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Objective: To compare the pharmacokinetics and efficacy of oral versus intravenous mixed micellar vitamin K prophylaxis in infants with cholestatic liver disease, a known risk factor for vitamin K deficiency bleeding.Design: Prospective randomised controlled study.Setting: Paediatric Liver Unit.Patients: Forty four infants less than 6 months of age with conjugated hyperbilirubinaemia.Main Outcome Measures: Serum concentrations of vitamin K(1) and undercarboxylated prothrombin (PIVKA-II; a sensitive functional indicator of vitamin K status) before and for up to four days after a single dose of mixed micellar K(1) 1 mg intravenously or 2 mg orally. Comparison of K(1) levels 24 hours after oral K(1) with those from 14 healthy newborns given the same dose.Results: At admission, 18 infants (41%) had elevated levels of serum PIVKA-II and eight (18%) had low K(1) concentrations, indicative of subclinical vitamin K deficiency. Median serum K(1) concentrations were similar in the oral and intravenous groups at baseline (0.92 v 1.15 ng/ml), rising to 139 ng/ml six hours after intravenous K(1) but to only 1.4 ng/ml after oral administration. In the latter group, the low median value (0.95 ng/ml) and wide range (< 0.15-111 ng/ml) of serum K(1) compared unfavourably with the much higher levels (median 77, range 11-263 ng/ml) observed in healthy infants given the same oral dose, and suggested impaired and erratic intestinal absorption in cholestatic infants. The severity of malabsorption was such that only 4/24 (17%) achieved an incremental rise in serum K(1) > 10 ng/ml.Conclusions: The intestinal absorption of mixed micellar K(1) is unreliable in infants with conjugated hyperbilirubinaemia. Given the strong association between cholestasis and late vitamin K deficiency bleeding, these data provide an explanation for the failure of some oral vitamin K(1) prophylaxis regimens in infants with latent cholestasis. [ABSTRACT FROM AUTHOR]

Pregnancy may be a challenging period for the maternal systems and has been regarded as a stress test, as imperceptible/mild dysfunctions eventually present may be exacerbated during this period. The cardiovascular system is no exception, and several morphological and functional adaptations accompanying pregnancy have been described. However, long-term pregnancy-induced cardiac molecular alterations remain highly unexplored. The postpartum is marked by reverse remodeling of the pregnancy-induced cardiovascular adaptations, representing a possible critical period for assessing future maternal cardiovascular health. The current study explored the molecular and metabolic alterations in the cardiac tissue eight weeks after a physiological uncomplicated pregnancy. Female Sprague-Dawley rats were fed a chow diet through pregnancy, lactation, and weaning and compared to their non-pregnant counterparts. Eight weeks postpartum, increased levels of the phosphorylated form of AMPKα (Thr172) and its ratio to total AMPKα indicated possible alterations in cardiac metabolic flexibility, accompanied by increased Pparα and Hif1α transcripts levels. Additionally, postpartum hearts exhibited higher mitochondrial ATP and NADH levels without major changes in mitochondrial respiratory function. Elevated Nrf2 levels in the cardiac tissue suggested potential implications for cardiac redox balance, further supported by increased levels or activity of proteins directly regulated by Nrf2. The findings herein reported suggest that at eight weeks postpartum, molecular alterations induced by pregnancy, especially regarding redox balance, are still observed in the mothers' heart. These alterations present at late postpartum may open new avenues to understand the different risk for cardiovascular complications development after normal pregnancies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paulo J. Oliveira reports financial support was provided by European Commission. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Weakly-supervised semantic segmentation (WSSS) methods, reliant on image-level labels indicating object presence, lack explicit correspondence between labels and regions of interest (ROIs), posing a significant challenge. Despite this, WSSS methods have attracted attention due to their much lower annotation costs compared to fully-supervised segmentation. Leveraging reinforcement learning (RL) self-play, we propose a novel WSSS method that gamifies image segmentation of a ROI. We formulate segmentation as a competition between two agents that compete to select ROI-containing patches until exhaustion of all such patches. The score at each time-step, used to compute the reward for agent training, represents likelihood of object presence within the selection, determined by an object presence detector pre-trained using only image-level binary classification labels of object presence. Additionally, we propose a game termination condition that can be called by either side upon exhaustion of all ROI-containing patches, followed by the selection of a final patch from each. Upon termination, the agent is incentivised if ROI-containing patches are exhausted or disincentivised if a ROI-containing patch is found by the competitor. This competitive setup ensures minimisation of over- or under-segmentation, a common problem with WSSS methods. Extensive experimentation across four datasets demonstrates significant performance improvements over recent state-of-the-art methods. Code: https://github.com/s-sd/spurl/tree/main/wss.

