bluuebunny/crossref_metadata_2025 huggingface dataset:
Zirconia spacer electrodes improve microstructural uniformity of flash sintered zirconia ceramics
Authors: Prajzler Vladimír , Todd Richard I.
Published: January 2025

The sample‐electrode contact often represents the most problematic part of the flash sintering circuit. We demonstrate that adding 3 mol% yttria‐stabilized zirconia (3YSZ) spacer electrodes between a 3YSZ powder compact and steel electrodes positively impacts the final density and microstructure in AC flash sintering. The 3YSZ spacer electrodes, with intrinsically low thermal conductivity, were also heated by Joule heating alongside the 3YSZ sample, reducing the temperature gradient at the specimen‐electrode interface and limiting heat loss from the specimen. A reference 3YSZ sample, which was sintered with stainless steel electrodes only, reached 98.2% of relative density with a notable grain size difference between the central (∼290 nm) and near‐electrode parts (∼160 nm). The addition of 3YSZ spacer electrodes improved the final density to 98.9 % and reduced the grain size difference between the central (∼300 nm) and near‐electrode parts (∼220 nm) almost by half compared to the reference sample.
Derivation of Economic Values for Breeding Objective Traits of Chinese Holstein Dairy Cows Using a Bio‐Economic Model
Authors: Shi R. , van der Linden A. , Oosting S. , Wang Y. , Ducro B.
Published: January 2025

Holstein cattle account for the largest proportion of dairy cattle in China. The current China Performance Index (CPI) consists mainly of production traits. To derive economic values (EV) of additional traits for balanced breeding programs, a bio‐economic model is necessary. Landless and intensive dairy farms are dominant in China, wherein all feed is purchased, and in‐farm technicians and veterinarians are employed. Therefore, in the present study, a tailored bio‐economic model was developed using the parameters of a typical dairy farm in North China. The typical farm had 1500 cows and 1400 youngstock, with a replacement rate of 33.5% per year and a productive life of 1090 days. The bio‐economic model was on a per cow per year basis and described the revenues and costs from different animal categories. The EVs of 17 traits, including production, calving, fertility, longevity, and health traits, were derived and used to develop a more balanced selection index. Results showed that the bio‐economic model can represent the typical dairy farm system in North China. The EVs of production traits were 2.39 Chinese Yuan (CNY), 32.85 CNY, and 89.60 CNY per kg milk yield, fat yield and protein yield, respectively. The EVs of production traits were two to three times higher than those in some European countries, due to the higher prices on milk volume and milk solids in China. The EVs of health traits ranged from −0.45 CNY to −11.95 CNY and were nearly half of those in other countries, due to the lower in‐farm veterinarian labour costs. The EVs of most other functional traits were in line with the published values of other countries with similar economic assumptions in the model. Using the calculated EVs, a more balanced selection index was derived by including functional traits. This index had higher relative weight (46.8%) on functional traits than the current CPI (12.5%). With the high milk prices, it is still most profitable to allow for a decline in functional traits, although the decline is considerably smaller with the developed balanced index than with the CPI. Collectively, the bio‐economic model and EVs provided the foundations for implementing balanced breeding programs in the Chinese Holstein population.
Associations Between Socioeconomic, Spatial and Educational Factors and Midlife Periodontal Disease Risk: Evidence From ‘High School and Beyond’
Authors: Warren John Robert , Himmelstern Jessie , Muller Chandra , Grodsky Eric , Demmer Ryan
Published: January 2025

Background

Periodontal disease (PD) is a prevalent, preventable and treatable oral infection associated with substantial morbidity globally. There is little information from population‐representative cohort studies about the sociodemographic, educational and other early life factors that stratify PD risk.

Methods

We used data from the U.S. ‘High School and Beyond’ (HS&B:80) study, which has followed a nationally representative sample of 26,820 people from high school in 1980 through midlife in 2021. Data from the 1980s include information about education, early life circumstances, spatial location and demographic attributes. Data from 13,080 sample members who responded in 2021 include indicators of self‐reported PD diagnosis.

Results

People with higher degrees and course grades have a lower risk of midlife PD. Rural adolescents and those who attended private schools are also at lower risk. We find little evidence of heterogeneity in correlates of midlife PD by gender or race/ethnicity.

Conclusions

The quantity and characteristics of people's schooling and their location of residence are associated with midlife PD.
A Note on the Use of Categorical Subscores
Authors: Gorney Kylie , Sinharay Sandip
Published: January 2025

Although there exists an extensive amount of research on subscores and their properties, limited research has been conducted on categorical subscores and their interpretations. In this paper, we focus on the claim of Feinberg and von Davier that categorical subscores are useful for remediation and instructional purposes. We investigate this claim by examining (a) the agreement between true and observed subscore classifications and (b) the agreement between subscore classifications across parallel forms of a test. Results show that the categorical subscores of Feinberg and von Davier are often inaccurate and/or inconsistent, pointing to a lack of justification for using them for remediation or instructional purposes.
Fracture Resistance and Wear Behavior of Ultra‐Thin Occlusal Veneers Made From Translucent Zirconia Ceramics Bonded to Different Tooth Substrates
Authors: Fulde Nele , Wille Sebastian , Kern Matthias
Published: January 2025

Objective

Investigation of the mechanical properties of occlusal veneers made from zirconia with varying translucency, bonded to different tooth substrates.

