bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute oral digoxin in healthy adults hastens fatigue and increases plasma K+ during intense exercise, despite preserved skeletal muscle Na+,K+‐ATPase
Authors: Atanasovska Tania , Farr Trevor , Smith Robert , Petersen Aaron C. , Garnham Andrew , Andersen Mitchell J. , Krum Henry , Wong Chiew , McKenna Michael J. 
Published: November 2024

AbstractWe investigated acute effects of the Na+,K+‐ATPase (NKA) inhibitor, digoxin, on muscle NKA content and isoforms, arterial plasma [K+] ([K+]a) and fatigue with intense exercise. In a randomised, crossover, double‐blind design, 10 healthy adults ingested 0.50 mg digoxin (DIG) or placebo (CON) 60 min before cycling for 1 min at 60% then at 95% until fatigue. Pre‐ and post‐exercise muscle biopsies were analysed for [3H]‐ouabain binding site content without (OB‐Fab) and after incubation in digoxin antibody (OB+Fab) and NKA α1‐2 and β1‐2 isoform proteins. In DIG, pre‐exercise serum [digoxin] reached 3.36 (0.80) nM [mean (SD)] and muscle NKA–digoxin occupancy was 8.2%. Muscle OB‐Fab did not differ between trials, whereas OB+Fab was higher in DIG than CON (8.1%, treatment main effect, P = 0.001), whilst muscle NKA α1‐2 and β1‐2 abundances were unchanged by digoxin. Fatigue occurred earlier in DIG than CON [−7.7%, 2.90 (0.77) vs. 3.14 (0.86) min, respectively; P = 0.037]. [K+]a increased during exercise until 1 min post‐exercise (P = 0.001), and fell below baseline at 3–10 (P = 0.001) and 20 min post‐exercise (P = 0.022, time main effect). In DIG, [K+]a (P = 0.035, treatment effect) and [K+]a rise pre‐fatigue were greater [1.64 (0.73) vs. 1.55 (0.73), P = 0.016], with lesser post‐exercise [K+]a decline than CON [−2.55 (0.71) vs. −2.74 (0.62) mM, respectively, P = 0.003]. Preserved muscle OB‐Fab with digoxin, yet increased OB+Fab with unchanged NKA isoforms, suggests a rapid regulatory assembly of existing NKA α and β subunits exists to preserve muscle NKA capacity. Nonetheless, functional protection against digoxin was incomplete, with earlier fatigue and perturbed [K+]a with exercise.
imageKey points
Intense exercise causes marked potassium (K+) shifts out of contracting muscle cells, which may contribute to muscle fatigue.
Muscle and systemic K+ perturbations with exercise are largely regulated by increased activity of Na+,K+‐ATPase in muscle, which can be specifically inhibited by the cardiac glycoside, digoxin.
We found that acute oral digoxin in healthy adults reduced time to fatigue during intense exercise, elevated the rise in arterial plasma K+ concentration during exercise and slowed K+ concentration decline post‐exercise.
Muscle functional Na+,K+‐ATPase content was not reduced by acute digoxin, despite an 8.2% digoxin occupancy, and was unchanged at fatigue. Muscle Na+,K+‐ATPase isoform protein abundances were unchanged by digoxin or fatigue. These suggest possible rapid assembly of existing subunits into functional pumps.
Thus, acute digoxin impaired performance and exacerbated plasma K+ disturbances with intense, fatiguing exercise in healthy participants. These occurred despite the preservation of functional Na+,K+‐ATPase in muscle.
Incretin impact on gastric function in obesity: physiology, and pharmacological, surgical and endoscopic treatments
Authors: Camilleri Michael 
Published: November 2024

