluating the outcomes. The service model was adapted from the Brazilian Ministry of Health guidelines and was evaluated by comparing results before and after the pharmacotherapeutic follow-up.

Results
The study began with 27 participants and concluded with 10. The feasibility of the service exceeded the goal, corresponding to 81.5%. The pharmacotherapeutic follow-up increased medication adherence, as indicated by the MAT scores (initial 4.44 ± 0.681 and final 5.22 ± 0.572, [P = .020]), and minimized anxiety symptoms, as indicated by the GAD-7 scores (initial 12.4 ± 4.40 and final 7.0 ± 4.76, [P = .004]). In addition, there was a reduction in the complexity of pharmacotherapy, drug-related problems, and potential drug interactions.

Conclusion
The study concluded that the service was feasible, as evidenced by consistent attendance. Moreover, postintervention evaluation showed positive outcomes for medication adherence and anxiety reduction. Thus, the implementation of this service in the studied setting is satisfactory for meeting the needs of patients with severe mental disorders.
Comparison of basic lymphocyte phenotype results between a diagnostic and a research laboratory
Authors: Aziz Najib , LaBelle Erik , Jamieson Beth D , Mimiaga Matthew J , Detels Roger 
Published: November 2024

Abstract

Objective
Lymphocyte phenotyping is a valuable tool for monitoring the effects of antiretroviral therapy on individuals living with HIV-1. A switch study was conducted to compare T-cell subset quantification performed by a research laboratory and a diagnostic, laboratory to understand the impact on the retrospective and prospective results of a long-term study.

Methods
Using FACSCanto II Flow Cytometers, EDTA anticoagulated peripheral blood from 73 males enrolled in the Multicenter AIDS Cohort Study/Women Interagency HIV Combined Cohort Study was analyzed by both a research (laboratory 1) and a diagnostics laboratory (laboratory 2) for quantification of cluster of differentiation (CD)3, CD4, and CD8 T-cells. There were 47 males living with and 26 living without HIV-1.

Results
Bland-Altman (B-A) analysis was applied to assess the agreement between laboratory 1 and laboratory 2 results. There were 69 out of 73 CD3, 71 out of 73CD4, and 72 out of 73 CD8 T-cell results that fell within acceptable B-A limits of agreement. The mean differences between the 2 laboratories were –1.000, –0.945, and +0.685(%), respectively.

Conclusion
The strong agreement between results from laboratory 1 and laboratory 2 for CD3, CD4, and CD8 T-cell percentage suggests that the difference between laboratories using the same instrumentation and methodology will have a minimal effect on long-term study results.
Remarkable Evolutionary Rate Variations Among Lineages and Among Genome Compartments in Malaria Parasites of Mammals
Authors: Abu-Elmakarem Hend , MacLean Oscar A , Venter Frank , Plenderleith Lindsey J , Culleton Richard L , Hahn Beatrice H , Sharp Paul M 
Published: November 2024

Abstract
Genes encoded within organelle genomes often evolve at rates different from those in the nuclear genome. Here, we analyzed the relative rates of nucleotide substitution in the mitochondrial, apicoplast, and nuclear genomes in four different lineages of Plasmodium species (malaria parasites) infecting mammals. The rates of substitution in the three genomes exhibit substantial variation among lineages, with the relative rates of nuclear and mitochondrial DNA being particularly divergent between the Laverania (including Plasmodium falciparum) and Vivax lineages (including Plasmodium vivax). Consideration of synonymous and nonsynonymous substitution rates suggests that their variation is largely due to changes in mutation rates, with constraints on amino acid replacements remaining more similar among lineages. Mitochondrial DNA mutation rate variations among lineages may reflect differences in the long-term average lengths of the sexual and asexual stages of the life cycle. These rate variations have far-reaching implications for the use of molecular clocks to date Plasmodium evolution.
There will always be variants of uncertain significance. Analysis of VUSs
Authors: Zhang Haoyang , Kabir Muhammad , Ahmed Saeed , Vihinen Mauno 
Published: November 2024