Materials and Methods

Sixty‐four extracted molars were divided into two groups: preparation within enamel (E) or extending into dentin (D). Veneers were milled from four zirconia ceramics (n = 8): 5Y‐TZP (HT), a multilayer of 5 and 3Y‐TZP (GT), 3Y‐TZP (LT), and 4Y‐TZP (MT). After bonding, specimens underwent thermocycling (7500 cycles; 5°C–55°C) and chewing simulation (1,200,000 cycles; 10 kg), followed by investigation of the wear behavior using optical and laser scanning microscopy. Specimens were then loaded to examine fracture resistance.

Results

All specimens except one in the HT group survived artificial aging. Zirconia wear was below the resolution of the 3D scanner, with no significant difference in antagonist vertical loss across materials (p > 0.05). Fracture resistance was significantly higher in E‐LT compared with E‐HT (p = 0.003). No significant differences (p > 0.05) were observed in fracture resistance between materials bonded to dentin, or between the materials within different substrates.

Conclusions

Veneers made of 3 and 4Y‐TZP zirconia showed promising in vitro performance and fracture resistance, regardless of the tooth substrate. All zirconia ceramics exhibited favorable wear behavior.

Clinical Significance

As tooth wear rates increase, the use of minimally invasive occlusal veneers is becoming more important. The goal is to create restorations that are both esthetically pleasing and mechanically durable, while keeping them thin to minimize occlusal preparation and still ensure sufficient fracture resistance. Ultra‐thin (0.3 mm in the fissures/0.6 mm at the cusps) occlusal veneers made of 4Y‐TZP, multilayer and 3Y‐TZP zirconia ceramics survived chewing simulation corresponding 5‐years. All zirconia restorations showed wear‐resistant behavior.
From local knowledge and science to policy: Lessons learned from Fiji's valuable grouper fisheries
Authors: Sadovy de Mitcheson Yvonne , Batibasaga Aisake , Hatten Chloe E. R. , Mangubhai Sangeeta
Published: January 2025

Pacific Island communities are heavily dependent on fisheries for subsistence and livelihoods. Yet, despite their importance, coastal fisheries are poorly managed and commercial pressures increasingly threaten them. Groupers (Epinephelidae) are exceptionally vulnerable to overexploitation due to aspects of their biology while their economic value makes them a prime target for commerce. Fiji has a significant grouper fishery and is a useful case study to assess a data‐poor, economically valuable sector to evaluate management measures, options, and needs. Data from multiple sources over three decades were integrated with original research involving fisher interviews, market surveys, stock assessments, and underwater census to assess the status of the country's grouper fishery. Catch rates are declining and trade now includes a high percentage of immature groupers, with aggregating species (mainly Epinephelus polyphekadion, Epinephelus fuscoguttatus, Plectropomus areolatus, Plectropomus leopardus) particularly at risk. Estimated annual grouper landings are increasing and now exceed 1000 mt. There is an urgent need to update Fiji's grouper size limits which are grossly inadequate. To build public support and increase awareness, government and nongovernmental organizations should invest in the national 4FJ Fish Smart campaign. Key management recommendations for groupers are (1) improved spatial and temporal protection of spawning aggregations and (2) increased minimum‐size restrictions for capture and sale. Findings apply broadly to valuable and vulnerable coastal fin‐fisheries in reef ecosystems across many Pacific Island countries and highlight the importance of using multiple data sources and approaches to understand and manage important data‐poor fisheries.
Efficacy of Radiofrequency Ablation as a Treatment for High‐Risk Gastric Intestinal Metaplasia: A Randomized, Self‐Control Study
Authors: Pittayanon Rapat , Tiankanon Kasenee , Faknak Natee , Lerttanatum Nathawadee , Sanpavat Anapat , Klaikaew Naruemon , Rerknimitr Rungsun
Published: January 2025

Background

Guidelines recommend endoscopic surveillance for gastric cancer without therapeutic intervention every 3 years in patients with high‐risk gastric intestinal metaplasia (GIM). This study aimed to evaluate the efficacy of radiofrequency ablation (RFA) in eradicating high‐risk GIM.

Methods

This randomized self‐control trial was conducted between June 2020 and February 2023. Patients with histology‐verified high‐risk GIM were enrolled. The endoscopist performed a biopsy on both the left and right sides of the stomach (five each) by targeting the suspected GIM area where available; otherwise, a random biopsy was taken. Patients were randomized to receive a unilateral RFA on either the left or right side. A repeated RFA on the assigned side was performed every 2–3 months for a total of two to three times. The primary outcome was complete resolution of GIM at 1 year after RFA.

