bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of DUSP4/6 overexpression as a potential rheostat to NRAS-induced hepatocarcinogenesis
Authors: Klemm Sophie , Evert Katja , Utpatel Kirsten , Muggli Alexandra , Simile Maria M. , Chen Xin , Evert Matthias , Calvisi Diego F. , Scheiter Alexander
Published: November 2023

Background

Upregulation of the mitogen-activated protein kinase (MAPK) cascade is common in hepatocellular carcinoma (HCC). Neuroblastoma RAS viral oncogene homolog (NRAS) is mutated in a small percentage of HCC and is hitherto considered insufficient for hepatocarcinogenesis. We aimed to characterize the process of N-Ras-dependent carcinogenesis in the liver and to identify potential therapeutic vulnerabilities.

Methods

NRAS V12 plasmid was delivered into the mouse liver via hydrodynamic tail vein injection (HTVI). The resulting tumours, preneoplastic lesions, and normal tissue were characterized by NanoString® gene expression analysis, Western Blot, and Immunohistochemistry (IHC). The results were further confirmed by in vitro analyses of HCC cell lines.

Results

HTVI with NRAS V12 plasmid resulted in the gradual formation of preneoplastic and neoplastic lesions in the liver three months post-injection. These lesions mostly showed characteristics of HCC, with some exceptions of spindle cell/ cholangiocellular differentiation. Progressive upregulation of the RAS/RAF/MEK/ERK signalling was detectable in the lesions by Western Blot and IHC. NanoString® gene expression analysis of preneoplastic and tumorous tissue revealed a gradual overexpression of the cancer stem cell marker CD133 and Dual Specificity Phosphatases 4 and 6 (DUSP4/6). In vitro, transfection of HCC cell lines with NRAS V12 plasmid resulted in a coherent upregulation of DUSP4 and DUSP6. Paradoxically, this upregulation in PLC/PRF/5 cells was accompanied by a downregulation of phosphorylated extracellular-signal-regulated kinase (pERK), suggesting an overshooting compensation. Silencing of DUSP4 and DUSP6 increased proliferation in HCC cell lines.

Conclusions

Contrary to prior assumptions, the G12V NRAS mutant form is sufficient to elicit hepatocarcinogenesis in the mouse. Furthermore, the upregulation of the MAPK cascade was paralleled by the overexpression of DUSP4, DUSP6, and CD133 in vivo and in vitro. Therefore, DUSP4 and DUSP6 might fine-tune the excessive MAPK activation, a mechanism that can potentially be harnessed therapeutically.
Two- and three-dimensional measurements of leg length change using an accelerometer-based portable navigation system in total hip arthroplasty
Authors: Hasegawa Masahiro , Naito Yohei , Tone Shine , Sudo Akihiro
Published: November 2023

Background

The aim of this study was examining the accuracy of accelerometer-based portable navigation systems (HipAlign) when measuring leg length changes using two-dimensional (2D) and three-dimensional (3D) methods.

Methods

Inclusion criteria were patients ≥ 20 years old with symptomatic hip disease who underwent primary total hip arthroplasty (THA) in the supine position using HipAlign between June 2019 and April 2020. The exclusion criteria were patients who underwent THA via a posterior approach. We examined correlations between the leg length change measurement with HipAlign and either 2D or 3D measurement. We performed a multivariate analysis to determine which factors may have influenced the absolute error results.

Results

This study included 34 patients. The absolute error in leg length change between the HipAlign and 3D measurement (4.0 mm) was greater than the HipAlign and 2D measurement (1.7 mm). There were positive correlations between leg length change with HipAlign and 2D and 3D measurements. Male patients had larger errors with 2D measurement. No significant factors were identified for 3D measurement.

Conclusion

HipAlign provided acceptable measurement accuracy for leg length changes.
Association between segmental body composition and bone mineral density in US adults: results from the NHANES (2011–2018)
Authors: Lin Yanze , Wang Xun , Wu Ruiji , Zhou Jinlei , Feng Fabo
Published: November 2023

Objective

The association between segmental body composition and bone mineral density (BMD) remains uncertain. The primary aim of this cross-sectional investigation was to elucidate the connection between segmental body composition and BMD within the United States adult population.