AbstractThe aims of this review are to appraise the role of the stomach in satiation, the effects of incretin and other hormone agonists on weight loss and the role of altered gastric functions in their effects on obesity or glycaemic control. In addition to the gut in its role in enzymatic digestion and hormonal responses to nutrient ingestion, gastric motor functions include accommodation, trituration and emptying [gastric emptying (GE)] of food and elicitation of postprandial satiation and satiety. The postprandially released hormones most extensively studied and utilized therapeutically are glucagon‐like peptide 1 (GLP‐1) and glucose‐dependent insulinotropic peptide (GIP). Their mechanisms of action include stimulation of pancreatic β cells to produce insulin. However, GLP‐1 reduces glucagon and slows GE, whereas GIP increases glucagon and does not alter GE. Molecular modifications of GLP‐1 (which has a T1/2 of 3 min) led to the development of long‐acting subcutaneous or oral pharmacological agents that have been approved for the treatment of obesity, and their effects on gastric function are documented. Other medications in development target other molecular mechanisms, including glucagon and amylin. Small‐molecule GLP‐1 receptor agonists are promising for the treatment of obesity and may also slow GE. Bariatric surgery and endoscopy increase satiation by restricting gastric size; in addition Roux‐en‐Y gastric bypass and to a lesser extent sleeve gastrectomy (but not endoscopic gastroplasty) increase postprandial circulating incretins, reducing appetite. In conclusion the stomach's function is integral to the impact of the most effective pharmacological and procedural reversal of obesity related to the incretin revolution.
image
On the Application of Background Oriented Schlieren to a Transonic Low-Reynolds Turbine Cascade
Authors: Halby Alexandre , Cakir Bora O. , Da Valle Lorenzo , Lopes Gustavo , Okada Mizuki , Lavagnoli Sergio 
Published: November 2024

Abstract
Qualitative and quantitative visualizations of transonic turbomachinery flows provide essential information on compressibility and Mach number effects on boundary layer development, shock-boundary layer interactions, and trailing edge flows. Background oriented Schlieren (BOS) is a relatively new optical technique that allows capturing unsteady density gradient fields through turbomachinery cascades and thus quantitative experimental data to validate transonic and supersonic blade designs. However, only very few experimental works in the open literature have successfully applied BOS to transonic turbine or compressor flows. The current study presents the application of BOS to a transonic low-pressure turbine cascade, the VKI SPLEEN C1 cascade for a range of Reynolds numbers (70,000–140,000) and transonic Mach numbers (0.90–1.00). The linear turbine cascade is tested at the von Karman Institute in the S-1/C high-speed wind tunnel. The test section is instrumented with different BOS optical setups to visualize the time-resolved density gradients through the turbine passage and at the trailing edge plane with dedicated field of views. The BOS images are processed using the classical cross-correlation algorithm, and the optical flow approach, recently introduced in BOS applications to gain spatial resolution and increased sensitivity. Steady-state density gradients of the cascade flow characterize the airfoil boundary layers, wakes, and shock waves. The results from the two data reduction methods are assessed and compared against available RANS CFD predictions. Time-resolved measurements reveal the low-frequency motion of weak shock waves generated in the blade passage using proper orthogonal decomposition (POD) and spectra analysis.
Numerical Simulations and Sensitivity Analysis of Ice Formation on Fan Blades
Authors: Müller Katja , Flassig Peter , Flassig Robert 
Published: November 2024

Abstract
In-flight icing, the formation of ice during flight, poses risks to the safety and reliability of aircraft. Due to environmental conditions, ice accumulation occurs on the low-pressure compressor blades of an engine, diminishing aerodynamic performance and potentially causing damage to the engine. Numerical simulations of ice accretion are conducted on the blades of the NASA Rotor 67 utilizing the computational fluid dynamics software ansys cfx and the in-flight icing software fensap-ice. One-dimensional and two-dimensional sensitivity studies aim to analyze the influences of temperature, droplet diameter, and liquid water content (LWC) on the resulting ice buildup on the blade. The analyses reveal that ice accumulates predominantly at the leading edge of the blade, where collection efficiency is maximal. Additionally, an ice layer forms at the blade root on the pressure side. While LWC and temperature exert a significant influence on the ice mass, only a marginal impact on droplet diameter is observed.
Efficacy and
in vitro
pharmacological assessment of novel
N
-hydroxypyridinediones as hepatitis B virus ribonuclease H inhibitors
Authors: Woodson Molly E. , Walden Holly F. , Mottaleb M. Abdul , Makri Maria , Prifti Georgia-Myrto , Moianos Dimitrios , Pardali Vasiliki , Zoidis Grigoris , Tavis John E. 
Published: November 2024