Results

Forty‐six patients with a mean age of 66 ± 8 years were analyzed. The complete resolution rate of overall GIM lesions after RFA was significantly higher (49/142; 34/5%) than that in the observation group (29/127; 22.8%, RR = 0.84, 0.73–0.98, p = 0.03). For the subgroup analysis, the complete resolution rate after RFA revealed a significantly higher value than observation only in the incomplete GIM group (24/87; 27.6% vs. 11/82; 13.4%, RR = 0.83, 0.71–0.97, p = 0.02). The percentage of patients with extensive GIM regression after RFA (15/25; 60%) was higher than in the observation group (9/25; 36%) but did not meet statistical significance (RR = 0.62, 0.35–1.09, p = 0.09).

Conclusion

In high‐risk GIM, RFA can significantly eradicate incomplete GIM when compared with observation alone.
Nutrient Intake Among Lactating Women With Overweight and Obesity in Norway: A Comparison With the Nordic Nutrition Recommendations 2023
Authors: Fossli Maria , Øhman Elisabeth A. , Andal Malin , Løland Beate F. , Holven Kirsten B. , Brekke Hilde K.
Published: January 2025

Background

During lactation, maternal requirements for many nutrients increase due to the physiological demands of breast milk production, reflected in dietary recommendations. BMI is negatively associated with dietary quality postpartum, and 40% of women in Norway have pre‐pregnancy overweight and obesity. Currently, there is limited data on dietary intake among lactating women in Norway and whether they meet nutritional requirements. We aimed to evaluate the nutrient intake in a study sample of lactating women with overweight and obesity, compared with the Nordic Nutrition Recommendations (NNR 2023).

Methods

In this cross‐sectional analysis, we included baseline data from 112 lactating women with a pre‐pregnancy BMI of 25–35 kg/m2, participating in a weight loss and breastfeeding promotion intervention trial in Oslo, Norway. Data were collected at 2 weeks postpartum (subject characteristics, anthropometry and dietary supplement use), at 7 weeks postpartum (dietary assessment) and post‐weaning (retrospective dietary supplement use). Dietary data were obtained from a 4‐day dietary record before randomisation to dietary treatment for weight loss. Nutrient intake was compared to the dietary reference values for lactating women in NNR 2023. Increased risk of inadequate intake of micronutrients was assessed as the proportion of women with intakes below the average requirement (AR), with and without dietary supplements.

Results

Mean ± SD BMI at 2 weeks postpartum was 30.7 ± 2.5 kg/m2. At 7 weeks postpartum the women reported a mean energy intake of 9.2 ± 2.0 MJ/day, with a higher intake of saturated fat and a lower intake of carbohydrate, dietary fibre and docosahexaenoic acid than recommended. The majority had an increased risk of inadequate intake of vitamin A (92%), folate (92%), vitamin D (84%), selenium (87%) and iodine (71%) from the diet alone. When dietary supplements were taken into account, ≥ 50% of the women still had an increased risk of inadequate intake of vitamin A, folate and selenium.

Conclusions

The high proportion of lactating women with overweight and obesity failing to meet the newly updated Nordic Nutrition Recommendations highlights the need to raise awareness among new mothers and healthcare professionals about the increased maternal nutritional demands during lactation and hence, the importance of nutrient‐dense diets.
Train‐the‐Educator: Boosting Knowledge and Confidence for Conducting Substance Use Prevention Education
Authors: Liu Jessica , Kajiwara Carly , McCauley Devin , Halpern‐Felsher Bonnie
Published: January 2025

Background

School‐based substance use prevention is important, yet many educators are not trained in the curriculums. The purpose of this study was to assess changes in educators' knowledge about substances and confidence in delivering drug education before and after participating in educator trainings, as well as overall perceptions of the trainings, for three curriculums: tobacco, cannabis, and all drugs prevention.

Methods

We conducted one‐arm pre–post analyses evaluating educators' changes in knowledge about products and confidence to deliver curriculums. A total of 1064, 648, and 171 educators participated in the trainings and completed surveys (June 2021–November 2023) about drug knowledge (closed‐ended, three items for tobacco, five for cannabis), confidence to deliver curriculums (Likert, four items for all trainings), and perceptions of the trainings (open‐ended, four items for all trainings). Paired‐sample t‐tests and McNemar tests of paired proportions were conducted for the matched sample. Two coders double‐coded open‐ended responses to identify key themes.

Results

The training for tobacco was associated with pre–post improvements on all knowledge questions (p's ≤ 0.001). Trainings for all three curriculums were associated with pre–post improvements for all confidence questions (p's < 0.007). Participants qualitatively reported wanting longer trainings with more in‐depth content and navigation of materials.

Implications for School Health Policy, Practice, and Equity

Our findings suggest that trainings are a promising method that may improve the knowledge and confidence of educators who deliver drug education curriculums.