Methods

We selected a cohort of 10,096 individuals from the National Health and Nutrition Examination Survey (NHANES) database, with a mean age of 39 years and a mean BMI of 28.5 kg/m². The parameter of segmental body composition was achieved by quantifying body fat and lean mass percentages across various anatomical regions, including the torso, Android, Gynoid, arms and legs. We conducted a weighted multivariate linear regression analysis to investigate the association between segmental body composition and total BMD. Additionally, subgroup analysis was performed based on age and gender.

Results

We found an inverse association between fat proportion in each anatomical region and total BMD, with the arm and leg regions demonstrating the most significant negative correlation. Conversely, a positive correlation was observed between lean mass and BMD across all anatomical regions. These associations remained consistent in subgroup analyses.

Conclusion

Our investigation revealed a negative association between adipose levels in various anatomical regions and BMD among Americans aged 20 to 59. Importantly, higher fat proportion in the extremities exerted the most deleterious impact on BMD. Furthermore, an increase in lean mass within each anatomical region was ascertained to confer a positive effect on bone health. Consequently, the evaluation of segmental body composition is well-positioned to predict bone health status.
Exploring the variations in death anxiety among oncology nurses in China: a latent class analysis
Authors: Chen Xian , Su Mengyu , Arber Anne , Qiao Chengping , Wu Jinfeng , Sun Cuihua , Wang Dan , Zhou Hui , Zhu Zhu
Published: November 2023

Background

Various factors have been found to be associated with high levels of death anxiety experienced by oncology nurses. The aim of this study was to use a person-oriented approach to examine the death anxiety patterns of Chinese oncology nurses and to analyze the differences in anxiety characteristics and their associated influencing factors.

Methods

A cross-sectional survey regarding palliative care among registered oncology nurses was conducted in Jiangsu Province, China.Latent class analyses was applied to identify their patterns of death anxiety. The score of PCQN-C (The Chinese version of the Palliative Care Quiz for Nursing) and FATCOD-B-C (The Chinese version of the Frommelt Attitude Toward Care of the Dying scale), the demographic and working characteristics were further analyzed through covariance analysis (ANCOVA) and multivariate (or logistic) regression across the subgroups.

Results

A two-potential-category model was selected based on the fit index. The results showed that 79% of oncology nurses belonged to the high pressure and pain group and 21% belonged to the low death anxiety group. The high pressure and pain group had significantly higher scores in the dimensions of emotion, stress and pain, time awareness, and cognition compared to the low death anxiety group. Factors influencing the high pressure and pain group included shorter working years, non-national or provincial oncology nursing specialists, non-national palliative care specialists, never discussing the topic of death with patients or family members, no palliative care related training, and PCQN and FATCOD scores.

Conclusions

Our study suggests that oncology nurses’ death anxiety can be divided into two categories: low death anxiety and high stress pain, and certain factors, such as being female, having a short work experience, and lacking palliative care-related training, increase the likelihood of death anxiety.
Effectiveness of an amygdala and insula retraining program combined with mindfulness training to improve the quality of life in patients with long COVID: a randomized controlled trial protocol
Authors: Gasión Virginia , Barceló-Soler Alberto , Beltrán-Ruiz María , Hijar-Aguinaga Rinchen , Camarero-Grados Loreto , López-del-Hoyo Yolanda , García-Campayo Javier , Montero-Marin Jesus
Published: November 2023

Background

There has been growing clinical awareness in recent years of the long-term physical and psychological consequences of the SARS-CoV-2 virus, known as Long COVID. The prevalence of Long COVID is approximately 10% of those infected by the virus. Long COVID is associated with physical and neuropsychological symptoms, including those related to mental health, psychological wellbeing, and cognition. However, research on psychological interventions is still in its early stages, in which means that available results are still limited. The main objective of this study is to evaluate the effects of a program based on amygdala and insula retraining (AIR) combined with mindfulness training (AIR + Mindfulness) on the improvement of quality of life, psychological well-being, and cognition in patients with Long COVID.

Methods

This study protocol presents a single-blind randomized controlled trial (RCT) that encompasses baseline, post-treatment, and six-month follow-up assessment time points. A total of 100 patients diagnosed with Long COVID by the Spanish National Health Service will be randomly assigned to either AIR + Mindfulness (n = 50) or relaxation intervention (n = 50), the latter as a control group. The primary outcome will be quality of life assessed using the Short Form-36 Health Survey (SF-36). Additional outcomes such as fatigue, pain, anxiety, memory, and sleep quality will also be evaluated. Mixed effects regression models will be used to estimate the effectiveness of the program, and effect size calculations will be made.

