bluuebunny/crossref_metadata_2025_split huggingface dataset:
Physicians’ views on the role of relatives in euthanasia and physician-assisted suicide decision-making: a mixed-methods study among physicians in the Netherlands
Authors: Renckens Sophie C. , Onwuteaka-Philipsen Bregje D. , van der Heide Agnes , Pasman H. Roeline 
Published: April 2024

Abstract
Background
Relatives have no formal position in the practice of euthanasia and physician-assisted suicide (EAS) according to Dutch legislation. However, research shows that physicians often involve relatives in EAS decision-making. It remains unclear why physicians do (not) want to involve relatives. Therefore, we examined how many physicians in the Netherlands involve relatives in EAS decision-making and explored reasons for (not) involving relatives and what involvement entails.

Methods
In a mixed-methods study, 746 physicians (33% response rate) completed a questionnaire, and 20 were interviewed. The questionnaire included two statements on relatives’ involvement in EAS decision-making. Descriptive statistics were used, and multivariable logistic regression analyses to explore characteristics associated with involving relatives. In subsequent interviews, we explored physicians’ views on involving relatives in EAS decision-making. Interviews were thematically analysed.

Results
The majority of physicians want to know relatives’ opinions about an EAS request (80%); a smaller group also takes these opinions into account in EAS decision-making (35%). Physicians who had ever received an explicit EAS request were more likely to want to know opinions and clinical specialists and elderly care physicians were more likely to take these opinions into account. In interviews, physicians mentioned several reasons for involving relatives: e.g. to give relatives space and help them in their acceptance, to tailor support, to be able to perform EAS in harmony, and to mediate in case of conflicting views. Furthermore, physicians explained that relatives’ opinions can influence the decision-making process but cannot be a decisive factor. If relatives oppose the EAS request, physicians find the process more difficult and try to mediate between patients and relatives by investigating relatives’ objections and providing appropriate information. Reasons for not taking relatives’ opinions into account include not wanting to undermine patient autonomy and protecting relatives from a potential burdensome decision.

Conclusions
Although physicians know that relatives have no formal role, involving relatives in EAS decision-making is common practice in the Netherlands. Physicians consider this important as relatives need to continue with their lives and may need bereavement support. Additionally, physicians want to perform EAS in harmony with everyone involved. However, relatives’ opinions are not decisive.
Bacterial accumulation in intestinal folds induced by physical and biological factors
Authors: Yang Jinyou , Isaka Toma , Kikuchi Kenji , Numayama-Tsuruta Keiko , Ishikawa Takuji 
Published: April 2024

Abstract
Background
The gut microbiota, vital for host health, influences metabolism, immune function, and development. Understanding the dynamic processes of bacterial accumulation within the gut is crucial, as it is closely related to immune responses, antibiotic resistance, and colorectal cancer. We investigated Escherichia coli behavior and distribution in zebrafish larval intestines, focusing on the gut microenvironment.

Results
We discovered that E. coli spread was considerably suppressed within the intestinal folds, leading to a strong physical accumulation in the folds. Moreover, a higher concentration of E. coli on the dorsal side than on the ventral side was observed. Our in vitro microfluidic experiments and theoretical analysis revealed that the overall distribution of E. coli in the intestines was established by a combination of physical factor and bacterial taxis.

Conclusions
Our findings provide valuable insight into how the intestinal microenvironment affects bacterial motility and accumulation, enhancing our understanding of the behavioral and ecological dynamics of the intestinal microbiota.
Association between triglyceride–glucose index trajectories and radiofrequency ablation outcomes in patients with stage 3D atrial fibrillation
Authors: Jia Sixiang , Yin Yanping , Mou Xuanting , Zheng Jing , Li Zhe , Hu Tianli , Zhao Jianqiang , Lin Jiangbo , Song Jiaqi , Cheng Fanli , Wang Yiran , Li Kaini , Lin Wenting , Feng Chao , Ge Weili , Xia Shudong 
Published: April 2024

Abstract
Background
This study investigates the relationship between triglyceride-glucose (TyG) index trajectories and the results of ablation in patients with stage 3D atrial fibrillation (AF).

Methods
A retrospective cohort study was carried out on patients who underwent AF Radiofrequency Catheter Ablation (RFCA) at the Cardiology Department of the Fourth Affiliated Hospital of Zhejiang University and Taizhou Hospital of Zhejiang Province from January 2016 to December 2022. The main clinical endpoint was determined as the occurrence of atrial arrhythmia for at least 30 s following a 3-month period after ablation. Using a latent class trajectory model, different trajectory groups were identified based on TyG levels. The relationship between TyG trajectory and the outcome of AF recurrence in patients was assessed through Kaplan-Meier survival curve analysis and multivariable Cox proportional hazards regression model.