Conclusions

Educator trainings will likely benefit from detailed content on various substances, interactive activities, and show educators how to tailor curriculums based on their students' specific needs.
Early Initiation of Breastfeeding and Exclusive Breastfeeding in Anglophone and Francophone West African Countries: Systematic Review and Meta‐Analysis of Prevalence
Authors: Lewis‐Koku Martha Osekua , Fleming Catharine A. K. , Pachuau Lucy Ngaihbanglovi , Elmighrabi Nagwa Farag , Agho Kingsley Emwinyore
Published: January 2025

Early initiation of breastfeeding (EIBF) and exclusive breastfeeding (EBF) are highly effective forms of preventive medicine in many low‐ and middle‐income countries, including Anglophone and Francophone West African countries. Despite the proven benefits of EIBF and EBF in reducing mortality and morbidity, there is limited systematic evidence from West African countries. Hence, the aim of this systematic review and meta‐analysis was to estimate the pooled prevalence of EIBF and EBF in Anglophone and Francophone West African countries. Six databases were searched for eligible studies based on inclusion criteria and a systematic review and a further meta‐analysis were done. The weighted prevalence of EIBF was 51.7% (95% CI: 48.8, 54.6) in Anglophone West African countries and 45.5% (95% CI: 42.0, 48.9) in Francophone West African countries. The pooled prevalence of EBF was 41.2% (95% CI: 36.9, 45.5) in Anglophone West African countries and 30.1% (95% CI: 26.7, 33.5) in Francophone West African countries. Our study showed that the weighted average EIBF and EBF prevalence tended to be higher from studies in Anglophone West African countries than in Francophone West African countries. Despite these findings, EIBF and EBF rates overall in West African countries were suboptimal. A substantial improvement is necessary in promoting EIBF and EBF in West African countries. Programmes should target all mothers in the region no matter their colonial allegiance to achieve Sustainable Development Goals 2 and 3 by 2030.
“A withered olive branch”? The curious situation of Hungarian Jews during the dissolution of the Habsburg Empire
Authors: Adorjáni Anna
Published: January 2025

The Habsburg Empire dissolved after World War One. A new world order of nation‐states was emerging that acknowledged and distributed civic rights to non‐titular nations based on national minority status. How did Jewish communities in the former Kingdom of Hungary respond to the gradual change of sovereignty, the ethnicisation of everyday life and the escalating antisemitic violence? Focusing on the turbulent months between October 1918 and March 1919, this study examines the transformation of loyalty patterns among various Jewish communities at the local, regional, national and international levels. A pivotal aspect of the chaotic transition from empire to nation‐state was the intensified nationalism and the growing interest in models accommodating ethno‐confessional diversity. Amid the emerging solutions to the minority question in East‐Central Europe and worldwide, this paper focuses on the model of non‐territorial autonomy within Jewish communities in the territories that became part of Romania and Czechoslovakia.
Association between laboratory data‐based frailty index and clinical health outcomes in critically ill older patients: A retrospective correlational study
Authors: Ji Hyunju , Lee Jae Jun , Lee Kyung Hee
Published: January 2025

Background

Although frailty assessment is crucial for understanding critically ill patients' prognosis, traditional frailty measures require substantial efforts and time from health care professionals. To address this limitation, the laboratory frailty index (FI‐LAB) based on laboratory clinical data was developed. However, knowledge regarding its correlation with health outcomes among critically ill older patients is limited.

Aims

To identify the association between the FI‐LAB and acute, mid‐ and long‐term outcomes among critically ill older adults.

Study Design

This retrospective correlational study used electronic health records of 2106 older patients who were admitted to the intensive care unit at a tertiary hospital in Seoul, Korea. Acute and mid‐term outcomes included occurrence of delirium and in‐hospital mortality, and the long‐term outcome included 1‐year mortality. Logistic regression was used to explore the relationships across FI‐LAB, delirium, and in‐hospital mortality, while Cox proportional hazard regression was used to analyse the relationship between FI‐LAB and 1‐year mortality.

Results

Frailty assessed by FI‐LAB was significantly associated with increased risk of delirium (odds ratio [OR] = 6.21, 95% confidence interval [CI] = 2.31–25.39, p = .009), in‐hospital mortality (OR = 2.38, 95% CI = 1.15–5.79, p = .014), and 1‐year mortality (hazard ratio = 2.47, 95% CI = 1.16–5.25, p = .019) after controlling for covariates.

Conclusions

The study highlighted the importance of using FI‐LAB for screening frailty in critically ill older adults. Health care providers can improve patients' acute, mid‐ and long‐term outcomes to develop more individualised management plans based on FI‐LAB scores.

Relevance to Clinical Practice

The FI‐LAB score calculated from routine laboratory data can be used by nurses as a screening tool to identify frail older adults in critical care. Early detection of frailty would allow for closer monitoring and the implementation of interventions to reduce delirium and mortality.
Evaluation of Invisalign Wear Protocol on the Efficacy of Tooth Movement in Four First‐Premolar Extraction in Adolescent Patients: A Randomised Controlled Trial
Authors: Yu YaoHui , Zhou Yu
Published: January 2025

Background

Different protocols exist regarding wear time of invisible aligners. There is no study that compared the effect of different protocols. The aim of this study was to assess the effect of Invisalign aligners in four first‐premolar extraction treatments in adolescents using three aligner wear protocols, every 7, 10 and 14 days.