Discussion

Long COVID syndrome is a clinical condition characterized by the persistence of symptoms for at least 12 weeks after the onset of COVID-19 that significantly affects people’s quality of life. This will be the first RCT conducted in Spain to apply a psychotherapy program for the management of symptoms derived from Long COVID. Positive results from this RCT may have a significant impact on the clinical context by confirming the beneficial effect of the intervention program being evaluated on improving the symptoms of Long COVID syndrome and aiding the development of better action strategies for these patients.

Trial registration

Clinical Trials.gov NCT05956405. Registered on July 20, 2023.
AI in medical education: medical student perception, curriculum recommendations and design suggestions
Authors: Li Qianying , Qin Yunhao
Published: November 2023

Medical AI has transformed modern medicine and created a new environment for future doctors. However, medical education has failed to keep pace with these advances, and it is essential to provide systematic education on medical AI to current medical undergraduate and postgraduate students. To address this issue, our study utilized the Unified Theory of Acceptance and Use of Technology model to identify key factors that influence the acceptance and intention to use medical AI. We collected data from 1,243 undergraduate and postgraduate students from 13 universities and 33 hospitals, and 54.3% reported prior experience using medical AI. Our findings indicated that medical postgraduate students have a higher level of awareness in using medical AI than undergraduate students. The intention to use medical AI is positively associated with factors such as performance expectancy, habit, hedonic motivation, and trust. Therefore, future medical education should prioritize promoting students’ performance in training, and courses should be designed to be both easy to learn and engaging, ensuring that students are equipped with the necessary skills to succeed in their future medical careers.
An outcomes-based module education via flipped classroom enhances undergraduate oral histopathology learning
Authors: Zhong Yi , Zhang Yuyao , Sun Wen , Li Lu , Zhang Wei , Jiang Yue , Lu Xiaoqing , Cai Chenjie , Wang Huiling , Liu Laikui , Xu Yan
Published: November 2023

Introduction

Oral histopathology is a bridge course connecting oral basic medicine and clinical dentistry. However, the application of outcomes-based education via flipped classroom (FC) in oral histopathology has not been well explored. This study has assessed the efficacy of outcomes-based education via FC in undergraduate oral histopathology module learning in Nanjing Medical University of China.

Materials and methods

A total of 214 third-year students were enrolled and assigned to the FC group of the batch 2022-23 (n = 110) and the traditional classroom (TC) group of the batch 2021-22 (n = 104) to participate the oral histopathology sessions respectively in the study. The FC group were required to preview the online course materials pre-class, followed by in-class quizz, in-class interactive group discussion, and slides microscopic observation. The outcomes-based formative and summative assessments for FC were designed. The TC group attended traditional laboratory class for the same glass slides microscopic observation. In addition, a questionnaire was performed to investigate the satisfaction of learning. Along with this, the performances of FC group in written theory tests and oral histopathology slide tests were compared with TC group.

Results

Students in the FC group gained significantly final higher scores of the course than those in the TC group (score: 83.79 ± 11 vs. 76.73 ± 10.93, P<0.0001). Data from the student questionnaires indicated a preference for outcomes-based module education via FC. In the questionnaires, most students considered outcomes-based module education via FC to be beneficial to learning motivation, knowledge comprehension, critical thinking and teamwork. FC group had a higher level of satisfaction with oral histopathology teaching than TC group (satisfaction score: 4.599 ± 0.1027 vs. 4.423 ± 0.01366, P<0.01).

Conclusion

An outcomes-based module education via FC has a promising effect on undergraduate oral histopathology education.
Characteristics and quality assessment of online mentoring profile texts in academic medical mentoring
Authors: Gernert Jonathan A. , Warm Maximilian , Salvermoser Lukas , Krüger Nils , Bethe Stephan , Kocheise Lorenz , von Hake Malte , Meyer-Schwickerath Charlotte , Graupe Tanja , Fischer Martin R. , Dimitriadis Konstantinos
Published: November 2023

Background

Mentoring is important for a successful career in academic medicine. In online matching processes, profile texts are decisive for the mentor-selection. We aimed to qualitatively characterize mentoring-profile-texts, identify differences in form and content and thus elements that promote selection.