Results
The study included 997 participants, with an average age of 63.21 ± 9.84 years, of whom 630 were males (63.19%). The mean follow-up period for the participants was 30.43 ± 17.75 months, during which 200 individuals experienced AF recurrence. Utilizing the minimum Bayesian Information Criterion (BIC) and the maximum Entropy principle, TyG levels post-AF RFCA were divided into three groups: Locus 1 low-low group (n = 791), Locus 2 low-high-low group (n = 14), and Locus 3 high-high group (n = 192). Significant differences in survival rates among the different trajectories were observed through the Kaplan-Meier curve (P < 0.001). Multivariate Cox regression analysis showed a significant association between baseline TyG level and AF recurrence outcomes (HR = 1.255, 95% CI: 1.087–1.448). Patients with TyG levels above 9.37 had a higher risk of adverse outcomes compared to those with levels below 8.67 (HR = 2.056, 95% CI: 1.335–3.166). Furthermore, individuals in Locus 3 had a higher incidence of outcomes compared to those in Locus 1 (HR = 1.580, 95% CI: 1.146-2).

Conclusion
The TyG trajectories in patients with stage 3D AF are significantly linked to the outcomes of AF recurrence. Continuous monitoring of TyG levels during follow-up may help in identifying patients at high risk of AF recurrence, enabling the early application of effective interventions.
Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal
Authors: Yu Biao , Gao Qianmin , Sheng Shihao , Zhou Fengjin , Geng Zhen , Wei Yan , Zhang Hao , Hu Yan , Wang Sicheng , Huang Jianping , Li Mengmeng , Su Jiacan 
Published: April 2024

Abstract
Background
Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis.

Results
Osteoclasts’ microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model.

Conclusion
The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.
Substance use patterns, sociodemographics, and health profiles of harm reduction service recipients in Burlington, Vermont
Authors: Erath Tyler G. , LaCroix Rosalie , O’Keefe Erin , Higgins Stephen T. , Rawson Richard A. 
Published: April 2024

Abstract
Background
Understanding current substance use practices is critical to reduce and prevent overdose deaths among individuals at increased risk including persons who use and inject drugs. Because individuals participating in harm reduction and syringe service programs are actively using drugs and vary in treatment participation, information on their current drug use and preferred drugs provides a unique window into the drug use ecology of communities that can inform future intervention services and treatment provision.

Methods
Between March and June 2023, 150 participants in a harm reduction program in Burlington, Vermont completed a survey examining sociodemographics; treatment and medication for opioid use disorder (MOUD) status; substance use; injection information; overdose information; and mental health, medical, and health information. Descriptive analyses assessed overall findings. Comparisons between primary drug subgroups (stimulants, opioids, stimulants-opioids) of past-three-month drug use and treatment participation were analyzed using chi-square and Fisher’s exact test.

Results
Most participants reported being unhoused or unstable housing (80.7%) and unemployed (64.0%) or on disability (21.3%). The drug with the greatest proportion of participants reporting past three-month use was crack cocaine (83.3%). Fentanyl use was reported by 69.3% of participants and xylazine by 38.0% of participants. High rates of stimulant use were reported across all participants independent of whether stimulants were a participant’s primary drug. Fentanyl, heroin, and xylazine use was less common in the stimulants subgroup compared to opioid-containing subgroups (p < .001). Current- and past-year MOUD treatment was reported by 58.0% and 77.3% of participants. Emergency rooms were the most common past-year medical treatment location (48.7%; M = 2.72 visits).

Conclusions
Findings indicate high rates of polysubstance use and the underrecognized effects of stimulant use among people who use drugs—including its notable and increasing role in drug-overdose deaths. Crack cocaine was the most used stimulant, a geographical difference from much of the US where methamphetamine is most common. With the increasing prevalence of fentanyl-adulterated stimulants and differences in opioid use observed between subgroups, these findings highlight the importance and necessity of harm reduction interventions (e.g., drug checking services, fentanyl test strips) and effective treatment for individuals using stimulants alongside MOUD treatment.
Lymphovascular invasion is associated with poor long-term outcomes in patients with pT1N0-3 or pT2-3N0 remnant gastric cancer: a retrospective cohort study
Authors: Sumiyoshi Shutaro , Ohashi Takuma , Kubota Takeshi , Nishibeppu Keiji , Owada Kaho , Kiuchi Jun , Shimizu Hiroki , Arita Tomohiro , Iitaka Daisuke , Yamamoto Yusuke , Konishi Hirotaka , Morimura Ryo , Watanabe Kenji , Kuriu Yoshiaki , Shiozaki Atsushi , Ikoma Hisashi , Fujiwara Hitoshi , Yamaoka Nobuki , Otsuji Eigo 
Published: April 2024

Abstract
Background
Lymphovascular invasion (LVI) is a poor prognostic factor in various malignancies. However, its prognostic effect in remnant gastric cancer (RGC) remains unclear. We examined the correlation between LVI and disease prognosis in patients with T1N0-3 or T2-3N0 RGC in whom adjuvant chemotherapy was not indicated and a treatment strategy was not established.