Materials and Methods

In the experimental set‐up, 50 participants were divided into three distinct groups: group A, with a regimen of changing aligners every 7 days; group B, with a 10‐day interval for aligner replacement; and group C, where aligners were replaced every 14 days. The evaluation of occlusal adjustments was conducted employing the Discrepancy Index (DI) and the Cast‐Radiograph Evaluation (CRE), as defined by the American Board of Orthodontics for the purpose of recording orthodontic outcomes. The treatment duration, number of maxillary and mandibular Invisalign aligners, and number of Invisalign restarts were simultaneously recorded and evaluated. The data set was statistically examined using ANOVA, complemented by the F‐test, least significant difference (LSD) method and Tamhane's T2 test.

Results

The final sample size for analysis is 45 cases, with five cases lost to follow‐up. Before treatment, the three groups showed no significant difference in the degree of malocclusion or each item of DI (p > 0.05). Posttreatment, within groups, and regardless of the wearing protocol, the total CRE scores demonstrated no statistically significant differences (p > 0.05). For the other items, groups A and C completed occlusal relations and interproximal contacts significantly better than did group B (p < 0.05). The group C cases had the least number of Invisalign refinement (3.93 ± 0.96 vs. 4.93 ± 0.70 vs. 6.00 ± 1.25, p < 0.05), but the treatment duration and number of Invisalign aligners were not significantly different (p > 0.05).

Conclusions

The different treatment timing protocols showed equivalent effectiveness regarding treatment outcome, with significantly improved results for the 7‐ and 14‐day protocol in terms of occlusal relations and interproximal contacts. The attainment of comparable clinical accuracy between the 7‐ and 14‐day protocol, within a treatment duration of fewer than 3 months, indicates that the 7‐day protocol can be deemed an effective treatment approach.
Hydraulic Properties of a Rock‐Soil‐Root System: Insights From Fraxinus ornus L. Saplings Growing on Different Carbonate Rocks
Authors: Bert Sara Di , Tomasella Martina , Duddek Patrick , Natale Sara , Petruzzellis Francesco , Carminati Andrea , Zini Luca , D'Amico Lorenzo , Tromba Giuliana , Nardini Andrea
Published: January 2025

Drought impacts trees in varied temporal and spatial patterns, suggesting that heterogeneity of below‐ground water stores influences the fate of trees under water stress. Karst ecosystems rely on shallow soil overlying bedrock that can store available water in primary pores. A contribution of rock moisture to tree water status has been previously demonstrated, but actual mechanisms and rates of rock‐to‐root water delivery remain unknown. We report accurate measurements of hydraulic properties of two rock types (Breccia and Dolostone), of typical Karst red soil, and of roots of a common Karst tree species grown under different rock‐soil combinations. Experimental data were used to build a water exchange model that supported the hypothesis that roots can extract water from porous and highly conductive rocks (Breccia), but not from more compact ones (Dolostone), especially when plants grow in rocky substrate or experience water stress, and thus have low root hydraulic conductivity and low rates of water extraction from rocks. Our data support the hypothesis that rocks represent important water stores for plants growing in rock‐dominated habitats. Heterogeneous rock properties translate into different rates of water delivery to root systems, underlying complex patterns of tree mortality under severe drought stress.
Forward Ever: Grenada, the USA, Don Rojas, and All of Us
Authors: Meyer Matt
Published: January 2025

Reflecting upon international peace studies at the start of 2025, this piece looks both at the contexts of the 2023 IPRA global conference held in Trinidad and at the 2024 US elections. With a tribute to and extensive quote from Grenadian academic Don Rojas, we articulate the ways in which past “peaceful revolutions” such as the New Jewel Movement may provide guideposts for peace work in the years ahead.
More Than One Agent? Authority Expansion and Delegation Dynamics in the EU
Authors: Ershova Anastasia
Published: January 2025

Recent studies focus on the issue of authority transfer to supranational institutions. While examining the opportunities and obstacles for expanding the Union's competencies, this literature often overlooks the effects of adopting ambitious policies on their implementation modes. This paper argues that the costs associated with the expansion of EU authority and opportunities for blame‐shifting drive delegation choices and define the relative discretion granted to agents. Proposals for expanding EU authority increase the likelihood of the exclusively supranational implementation path being selected by the principals while undermining the appeal of the national path. In contrast, aiming to preserve opportunities for blame‐shifting while maintaining some degree of control over implementation, the EU principals increasingly turn to joint delegation, where the Commission and national administrations cooperate. Yet, even within the partner‐like relationship of joint implementation, national agents enjoy broader discretionary leeway.
Training Elite Athletes: 50 Years of Thinking About Practice and Research for Endurance Sports
Authors: Joyner Michael J.
Published: January 2025

This essay summarizes and integrates my experiences and observations—starting in the middle 1970s—as an athlete, scientist interested in human performance, biomedical researcher, and “expert,” who sometimes advises athletes, coaches, and sports policy‐makers. In this context, my focus has been primarily on endurance sports and five concepts underpin what I have learned over the last 50 years. (1) The “competitive significance principle” whereby athletes, coaches, and policy‐makers are frequently interested in performance improvements of 1% or less. This is especially true at the elite level. (2) Science frequently explains what coaches and athletes have already discovered in the field. (3) Many science‐based performance improvements have reduced the energy cost of moving a given speed. (4) Varied and eclectic training programs have been used by elite athletes with similar performance outcomes. (5) A few things that are actionable matter. Coaches, athletes, and administrators should focus their efforts on what is actionable.
Metabolic stimulation improves bioenergetics and haematologic indices of circulating erythrocytes from sickle cell mice
Authors: Almeida Luis E. F. , Smith Meghann L. , Kamimura Sayuri , Vogel Sebastian , Quezado Zenaide M. N.
Published: January 2025