Methods

In a mixed method study first, quality of texts in 150 selected mentoring profiles was evaluated (10-point Likert scale; 1 = insufficient to 10 = very good). Second, based on a thematic and content analysis approach of profile texts, categories and subcategories were defined. We compared the presence of the assigned categories between the 25% highest ranked profiles with the 25% lowest ranked ones. Finally, additional predefined categories (hot topics) were labelled on the selected texts and their impact on student evaluation was statistically examined.

Results

Students rated the quality of texts with a mean of 5.89 ± 1.45. 5 main thematic categories, 21 categories and a total of 74 subcategories were identified. Ten subcategories were significantly associated with high- and four with low-rated profiles. The presence of three or more hot topics in texts significantly correlated with a positive evaluation.

Conclusion

The introduced classification system helps to understand how mentoring profile texts are composed and which aspects are important for choosing a suited mentor.
The effect of simulation-based advanced cardiac life support training on nursing students’ self-efficacy, attitudes, and anxiety in Palestine: a quasi-experimental study
Authors: Kassabry Maysa Fareed
Published: November 2023

Background

Cardiac Arrest (CA) is one of the leading causes of death, either inside or outside hospitals. Recently, the use of creative teaching strategies, such as simulation, has gained popularity in Cardio Pulmonary Resuscitation (CPR) instruction. This study aimed to assess the effect of High-Fidelity Simulation (HFS) training on nursing students’ self-efficacy, attitude, and anxiety in the context of Advanced Cardiac Life Support (ACLS).

Methodology

The study design is quasi-experimental employing a pre-test and post-test approach during April and May 2023. A convenient sample of 60 undergraduate nursing students in a 4-year class from a nursing college at the Arab American University/ Palestine (AAUP) participated in this study. The data were analyzed using a paired sample t-test in SPSS program version 26. Three data collection tools were used pre- and post-intervention; the Resuscitation Self-Efficacy Scale (RSES), The Attitudinal instrument, and the State Anxiety Inventory (SAI).

Results

The total number of nursing students was 60, out of them (56.7%) were female, while the mean age was (22.2) years. Improvements were seen in all four domains of self-efficacy following HFS training: recognition, debriefing, recording, responding and rescuing, and reporting. (t (59) = 26.80, p < 0.001, confidence interval [29.32, 34.05]). After receiving HFS training on ACLS, the post-intervention for the same group attitude scores significantly increased from 32.83 (SD = 15.35) to 54.58 (SD = 8.540) for emotion, from 6.72 (SD = 2.44) to 10.40 (SD = 1.40) for behavior, and from 7.03 (SD = 2.03) to 10.33 (SD = 1.42) for cognitive. The anxiety level decreased post-simulation from 3.53 (SD = 0.3) to 2.14 (SD = 0.65), which was found to be statistically significant (t(59) = 16.68, p < 0.001, 95% CI [1.22 to 1.55]). Female students (M = 73.18), students who observed a real resuscitation (M = 71.16), and who were satisfied with their nursing major (M = 72.17) had significantly higher self-efficacy scores post-simulation.

Conclusion

The HFS can be recommended as an effective training strategy among nursing students. The ACLS training-based HFS was effective in improving the students’ self-efficacy and attitudes and decreasing their anxiety.
The association between telomere length and non-alcoholic fatty liver disease: a prospective study
Authors: Tang Linxi , Li Dankang , Ma Yudiyang , Cui Feipeng , Wang Jianing , Tian Yaohua
Published: November 2023

Background

Research on the association between telomere length (TL) and incident non-alcoholic fatty liver disease (NAFLD) is limited. This study examined this association and further assessed how TL contributes to the association of NAFLD with its known risk factors.

Methods

Quantitative PCR (polymerase chain reaction) was employed to assess leucocyte telomere length. Polygenic risk score (PRS) for NAFLD, air pollution score, and lifestyle index were constructed. Cox proportional hazard models were conducted to estimate the hazard ratios (HRs) and 95% confidence intervals.

Results

Among 467,848 participants in UK Biobank, we identified 4809 NAFLD cases over a median follow-up of 12.83 years. We found that long TL was associated with decreased risk of incident NAFLD, as each interquartile range increase in TL resulted in an HR of 0.93 (95% CI 0.89, 0.96). TL partly mediated the association between age and NAFLD (proportion mediated: 15.52%). When assessing the joint effects of TL and other risk factors, the highest risk of NAFLD was found in participants with low TL and old age, low TL and high air pollution score, low TL and unfavorable lifestyle, and low TL and high PRS, compared to each reference group. A positive addictive interaction was observed between high PRS and low TL, accounting for 14.57% (2.51%, 27.14%) of the risk of NAFLD in participants with low telomere length and high genetic susceptibility.