ABSTRACT

We previously reported
N
-hydroxypyridinedione (HPD) compounds with mid-nanomolar efficacy and selectivity indexes around 300 against hepatitis B virus (HBV) replication. However, they lack pharmacological evaluation. Here, we report
in vitro
anti-HBV efficacy, cytotoxicity, and pharmacological characterization of 29 novel HPDs within seven subgroups. The best two compounds had EC
50
s of 61 and 190 nM and selectivity indexes of 526 and 1,071. Compounds with one halogen on the major R group were most effective and compounds with large ether R groups were most cytotoxic. Compounds were not cytotoxic in primary human hepatocytes. All compounds were freely soluble in pHs reflecting plasma (7.4) and the gastrointestinal tract (5 and 6.5). Almost all highly soluble compounds were passively permeable at pH 5.0 and 7.4. Only 2 of 11 compounds tested were likely to be effluxed by p-glycoprotein. The most potent HPDs inhibited HBV replication over human ribonuclease H1 activity by 10-fold. Four of 19 compounds inhibited CYP2D6 >50%, but their CYP2D6 IC
50
s were >8× higher than their anti-HBV EC
50
. No compound substantially inhibited CYP3A4. Thirteen of 15 compounds had human microsomal half-lives >30 min with medium to low rates of intrinsic clearance. Eleven of 12 compounds bound plasma proteins by ≥80%; however, effects against HBV replication for only one would likely be physiologically relevant. These results identify two lead candidate HPDs with pharmacological characteristics resembling commercially available drugs that are suitable for
in vivo
pharmacological and efficacy studies.
Recombinant
Saccharomyces cerevisiae
EBY100/pYD1-FaeG: a candidate for an oral subunit vaccine against F4+ ETEC infection
Authors: Hu Dayue , Li Xiangmin , Duan Xiaochao , Yang Liuyue , Luo Baizhi , Wang Linkang , Hu Zihui , Zhou Yang , Qian Ping 
Published: November 2024

ABSTRACT

Diarrheal diseases attributable to multidrug-resistant F4+ enterotoxigenic
Escherichia coli
(ETEC) are escalating in severity, posing significant risks to the health and safety of both humans and animals. This study used
Saccharomyces cerevisiae
EBY100 to display the FaeG subunit of F4 colonizing factor as an oral vaccine against F4+ ETEC infection. Mice were orally immunized twice with 10
8
CFU of EBY100/pYD1-FaeG, followed by a challenge with F4+ ETEC EC6 on day 7 post-immunization. The results showed that the recombinant strain EBY100/pYD1-FaeG orally enhanced the growth of the small intestine villi, significantly boosted the expression of tight junction proteins (
ZO-1
,
Occludin
,
MUC2
, and
Claudin
) (
P
< 0.05), and modulated the gut microbiota composition. Additionally, immunization with EBY100/pYD1-FaeG also upregulated the levels of IL-2, IL-4, and IFN-γ in the intestines of mice (
P
< 0.01), while serum IgG and fecal sIgA titer significantly increased (
P
< 0.05). These immune responses enhanced the capacity to fight against ETEC, leading to an increased survival rate of mice and relieved damage to tissues and organs of mice infection. In summary, the study suggested that the recombinant
Saccharomyces cerevisiae
EBY100/pYD1-FaeG could effectively stimulate the immune response and generate specific antibodies against F4+ ETEC, showing its potential to serve as a subunit oral vaccine candidate for preventing F4+ ETEC infection.

IMPORTANCE

The multidrug-resistant F4+ enterotoxigenic
Escherichia coli
(ETEC) strains are the primary clinical pathogens responsible for post-weaning diarrhea in piglets, resulting in substantial economic losses in the pig farming industry. In the study, we developed an oral vaccine candidate,
Saccharomyces cerevisiae
EBY100/pYD1-FaeG, to prevent diarrhea caused by multidrug-resistant F4+ ETEC. Oral administration of EBY100/pYD1-FaeG significantly enhanced immune responses, improved intestinal health, and provided protection against F4+ ETEC infection in mice. This approach offers a potential application prospect for preventing F4+ ETEC infections that lead to post-weaning diarrhea in clinical settings and provides a promising solution for addressing the growing threat of antibiotic resistance in bacterial pathogens.
Gut microbiota dysbiosis induced by alcohol exposure in pubertal and adult mice
Authors: Yang Jinlong , Wang Haoyu , Lin Xiaoqian , Liu Jincen , Feng Yue , Bai Yuyin , Liang Hewei , Hu Tongyuan , Wu Zhinan , Lai Jianghua , Liu Jianmei , Zou Yuanqiang , Wei Shuguang , Yan Peng 
Published: November 2024