Circulating mature red blood cells (RBCs) from patients and mice with sickle cell disease (SCD) abnormally retain mitochondria, a factor shown to contribute to the disease's pathobiology. To further understand the functional implications of RBC mitochondria retention in SCD, we used mitochondria inhibitors and metabolites/substrates from the tricarboxylic acid cycle, oxidative phosphorylation and glycolysis pathways (ADP, glutamate, malate, pyruvate, succinate or all metabolites combined) and examined RBC bioenergetics, reactive oxygen species (ROS) levels, calcium flux and hydration. In RBCs from sickle mice, mitochondria inhibition reduced ATP levels by 30%–60%, whereas control RBCs were unaffected. Conversely, in vitro treatment with metabolites/substrates known to stimulate mitochondria function increased RBC ATP levels and reduced RBC ROS, and these effects were notably more pronounced in sickle RBCs compared to those in control mice. In sickle RBCs, the increases in ATP and decreases in ROS were associated with greater decreases in RBC baseline calcium concentration and improvements in calcium flux. These changes also led to greater increases in RBC volume and hydration, and greater decreases in mean corpuscular haemoglobin concentration in sickle RBCs compared to control RBCs. These results propose a novel model of RBC metabolism in SCD, where retained mitochondria in circulating RBCs are functional and can significantly impact RBC bioenergetics, ATP production and RBC hydration and redox status. These in vitro findings could inform the development of in vivo strategies aimed at increasing RBC ATP, reducing RBC ROS, improving RBC hydration, which could decrease sickling and prove beneficial in SCD.

image

Key points

Red blood cells (RBCs) from humans and mice with sickle cell disease (SCD) abnormally retain mitochondria.

Mitochondria inhibitors lower ATP in circulating RBCs from sickle mice indicating that retained mitochondria contribute to ATP levels in sickle RBC.

Metabolic stimulation of mitochondria function improves RBC bioenergetics, redox state and calcium flux, and increases RBC hydration.

These data propose a new model of RBC metabolism in SCD, where in addition to glycolysis, retained mitochondria contribute to RBC ATP production.

The effects of metabolic stimulation of RBCs resulting in improved RBC bioenergetics and hydration may prove beneficial in SCD.
Ultrahigh purity plasma-enhanced atomic layer deposition and electrical properties of epitaxial scandium nitride
Authors: Rayner Gilbert B. , O’Toole Noel , Liu Bangzhi , Shallenberger Jeffrey , Zhu Jiadi , Palacios Tomás , Behera Piush , Cheema Suraj , Johs Blaine , Strnad Nicholas A.
Published: January 2025

Scandium nitride (ScN) by plasma-enhanced atomic layer deposition (PEALD) was demonstrated on silicon (100), sapphire (0001), and magnesium oxide (001) substrates under ultrahigh purity conditions using a new Sc precursor, bis(ethylcyclopentadienyl)scandium-chloride [ClSc(EtCp)2]. Out-of-plane x-ray diffraction patterns indicated single-crystal, cubic phase ScN deposited at 215 °C on sapphire (0001) and magnesium oxide (001) substrates, whereas phi-scans confirmed epitaxial growth. The ScN thin films grown on silicon with native oxide were polycrystalline with no preferential orientation. The ScN films showed a nitrogen-to-scandium ratio of approximately 1:1 measured by x-ray photoelectron spectroscopy, with ultra-low levels of elemental impurities including 2.5 at. % chlorine, 0.9 at. % carbon, and 0.4 at. % oxygen. ClSc(EtCp)2 and N2–H2 plasma were evaluated as ScN co-precursors at substrate temperatures ranging from 200 to 300 °C, where we identified an atomic layer deposition window between 200 and 215 °C. Images by field emission scanning electron microscopy (FESEM) on 43 nm-thick films grown on untreated silicon revealed columnar grains with lateral sizes ranging from 16 to 28 nm. ScN conformality across 4:1 aspect ratio silicon trench structures with 312 nm-wide openings was also imaged by FESEM showing a top-to-bottom thickness ratio of 75%. ScN electrical properties were evaluated by performing Hall measurements to determine mobility, free electron concentration, and resistivity. For ScN PEALD on magnesium oxide (001), the average mobility was 298 cm2/V s with a carrier concentration of 2.35 × 1019 cm−3. The average resistivity was 1.01 mΩ cm.
Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model
Authors: Cairns Dana M. , Smiley Brooke M. , Smiley Jordan A. , Khorsandian Yasaman , Kelly Marilyn , Itzhaki Ruth F. , Kaplan David L.
Published: January 2025