Abstract
The ACMG/AMP guidelines include five categories of which variants of uncertain significance (VUSs) have received increasing attention. Recently, Fowler and Rehm claimed that all or most VUSs could be reclassified as pathogenic or benign within few years. To test this claim, we collected validated benign, pathogenic, VUS and conflicting variants from ClinVar and LOVD and investigated differences at gene, protein, structure, and variant levels. The gene and protein features included inheritance patterns, actionability, functional categories for housekeeping, essential, complete knockout, lethality and haploinsufficient proteins, Gene Ontology annotations, and protein network properties. Structural properties included the location at secondary structural elements, intrinsically disordered regions, transmembrane regions, repeats, conservation, and accessibility. Gene features were distributions of nucleotides, their groupings, codons, and location to CpG islands. The distributions of amino acids and their groups were investigated. VUSs did not markedly differ from other variants. The only major differences were the accessibility and conservation of pathogenic variants, and reduced ratio of repeat-locating variants in VUSs. Thus, all VUSs cannot be distinguished from other types of variants. They display one form of natural biological heterogeneity. Instead of concentrating on eradicating VUSs, the community would benefit from investigating and understanding factors that contribute to phenotypic heterogeneity.
Oral dysbiosis initiates periodontal disease in experimental kidney disease
Authors: Randall David , Alsam Asil , Kieswich Julius , Joseph Susan , Aduse-Opoku Joseph , Swann Jonathan , Boyde Alan , Davis Graham , Mills David , McCafferty Kieran , Curtis Michael , Yaqoob Muhammed M 
Published: November 2024

ABSTRACT

Background and hypothesis
It is presently unclear why there is a high prevalence of periodontal disease in individuals living with chronic kidney disease. Whilst some have argued that periodontal disease causes chronic kidney disease, we hypothesized that alterations in saliva and the oral microenvironment in organisms with kidney disease may initiate periodontal disease by causing dysbiosis of the oral microbiota.

Methods
Experimental kidney disease was created using adenine feeding and subtotal nephrectomy in rats, and by adenine feeding in mice. Loss of periodontal bone height was assessed using a dissecting microscope supported by micro-CT, light, confocal and electron microscopy, and immunohistochemistry. Salivary biochemistry was assessed using NMR spectroscopy. The oral microbiome was evaluated using culture-based and molecular methods, and the transmissibility of dysbiosis was assessed using co-caging and microbial transfer experiments into previously germ-free recipient mice.

Results
We demonstrate that experimental kidney disease causes a reproducible reduction of alveolar bone height, without gingival inflammation or overt hyperparathyroidism but with evidence of failure of bone formation at the periodontal crest. We show that kidney disease alters the biochemical composition of saliva and induces progressive dysbiosis of the oral microbiota, with microbial samples from animals with kidney disease displaying reduced overall bacterial growth, increased alpha diversity, reduced abundance of key components of the healthy oral microbiota such as Streptococcus and Rothia, and an increase in minor taxa including those from gram-negative phyla Proteobacteria and Bacteroidetes. Co-housing diseased rats with healthy ones ameliorates the periodontal disease phenotype, whilst transfer of oral microbiota from mice with kidney disease causes periodontal disease in germ-free animals with normal kidney function.

Conclusions
We advocate that periodontal disease should be regarded as a complication of kidney disease, initiated by oral dysbiosis through mechanisms independent of overt inflammation or hyperparathyroidism.
The uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) may enhance eryptosis and increase erythrocyte osmotic fragility through potential activation of Piezo1
Authors: Van Spitzenbergen Beatriz Akemi Kondo , Andrade Gabriela Bohnen , Dias Erika Sousa , Alegre Júlia Bacarin Monte , Dias Gabriela Ferreira , Grobe Nadja , Moreno-Amaral Andrea Novais , Kotanko Peter 
Published: November 2024

Abstract

Background and hypothesis
In patients with advanced chronic kidney disease (CKD), the lifespan of red blood cells (RBC) is often shortened, a condition attributed to the “uremic milieu.” We reported recently that the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) shares structural similarities with Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, whose activation increases calcium influx into cells. Against this backdrop, we hypothesized that CMPF may induce premature RBC death (eryptosis) through prolonged CMPF-induced activation of Piezo1 located on RBC. To test this hypothesis, we explored if CMPF, at concentrations found in uremia, interacts with Piezo1 located on RBC, increases intracellular calcium (icCa2+), and induces eryptosis.