ABSTRACT

Alcohol intake causes many diseases including neuropsychiatric symptoms, nutritional deficiency, progressive pancreatitis, liver cirrhosis, and ischemic heart disease. The gut microbiota changes significantly after alcohol exposure. Alcohol consumption tends to increase in underage and young people, but the feature of the gut microbiota in puberty remains largely unexplored. In this study, we conducted alcohol-exposed pubertal and adult mice model to investigate the intestinal damage and gut microbiota change. Interestingly, the responses of pubertal mice and adult mice after alcohol exposure were different. We found that alcohol dehydrogenase decreased and aldehyde dehydrogenase increased in the liver of pubertal mice, thus reducing the accumulation of toxic acetaldehyde. Furthermore, alcohol exposure caused less intestinal injury in pubertal mice. Through the analysis of metagenome assembly genome, we obtained many unrecognized bacterial genomes.
Limosillactobacillus reuteri
(cluster_56) and
Lactobacillus intestinalis
(cluster_57) were assembled from the samples of pubertal mice, which were involved in the production of indole acetic acid and the transformation of bile acids in response to alcohol exposure. This study provided a new insight to investigate the gut microbiota change and explained the difference of the gut microbiota after alcohol exposure between pubertal mice and adult mice.

IMPORTANCE

This study elucidates the significant impact of alcohol exposure on the gut microbiota and metabolic pathways in mice, highlighting the differential responses between adolescent and adult stages. Alcohol exposure was found to damage the intestinal barrier, alter the microbial composition by decreasing beneficial bacteria like
Lactobacillus
, and increase harmful bacteria such as
Alistipes
. The study also discovered unique microbial changes and resilience in pubertal mice. Species-level metagenomic analysis revealed specific microbial taxa and metabolic functions affected by alcohol. Metagenome-assembled genomes (MAGs) found many species that could not be annotated by conventional methods including many members of
Lachnospiraceae
, greatly expanding our understanding of the gut microbiota composition. These findings underscore the need for further research on alcohol’s effects on various organs and the implications of microbial metabolites on disease progression.
Real-world patient characteristics and survival outcomes in patients with advanced or recurrent endometrial cancer in England: a retrospective, population-based study
Authors: Banerjee Susana , Ingles Russo Garces Alvaro , Garside Jamie , Rahman Tameera , Pearson Clare , Heffernan Kiera 
Published: November 2024

ObjectiveThis study defined a retrospective cohort of patients in England with primary advanced or recurrent (A/R) endometrial cancer (EC) who may have been eligible for clinical trials evaluating immune checkpoint inhibitors (ICIs) in the first-line (1L) setting within a real-world dataset, and described the characteristics, treatment patterns and outcomes within this cohort.DesignThis was a retrospective, population-based study.SettingRoutine population-level data from the National Cancer Registration and Analysis Service in England were used. Patients diagnosed with A/R EC between 1 January 2013 and 31 December 2019 were included (follow-up until 23 August 2021). ICI-eligible patients who received any 1L therapy (defined as first systemic treatment for A/R EC with or without radiotherapy) and met key eligibility criteria for the RUBY trial (NCT03981796; 1L cohort) were included. A subpopulation who solely received carboplatin–paclitaxel at 1L (carboplatin–paclitaxel subcohort) was identified.MethodsDemographics, characteristics and therapy received were reported. Overall survival (OS), time to next treatment (TTNT) and time to treatment discontinuation (TTD) from 1L chemotherapy initiation were assessed using Kaplan-Meier methodology.ResultsOf 13 954 patients identified, 2376 ICI-eligible patients were included in the 1L cohort (median [range] age: 67.9 [26.7–94.0] years); 902 patients received solely carboplatin–paclitaxel at 1L. Demographics and disease characteristics were generally similar between cohorts. Median (95% CI) OS, TTNT and TTD from 1L chemotherapy were 27.2 (24.7, 30.2), 16.9 (15.8, 18.5) and 3.4 (3.4, 3.4) months, respectively, in the 1L cohort, and 17.2 (15.5, 19.0), 12.4 (11.6, 13.5) and 3.4 (3.4, 3.4) months, respectively, in the carboplatin–paclitaxel subcohort.ConclusionLong-term outcomes were poor for both cohorts, particularly the carboplatin–paclitaxel subcohort, where patients did not receive radiotherapy and had predominantly metastatic disease. This reflects the unmet need for more durable treatment options to prevent relapse and prolong survival in this patient population. This real-world study will help contextualise outcomes from ongoing phase III clinical trials investigating 1L ICI treatments.
Multicentre online registration of bronchopulmonary dysplasia in very preterm infants in China: protocol for a prospective, open, observational cohort study
Authors: He Shengnan , Peng Haibo , Zhou Ping , Hu Fei , Yan Xudong , Su Qian , Yu Boshi , Li Yubai , Chen Cheng , Guo Xin , Liu Ying , Guo Yanping , Liu Jiebo , Rao Dan Dan , Zhang Lian , Yu Zhangbin 
Published: November 2024