Infection with herpes simplex virus type 1 (HSV-1) in the brains of
APOE4
carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of
APOE4
-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.
Antibiotic candidates for Gram-positive bacterial infections induce multidrug resistance
Authors: Martins Ana , Judák Fanni , Farkas Zoltán , Szili Petra , Grézal Gábor , Csörgő Bálint , Czikkely Márton Simon , Maharramov Elvin , Daruka Lejla , Spohn Réka , Balogh Dávid , Daraba Andreea , Juhász Szilvia , Vágvölgyi Máté , Hunyadi Attila , Cao Yihui , Sun Zhenquan , Li Xuechen , Papp Balázs , Pál Csaba
Published: January 2025

Several antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not yet reached the market. We found that, with the exception of compound SCH79797, antibiotic resistance generally readily evolves in
Staphylococcus aureus
. Cross-resistance was detected between such candidates and antibiotics currently in clinical use, including vancomycin, daptomycin, and the promising antibiotic candidate teixobactin. These patterns were driven by overlapping molecular mechanisms through mutations in regulatory systems. In particular, teixobactin-resistant bacteria displayed clinically relevant multidrug resistance and retained their virulence in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against candidate antibiotics are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve readily from the selection of preexisting genetic variants. Our work highlights the importance of predicting future evolution of resistance to antibiotic candidates at an early stage of drug development.
An engineered immunogen activates diverse HIV broadly neutralizing antibody precursors and promotes acquisition of improbable mutations
Authors: Swanson Olivia M. , Zhang Qianyi E. , Van Itallie Elizabeth , Tian Ming , Brown Alecia R. , Harris Caitlin , Kapingidza Anyway Brenda , Rhodes Brianna , Smith Lena M. , Venkatayogi Sravani , Cronin Kenneth , Frazier McKenzie , Parks Rob , Bar Maggie , Jiang Chuancang , Martin Beem Joshua S. , Cheng Hwei-Ling , Davis Jillian , McGovern Kelly , Newman Amanda , Edwards Robert J. , Cain Derek , Alam S. Munir , Wiehe Kevin , Saunders Kevin O. , Acharya Priyamvada , Alt Fred , Haynes Barton F. , Azoitei Mihai L.
Published: January 2025

Elicitation of HIV broadly neutralizing antibodies (bnAbs) by vaccination first requires the activation of diverse precursors, followed by successive boosts that guide these responses to enhanced breadth through the acquisition of somatic mutations. Because HIV bnAbs contain mutations in their B cell receptors (BCRs) that are rarely generated during conventional B cell maturation, HIV vaccine immunogens must robustly engage and expand B cells with BCRs that contain these improbable mutations. Here, we engineered an immunogen that activates diverse precursors of an HIV V3-glycan bnAb and promotes their acquisition of a functionally critical improbable mutation. This immunogen was validated biochemically, structurally, and in three different humanized immunoglobulin mouse models that were designed to test HIV immunogens. These results provide a blueprint for rationally designing priming immunogens that explicitly target the elicitation of antibodies with functional yet improbable mutations.
Reassessing the possibility of marine incursion into a paleo-lake under the constraints of a chronological framework: Implications for lake salinization mechanisms
Authors: Li Qiqi , Xu Shang , Hao Fang
Published: January 2025

The issue of marine incursion into paleo-lakes has been a topic of considerable debate, which has led to ambiguity about the processes of lake salinization. A case in point is the decades-long debate over the salinization mechanism of paleo-lakes in the Eocene Bohai Bay Basin of eastern China. Despite the longstanding preference for the marine incursion model as an explanation, there is currently no comprehensive and convincing chain of evidence validating the occurrence of marine incursions. The present study conducted cyclostratigraphic analyses on lacustrine sedimentary sequences from the Dongying Depression in the Bohai Bay Basin, established an astronomical time scale for the middle−late Eocene, and reconstructed continuous and objective lake-level records. The possibility of marine incursions was reassessed by examining the relationships between paleo-lake salinity and lake-level and sea-level variations through isochronous comparison. The results indicate that the lake-level changes at 2.4 m.y. cycles in the Dongying Depression were in-phase with global sea-level changes during the middle−late Eocene. However, these changes were not completely synchronous on millennial time scales, but rather exhibited an antiphase relationship in most periods. Concurrently, high lake water salinity was predominantly observed during periods of low lake level. These phenomena are incongruous with the conventional characteristics of marine incursion. Nevertheless, they still imply interactions between lake and sea, which we suggest are primarily caused by the subsurface seepage of seawater through the barrier separating the sea and direct modulation of the groundwater table by sea-level fluctuations. We subsequently propose a new mechanism for the salinization of paleo-lakes in the Dongying Depression. This mechanism emphasizes the combined contribution of terrigenous supply and seawater seepage as sources of salt ions, and incorporates fluctuations in climate as a crucial factor in maintaining perennial salinization. A primary process of this mechanism occurs during periods of arid climate, when enhanced evaporation results in the concentration of lake water and a significant drop in lake level, causing a difference in elevation between the ocean surface and the lake. This creates a hydraulic gradient sufficient to drive seawater seepage through the barrier, thereby further accelerating lake salinization. The proposed model offers a potential resolution to the long-standing debate surrounding the marine incursion hypothesis and empirical geological evidence for the study of lake salinization in analogous geological settings.
Severe heat stroke with multiorgan failure following collapse in a sauna
Authors: McIver William Jack , Zia Muhammad
Published: January 2025