Methods
RBC from healthy individuals were incubated with CMPF or Jedi1 (both at a concentration of 87 µM), in the presence or absence of the Piezo1 inhibitor GsMTx-4 (2 µM). We challenged RBC osmotically through incubation in solutions of NaCl at concentrations between 3.0 and 9.0 g/L and determined their osmotic fragility. Using flow cytometry, we quantified in incubated RBC icCa2+ levels and phosphatidylserine exposure, a cellular marker of eryptosis.

Results
Incubation of RBC with CMPF and Jedi1 significantly increased RBC osmotic fragility, an effect prevented by GsMTx-4. At 6.0 g/L NaCl, incubation with CMPF and Jedi1 increased exposure of phosphatidylserine and elevated icCa2+ levels of RBC, indicating increased eryptosis. Notably, at an isotonic NaCl concentration of 9.0 g/L, CMPF - but not Jedi1 - significantly increased RBC phosphatidylserine exposure and icCa2+ levels; both effects were diminished by GsMTx-4.

Conclusion
Our findings support the hypothesis that CMPF may function as an endogenous activator of Piezo1, increase icCa2+ levels, trigger eryptosis, and, through this pathway, possibly shorten the RBC life span. To what extent these in vitro findings are operative in advanced CKD warrants clinical studies.
G-quadruplex stabilizer CX-5461 effectively combines with radiotherapy to target α-thalassemia/mental retardation X-linked-deficient malignant glioma
Authors: Dharmaiah Sharvari , Malgulwar Prit Benny , Johnson William E , Chen Brandon A , Sharin Vladislav , Whitfield Benjamin T , Alvarez Christian , Tadimeti Vasudev , Farooqi Ahsan S , Huse Jason T 
Published: November 2024

Abstract

Background
Inactivation of α-thalassemia/mental retardation X-linked (ATRX) represents a defining molecular feature in large subsets of malignant glioma. ATRX deficiency gives rise to abnormal G-quadruplex (G4) DNA secondary structures, enhancing replication stress and genomic instability. Building on earlier work, we evaluated the extent to which pharmacological G4 stabilization selectively enhances DNA damage and cell death in ATRX-deficient preclinical glioma models.

Methods
Using the G4 stabilizer CX-5461, we treated patient-derived glioma stem cells (GSCs) in vitro and GSC flank and intracranial murine xenografts in vivo to evaluate efficacy as both a single agent and in combination with ionizing radiation (IR), the latter a central element of current treatment standards.

Results
CX-5461 promoted dose-sensitive lethality in ATRX-deficient GSCs relative to ATRX-intact controls. Mechanistic studies revealed that CX-5461 disrupted histone variant H3.3 deposition, enhanced replication stress and DNA damage, activated p53-independent apoptosis, and induced G2/M arrest to a greater extent in ATRX-deficient GSCs than in ATRX-intact counterparts. These data were corroborated in vivo, where CX-5461/IR treatment profoundly delayed tumor growth and prolonged survival in mice bearing ATRX-deficient flank xenografts. Histopathological analyses revealed decreased proliferation, increased apoptosis, and significant G4 induction, replication stress, and DNA damage in CX-5461-treated tumors, both alone and in combination with IR. Finally, despite suboptimal blood-brain-barrier penetration, systemic CX-5461 treatment induced tangible pharmacodynamic effects in ATRX-deficient intracranial GSC models.

Conclusions
In totality, our work substantively demonstrates efficacy and defines mechanisms of action for G4 stabilization as a novel therapeutic strategy targeting ATRX-deficient malignant glioma, laying the groundwork for clinical translation.