IntroductionBronchopulmonary dysplasia (BPD) in very preterm infants (VPIs) has adverse long-term outcomes and affects the quality of survival. There are no registry studies on BPD in VPIs in China. Our aim was to conduct a prospective, multicentre, open, longitudinal, observational cohort study to investigate the epidemiological characteristics, diagnosis, treatment, and short-term and long-term outcomes of BPD in a real-life setting in China and lay the grounds for establishing a nationwide registry with clinical data and biological specimens.MethodsThis study aims to recruit a minimum of 2000 VPIs and start research in January 2024 in Shenzhen, China. We will collect clinical data from the beginning of the life of VPIs and follow them up to 3 years old. Short-term outcomes, such as the incidence of BPD, necrotising enterocolitis, retinopathy of prematurity, intraventricular haemorrhage and porencephalic ventricular leukomalacia, as well as the cost of hospitalisation, are the major variables of concern. Bayley-III Scale assessment, gross motor function and pulmonary function evaluation will be performed at the age of correction, that is, 18–24 months and 30–36 months. The follow-up outcomes include loss to follow-up, survival status, moderate-to-severe neurodevelopmental deficits and severe respiratory complications. Cord blood, peripheral blood, tracheal aspirate, faeces and urine from VPIs, as well as mother’s milk, will be collected and stored at −80°C. All the data will be registered, stored and managed in a cloud-based database. This knowledge will be useful for establishing diagnostic criteria and predictive models for BPD in the Chinese population.Ethics and disseminationOur protocol has been approved by the Medical Ethics Committee of Shenzhen People’s Hospital (LL-KY-2023174-02) and the local ethics committee of each participating centre. Our goal is to present our findings at national conferences and in peer-reviewed paediatric journals.Trial registration numberChinese Clinical Trial Registry (ChiCTR2400081615).
Predictors of medicine-related perceptions towards deprescribing inappropriate medications among older adult outpatients in Jordan: a cross-sectional study
Authors: Rababa Mohammad J , Al Ghazo Ali , Hayajneh Audai A 
Published: November 2024

ObjectivesTo examine the predictors of medicine-related perceptions towards deprescribing inappropriate medications among older adults in Jordan.DesignA cross-sectional, correlational study.SettingData were collected by a graduate nursing student from five outpatient clinics in a selected public hospital in Jordan via inperson interviews 5 days a week over a period of 4 months.ParticipantsA convenience sample of 200 older adults who regularly visited the outpatient clinics of the selected public hospital for regular check-ups during July 2023 were recruited.Outcome measuresPredictors of patients’ perceived medication concerns, interest in stopping medications, perceived unimportance of medications, and beliefs about medication overuse were examined.ResultsIncreased perceived medication concerns among patients were significantly associated with older age (p=0.037), lower level of self-rated general health (p=0.002), less perceived care-provider knowledge of medications (p=0.041), higher perceived unimportance of medicines (p=0.018), less collaboration with care providers (p=0.017), being seen by a clinical pharmacist (p<0.001) and an increased number of prescribed medicines (p<0.001). Increased perceived interest in stopping medications was significantly associated with lower levels of self-rated general health (p=0.029), less perceived involvement in decision-making (p=0.013), higher perceived unimportance of medicines (p=0.002), being seen by a clinical pharmacist (p=0.024) and an increased number of prescribed medicines (p=0.001). Furthermore, increased perceived unimportance of medications among patients was significantly associated with more perceived beliefs about medication overuse (p=0.007), more perceived interest in stopping medicines (p=0.001) and greater perceived medication concerns (p=0.001). Moreover, greater perceived beliefs about medication overuse were significantly associated with older age (p=0.018), higher perceived unimportance of medicines (p=0.016), more collaboration with care providers (p=0.038), having post-traumatic disorder (p=0.018) and an increased number of prescribed medicines (p=0.038).ConclusionsThe current study examined predictors of medicine-related perceptions towards deprescribing inappropriate medications among older adults. Care providers should discuss the benefits of deprescribing inappropriate medications with their patients to prevent the side effects associated with long-term unnecessary use. Future studies on the effectiveness of an evidence-based deprescribing protocol on minimising the clinical side effects associated with the inappropriate prescription of medications among older adults are recommended.