Methods
We retrospectively analyzed patients with T1N0-3 and T2-3N0 RGC who underwent curative surgery at the Kyoto Prefectural University of Medicine between 1997 and 2019 and at the Kyoto Chubu Medical Center between 2009 and 2019.

Results
Fifteen of 38 patients (39.5%) with RGC were positive for LVI. Patients with LVI had a significantly poorer prognosis for both overall survival ([OS]: P = 0.006) and recurrence-free survival ([RFS]: P = 0.001) than those without LVI. Multivariate analyses using the Cox proportional hazards model revealed LVI as an independent prognostic factor affecting OS (P = 0.024; hazard ratio 8.27, 95% confidence interval:1.285–161.6) and RFS (P = 0.013; hazard ratio 8.98, 95% confidence interval:1.513–171.2).

Conclusions
LVI is a prognostic factor for patients with T1N0-3 or T2-3N0 RGC. Evaluating LVI may be useful for determining treatment strategies for RGC.
Consumption of dietary fiber and APOA5 genetic variants in metabolic syndrome: baseline data from the Korean Medicine Daejeon Citizen Cohort Study
Authors: Kim Jimi , Baek Younghwa , Lee Siwoo 
Published: April 2024

Abstract
Background
Consumption of dietary fiber has been suggested as an important aspect of a healthy diet to reduce the risk of metabolic syndrome (MetS), including cardiovascular disease. The role of fiber intake in MetS might differ by individual genetic susceptibility. APOA5 encodes a regulator of plasma triglyceride levels, which impacts the related mechanisms of MetS. This study investigated the association between dietary fiber and the risk of MetS, assessing their associations according to APOA5 genetic variants.

Methods
A total of 1985 participants aged 30–55 years were included from a cross-sectional study based on the Korean Medicine Daejeon Citizen Cohort study at baseline (2017–2019). Dietary fiber intake was measured using a semiquantitative food frequency questionnaire. The APOA5 polymorphisms (rs2266788 A > G, rs662799 A > G, and rs651821 T > C) were genotyped using the Asia Precision Medicine Research Array. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs).

Results
A higher consumption of dietary fiber was associated with a lower prevalence of MetS (P = 0.025). Among the components of MetS, an inverse association with dietary fiber was observed in increased waist circumference (OR, 95% CI = 0.60, 0.41–0.88, P for trend = 0.009) and elevated triglycerides (OR, 95% CI = 0.69, 0.50–0.96, P for trend = 0.012). Regarding the interaction with APOA5 genetic variants, a stronger association with dietary fiber intake was shown in G allele carriers of rs662799 than in A/A carriers (OR, 95% CI = 2.34, 1.59–3.44, P for interaction = 0.024) and in C allele carriers of rs651821 than in T/T carriers (OR, 95% CI = 2.35, 1.59–3.46, P for interaction = 0.027).

Conclusions
The findings of this study suggest that the benefits of dietary fiber on the risk of MetS could be modified by genetic variants of the APOA5 gene, providing a more effective strategy for preventing MetS.
Sleep disturbance in Angelman syndrome patients
Authors: Qu Song , Wang Junyi , Guan Xingying , Song Cui , Wang Yanyan 
Published: April 2024

AbstractAngelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression of the maternal ubiquitin protein ligase E3A gene (UBE3A). As one of the most challenging symptoms and important focuses of new treatment, sleep disturbance is reported to occur in 70–80% of patients with AS and has a serious impact on the lives of patients and their families. Although clinical studies and animal model studies have provided some clues, recent research into sleep disorders in the context of AS is still very limited. It is generally accepted that there is an interaction between neurodevelopment and sleep; however, there is no recognized mechanism for sleep disorders in AS patients. Accordingly, there are no aetiologically specific clinical treatments for AS-related sleep disorders. The most common approaches involve ameliorating symptoms through methods such as behavioural therapy and symptomatic pharmacotherapy. In recent years, preclinical and clinical studies on the targeted treatment of AS have emerged. Although precision therapy for restoring the UBE3A level and the function of its signalling pathways is inevitably hindered by many remaining obstacles, this approach has the potential to address AS-related sleep disturbance.
An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders
Authors: Dorion Marie-France , Casas Diana , Shlaifer Irina , Yaqubi Moein , Fleming Peter , Karpilovsky Nathan , Chen Carol X.-Q. , Nicouleau Michael , Piscopo Valerio E. C. , MacDougall Emma J. , Alluli Aeshah , Goldsmith Taylor M. , Schneider Alexandria , Dorion Samuel , Aprahamian Nathalia , MacDonald Adam , Thomas Rhalena A. , Dudley Roy W. R. , Hall Jeffrey A. , Fon Edward A. , Antel Jack P. , Stratton Jo Anne , Durcan Thomas M. , La Piana Roberta , Healy Luke M. 
Published: April 2024

Abstract
Background
Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R.