Background: Therapy adherence is a key factor in the control of type 2 diabetes mellitus (T2DM). Optimal self-care requires skills in health literacy (HL)., Objective: This study aims to analyze the relationship between HL and adherence to therapy and to understand the possible influence of other sociodemographic and disease variables., Methods: A multicenter, cross-sectional study was conducted in Portuguese in 13 different primary health care units in both rural and urban environments. A sociodemographic questionnaire and two validated instruments, "Medical Term Recognition Test" and "Summary of Diabetes Self-Care Activities," were applied. The last value of hemoglobin A1c (HbA1c) and the number of chronic medications were collected from clinical records. Descriptive statistics and bivariate correlations were performed as well as multivariable linear regression to assess the association between HL and adherence to therapy., Key Results: Participants (n = 354) were on average age 63.67 ± 10.39 years, 57.1% male and 42.9% female, 68.4% with inadequate HL and an average HbA1c of 7 ± 1.18%. Better HL was correlated with higher adherence to the total of self-care activities, nonpharmacological therapy, and foot care. In multivariable linear regression analyses, better HL ( β = 0.176, p = .003), less than minimum wage (β = -0.197, p = .001) and insulin therapy ( β = 0.272, p = .001) were independently associated with increased adherence to overall self-care activities., Conclusion: In a representative sample of people with T2DM in Portugal, HL was a key factor for greater adherence to demanding self-care activities. [ HLRP: Health Literacy Research and Practice . 2024;8(4):e194-e203. ].

Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. Up to now, no specific screening or diagnostic tests are available for early PDAC detection. As a result, most patients are diagnosed with advanced or metastatic disease, which leads to a poor prognosis. In this study, we aimed to evaluate the diagnostic value of urinary CRP (uCRP) alone and in combination with our previously established urine biomarker panel (REG1B, LYVE1 and TFF1) for early detection of PDAC. A total of 534 urine samples from multiple centres were analysed: 93 from healthy individuals, 265 from patients with benign hepatobiliary diseases and 176 from PDAC patients. The uCRP and the urinary biomarker panel were assessed using commercial ELISA assays, while plasma CA19-9 and blood CRP (bCRP) were measured using Roche Cobas platform. Multiple logistic regression and nonparametric Kruskal-Wallis test were used for statistical analysis. An internal validation approach was applied, and the validated AUC estimators were reported to ensure accuracy. A significant difference was observed in the medians of uCRP between healthy and benign controls and PDAC sample groups (p < 0.001). uCRP levels were not dependent on gender and age, as well as cancer stage. When uCRP was combined with the urinary biomarker panel, it achieved AUCs of 0.878 (95% CI: 0.802-0.931), 0.798 (95% CI: 0.738-0.859) and 0.813 (95% CI: 0.758-0.869) in healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC sample groups, respectively. However, adding plasma CA19-9 to the urinary biomarker panel yielded a better performance, with AUCs of 0.978 (95% CI: 0.959-0.996), 0.911 (95% CI: 0.873-0.949) and 0.919 (95% CI: 0.883-0.955) in the healthy vs PDAC, benign vs PDAC and healthy and benign vs PDAC comparisons, respectively. In conclusion, we show that measuring CRP in urine is a feasible analytical method, and that uCRP could potentially be a promising biomarker in various diseases including other cancer types., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ali, Debernardi, Kurotova, Tajbakhsh, Gupta, Pandol, Wilson, Pereira, Greenhalf, Blyuss and Crnogorac-Jurcevic.)