Heat stroke is characterised by hyperthermia and acute encephalopathy. We describe a rare case of classical heat stroke secondary to prolonged sauna use with multiorgan sequelae including seizures, liver injury, kidney injury, disseminated intravascular coagulation, rhabdomyolysis and type 2 myocardial infarction. The patient was treated with external cooling, intravenous fluid therapy and blood products, and made a full recovery without need for advanced organ support. We discuss the evidence base surrounding the immediate treatment of heat stroke in the emergency department.
Cardiovascular events observed among patients in the etrasimod clinical programme: an integrated safety analysis of patients with moderately to severely active ulcerative colitis
Authors: Vermeire Séverine , Rubin David T , Peyrin-Biroulet Laurent , Dubinsky Marla C , Regueiro Miguel , Irving Peter M , Goetsch Martina , Lazin Krisztina , Gu Guibao , Wu Joseph , Modesto Irene , McDonnell Aoibhinn , Guo Xiang , Green Jesse , Dalam Alexis B , Yarur Andres J
Published: January 2025

Objective

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate (S1P)1,4,5receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P1receptor expression on cardiac cells is involved in cardiac conduction. We report cardiovascular treatment-emergent adverse events (TEAEs) associated with S1P receptor modulators and other cardiovascular events in the etrasimod UC clinical programme.

Methods

Patients were analysed in the Placebo-controlled UC cohort and All UC cohort. Incidence rates (IRs, per 100 patient-years) of cardiovascular-related TEAEs associated with S1P receptor modulators, including bradycardia/atrioventricular (AV) block and hypertension, and other cardiovascular events, including coronary artery disease (CAD) and cerebrovascular disease (CVD), were analysed.

Results

In patients receiving etrasimod, cardiovascular-related TEAEs were infrequent (≤2.6% per AE). In the Placebo-controlled UC cohort, IRs (95% CIs) for cardiovascular-related TEAEs were higher for patients receiving etrasimod (n=577) vs placebo (n=314), respectively, for bradycardia/sinus bradycardia, 3.85 (1.58 to 6.13) vs 0 and AV block, 1.40 (0.03 to 2.76) vs 0; and numerically higher for hypertension, 5.31 (2.62 to 7.99) vs 3.40 (0.07 to 6.72). Most bradycardia/AV block events were reported on day 1. All bradycardia and hypertension TEAEs were non-serious. One serious second-degree AV block type 1 TEAE occurred in the etrasimod group; no events of second-degree AV block type 2 or higher were reported. One event each of CAD and CVD occurred in two patients receiving etrasimod.

Conclusions

In the etrasimod UC clinical programme, IRs of cardiovascular-related TEAEs and other cardiovascular events were low. Most cardiovascular-related TEAEs were non-serious.

Trial registration numbers

NCT02447302;NCT03945188;NCT03996369;NCT02536404;NCT03950232;NCT04176588.
Developing an adaptive paediatric intensive care unit platform trial with key stakeholders: a qualitative study
Authors: Mitchell Tracy Karen , Menzies Julie C , Ramnarayan Padmanabhan , Gould Doug William , Deja Elizabeth , Marsh Shelley , Ainsworth Jennifer , Preston Jennifer , Sedgwick Hannah , Tibbins Carly , Mouncey Paul R , Peters Mark J , Woolfall Kerry
Published: January 2025

Objectives

Platform trials were used successfully in adult populations during the COVID-19 pandemic. By testing multiple treatments within a single trial, platform trials can help identify the most effective treatments (and any interactions between treatments) for patients more quickly and with less burden for patients and their families. The aim of this qualitative research was to inform the design of the first adaptive platform trial for paediatric intensive care in the UK with young people, parents/carers and paediatric intensive care unit (PICU) staff.

Design

Qualitative semistructured focus group study. Data were analysed using reflexive thematic analysis.

Participants

Young people, parents/carers, and PICU medical, nursing and research staff.

Setting

The UK.

Results

A total of 86 participants (18 young people; 15 parents/carers; 53 PICU staff) took part in 1 of 10 focus groups between May and September 2023. Participants viewed the proposed PICU platform trial and use of research without prior consent to be acceptable. Findings provide insight into how the PICU platform trial should be designed and operationalised, including having a broad and inclusive population eligible for inclusion onto the platform trial, with different inclusion and exclusion criteria for each domain; starting the trial with no more than three domains and prioritising the outcomes ofChild quality of lifeandSurvival(all participants). Optimal governance structure and suggestions about how any challenges to the success of the full trial can be overcome are also presented.

Conclusions

Young people, parents/carers and PICU staff viewed the proposed PICU platform trial to be acceptable. These key stakeholders supported us with the design of an adaptive platform trial for PICU that has a rigorous methodology, yet can be operationalised in a family-centred way, to provide high-quality evidence that can support clinical decision-making and guide the treatment of critically ill children. Our findings have informed the PICU platform trial protocol.