Methods
Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL.

Results
The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls.

Conclusions
We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities.

Graphical Abstract
Increased DNA methylation contributes to the early ripening of pear fruits during domestication and improvement
Authors: Song Bobo , Yu Jinshan , Li Xiaolong , Li Jiaming , Fan Jing , Liu Hainan , Wei Weilin , Zhang Lingchao , Gu Kaidi , Liu Dongliang , Zhao Kejiao , Wu Jun 
Published: April 2024

AbstractBackgroundDNA methylation is an essential epigenetic modification. However, its contribution to trait changes and diversity in the domestication of perennial fruit trees remains unknown.ResultsHere, we investigate the variation in DNA methylation during pear domestication and improvement using whole-genome bisulfite sequencing in 41 pear accessions. Contrary to the significant decrease during rice domestication, we detect a global increase in DNA methylation during pear domestication and improvement. We find this specific increase in pear is significantly correlated with the downregulation ofDemeter-like1(DML1, encoding DNA demethylase) due to human selection. We identify a total of 5591 differentially methylated regions (DMRs). Methylation in the CG and CHG contexts undergoes co-evolution during pear domestication and improvement. DMRs have higher genetic diversity than selection sweep regions, especially in the introns. Approximately 97% of DMRs are not associated with any SNPs, and these DMRs are associated with starch and sucrose metabolism and phenylpropanoid biosynthesis. We also perform correlation analysis between DNA methylation and gene expression. We find genes close to the hypermethylated DMRs that are significantly associated with fruit ripening. We further verify the function of a hyper-DMR-associated gene,CAMTA2, and demonstrate that overexpression ofCAMTA2in tomato and pear callus inhibits fruit ripening.ConclusionsOur study describes a specific pattern of DNA methylation in the domestication and improvement of a perennial pear tree and suggests that increased DNA methylation plays an essential role in the early ripening of pear fruits.
Impact of CT-determined low kidney volume on renal function decline: a propensity score-matched analysis
Authors: Kikuchi Tomohiro , Hanaoka Shouhei , Nakao Takahiro , Nomura Yukihiro , Mori Harushi , Yoshikawa Takeharu 
Published: April 2024

Abstract
Objectives
To investigate the relationship between low kidney volume and subsequent estimated glomerular filtration rate (eGFR) decline in eGFR category G2 (60–89 mL/min/1.73 m2) population.

Methods
In this retrospective study, we evaluated 5531 individuals with eGFR category G2 who underwent medical checkups at our institution between November 2006 and October 2017. Exclusion criteria were absent for follow-up visit, missing data, prior renal surgery, current renal disease under treatment, large renal masses, and horseshoe kidney. We developed a 3D U-net-based automated system for renal volumetry on CT images. Participants were grouped by sex-specific kidney volume deviations set at mean minus one standard deviation. After 1:1 propensity score matching, we obtained 397 pairs of individuals in the low kidney volume (LKV) and control groups. The primary endpoint was progression of eGFR categories within 5 years, assessed using Cox regression analysis.

Results
This study included 3220 individuals (mean age, 60.0 ± 9.7 years; men, n = 2209). The kidney volume was 404.6 ± 67.1 and 376.8 ± 68.0 cm3 in men and women, respectively. The low kidney volume (LKV) cutoff was 337.5 and 308.8 cm3 for men and women, respectively. LKV was a significant risk factor for the endpoint with an adjusted hazard ratio of 1.64 (95% confidence interval: 1.09–2.45; p = 0.02).

Conclusion
Low kidney volume may adversely affect subsequent eGFR maintenance; hence, the use of imaging metrics may help predict eGFR decline.

Critical relevance statement
Low kidney volume is a significant predictor of reduced kidney function over time; thus, kidney volume measurements could aid in early identification of individuals at risk for declining kidney health.

Key points
• This study explores how kidney volume affects subsequent kidney function maintenance.
• Low kidney volume was associated with estimated glomerular filtration rate decreases.
• Low kidney volume is a prognostic indicator of estimated glomerular filtration rate decline.

Graphical Abstract