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19-9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers. Using a selected patient cohort with benign pancreatic and biliary tract conditions we aimed to develop a data analysis protocol leading to a biomarker signature capable of distinguishing patients with non-specific yet concerning clinical presentations, from those with PDAC., Methods: 539 patient serum samples collected under the Accelerated Diagnosis of neuro Endocrine and Pancreatic TumourS (ADEPTS) study (benign disease controls and PDACs) and the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, healthy controls) were screened using the Olink Oncology II panel, supplemented with five in-house markers. 16 specialized base-learner classifiers were stacked to select and enhance biomarker performances and robustness in blinded samples. Each base-learner was constructed through cross-validation and recursive feature elimination in a discovery set comprising approximately two thirds of the ADEPTS and UKCTOCS samples and contrasted specific diagnosis with PDAC., Results: The signature which was developed using diagnosis-specific ensemble learning demonstrated predictive capabilities outperforming CA19-9, the only biomarker currently accepted by the FDA and the National Comprehensive Cancer Network guidelines for pancreatic cancer, and other individual biomarkers and combinations in both discovery and held-out validation sets. An AUC of 0.98 (95% CI 0.98-0.99) and sensitivity of 0.99 (95% CI 0.98-1) at 90% specificity was achieved with the ensemble method, which was significantly larger than the AUC of 0.79 (95% CI 0.66-0.91) and sensitivity 0.67 (95% CI 0.50-0.83), also at 90% specificity, for CA19-9, in the discovery set (p = 0.0016 and p = 0.00050, respectively). During ensemble signature validation in the held-out set, an AUC of 0.95 (95% CI 0.91-0.99), sensitivity 0.86 (95% CI 0.68-1), was attained compared to an AUC of 0.80 (95% CI 0.66-0.93), sensitivity 0.65 (95% CI 0.48-0.56) at 90% specificity for CA19-9 alone (p = 0.0082 and p = 0.024, respectively). When validated only on the benign disease controls and PDACs collected from ADEPTS, the diagnostic-specific signature achieved an AUC of 0.96 (95% CI 0.92-0.99), sensitivity 0.82 (95% CI 0.64-0.95) at 90% specificity, which was still significantly higher than the performance for CA19-9 taken as a single predictor, AUC of 0.79 (95% CI 0.64-0.93) and sensitivity of 0.18 (95% CI 0.03-0.69) (p = 0.013 and p = 0.0055, respectively)., Conclusion: Our ensemble modelling technique outperformed CA19-9, individual biomarkers and indices developed with prevailing algorithms in distinguishing patients with non-specific but concerning symptoms from those with PDAC, with implications for improving its early detection in individuals at risk., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: UM reports stock ownership in Abcodia UK between 2011 and 2021; UM has received grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), the India Alliance, NIHR Biomedical Research Centre at University College London Hospital, and The Eve Appeal; UM currently has research collaborations with iLOF, RNA Guardian and Micronoma, with funding paid to UCL; UM holds patent number EP10178345.4 for Breast Cancer Diagnostics; AG currently has research collaborations with Micronoma and iLoF, with the research funding awarded to UCL. The other authors have declared that no competing interests exist., (Copyright: © 2024 Ney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Obesity during pregnancy has been escalating, becoming a huge problem that poses consequences not only for the health of the offspring but also for the maternal well-being. Women's adipose and hepatic tissue metabolism undergoes significant changes during the gestational period. During pregnancy, obesity is a primary instigator of steatosis, increasing the risk of non-alcholic fatty liver disease (NAFLD), now recognized under the updated nomenclature metabolic dysfunction-associated steatotic liver disease (MASLD). Pregnant women with obesity present higher levels of free fatty acids and glucose, reduction in insulin sensitivity, and adipose tissue endocrine dysregulation. Furthermore, obesity-induced modifications in clock genes and lipid-associated gene expression within adipose tissue disrupt crucial metabolic adaptations, potentially culminating in adipose tissue dysfunction. Thus, the liver experiences increased exposure to free fatty acids through the portal vein. Higher uptake of free fatty acids into the liver disrupts hepatic lipid oxidation while enhances lipogenesis, thereby predisposing to ectopic fat deposition within the liver. This review focuses on the obesity-induced changes during pregnancy in both liver and adipose tissue metabolism, elucidating how the metabolic crosstalk between these two organs can be dysregulated in pregnant women living with obesity., (© 2024 The Author(s).)

Guatteria olivacea R.E. Fries is an Amazonian species known as 'envira-bobó' and 'envira-fofa' and is common in the states of Amazonas, Acre, and Pará. Recently, the essential oil from the leaves of this species has shown promising antitumor activity both in vitro and in vivo. The presence of isoquinoline-derived alkaloids, including aporphinoids and tetrahydroprotoberberine alkaloids, has also been previously reported. In our ongoing search for bioactive compounds from Annonaceae Amazonian plants, the bark of G. olivacea was investigated via classical chromatography techniques, which revealed nine compounds, eight isoquinoline-derived alkaloids, a rare alkaloid with a α -gem-dimethyltetradehydrocularine structure known as gouregine, seven known aporphinoid alkaloids: isopiline, O -methylisopiline, melosmine, 9-hydroxyiguattescine, dihydromelosmine, lysicamine, and guattouregidine, and one known pimaradiene diterpene: acanthoic acid. All the isolated compounds were described for the first time in the bark of G. olivacea, and their structures were elucidated by extensive analyses of their 1D and 2D NMR spectra in combination with MS data. The NMR data of the alkaloids isopiline, O -methylisopiline, melosmine, dihydromelosmine, and guattouregidine were revised due to incomplete data in the literature and some ambiguities. The in vitro cytotoxic activities of the isolated compounds were evaluated against human cancer (HepG2, KG-1a, and HCT116) and noncancerous (MRC-5) cell lines via the Alamar blue assay after 72 h of incubation. Among the compounds evaluated against human cancer cell lines, the most active was the oxoaporphine alkaloid lysicamine, which has strong activity against HCT116 cells, with an IC 50 value of 6.64 µg/mL (22.79 µmol/L). Melosmine had a moderate effect on HCT116 cells, with an IC 50 value of 16.77 µg/mL (49.70 µmol/L), whereas acanthoic acid had moderate effects on HepG2 and HCT116 cells, with IC 50 values of 14.63 µg/mL (48.37 µmol/L) and 21.25 µg/mL (70.25 µmol/L), respectively.