Conclusions

Long telomere length was associated with decreased risk of NAFLD incidence. Telomere length played an important role in NAFLD.

Graphical Abstract
The oral bacterial microbiota facilitates the stratification for ulcerative colitis patients with oral ulcers
Authors: Xu Jun , Zhang Yu , Fang Xiao-Hui , Liu Yun , Huang Yi-Bo , Ke Zi-Liang , Wang Yang , Zhang Yi-Fan , Zhang Yang , Zhou Jian-Hua , Su Hui-Ting , Chen Ning , Liu Yu-Lan
Published: November 2023

Background

Clinically, a large part of inflammatory bowel disease (IBD) patients is complicated by oral lesions. Although previous studies proved oral microbial dysbiosis in IBD patients, the bacterial community in the gastrointestinal (GI) tract of those IBD patients combined with oral ulcers has not been profiled yet.

Methods

In this study, we enrolled four groups of subjects, including healthy controls (CON), oral ulcer patients (OU), and ulcerative colitis patients with (UC_OU) and without (UC) oral ulcers. Bio-samples from three GI niches containing salivary, buccal, and fecal samples, were collected for 16S rRNA V3-V4 region sequencing. Bacterial abundance and related bio-functions were compared, and data showed that the fecal microbiota was more potent than salivary and buccal microbes in shaping the host immune system. ~ 22 UC and 10 UC_OU 5-aminosalicylate (5-ASA) routine treated patients were followed-up for six months; according to their treatment response (a decrease in the endoscopic Mayo score), they were further sub-grouped as responding and non-responding patients.

Results

We found those UC patients complicated with oral ulcers presented weaker treatment response, and three oral bacterial genera, i.e., Fusobacterium, Oribacterium, and Campylobacter, might be connected with treatment responding. Additionally, the salivary microbiome could be an indicator of treatment responding in 5-ASA routine treatment rather than buccal or fecal ones.

Conclusions

The fecal microbiota had a strong effect on the host’s immune indices, while the oral bacterial microbiota could help stratification for ulcerative colitis patients with oral ulcers. Additionally, the oral microbiota had the potential role in reflecting the treatment response of UC patients. Three oral bacteria genera (Fusobacterium, Oribacterium, and Campylobacter) might be involved in UC patients with oral ulcers lacking treatment responses, and monitoring oral microbiota may be meaningful in assessing the therapeutic response in UC patients.
Quantitative assessment of asbestos fibers in some normal and pathological extra-abdominal tissues—a scoping review
Authors: Graziosi Francesca , Caffaro Paola , Bonetti Mattia , Roccuzzo Francesco , Rota Samantha , Boffetta Paolo , Caraballo-Arias Yohama Auxiliadora , Zunarelli Carlotta , Danilevskaia Nataliia , Violante Francesco Saverio
Published: November 2023

Background

Asbestos is a mineral present in nature and it has been used for years in numerous settings. Asbestos enters the bloodstream and lymphatic system mainly through breathing.

Objectives

Studies with asbestos fiber’s quantification in human tissues are scarce except for the lung. This article summarizes asbestos studies in some extra-abdominal tissues.

Methods

A scoping review of articles that quantified asbestos fibers in extra-abdominal tissues (lymph nodes, pharynx, larynx, trachea, heart) by electron microscopy (Scanning—SEM or Transmission—TEM) was performed.

Results

The 10 studies selected comprised 52 cases, out of whom 108 samples were analyzed. Mostly samples were lymph node tissues (102), followed by larynx (3) and myocardium (3). No studies were found that determined the presence of asbestos in the pharynx or trachea. The concentration of asbestos fibers detected in the lymph nodes was from 0.003 million fibers per gram of dry tissue (mfgdt) up to 7400 mfgdt, in the larynx the range was from 0.5 mfgdt up to 3.6 mfgdt, in myocardium no asbestos fibers were detected.

Discussion

The studies included were heterogeneous in terms of case and sample characteristics and analytical techniques. As subjects exposed to asbestos are often positive for fibers in thoracic lymph nodes, we suggest that whenever a human tissue sample is analyzed for asbestos presence, the relevant draining lymph node should be concomitantly studied.
Screening tools for sepsis identification in paramedicine and other emergency contexts: a rapid systematic review
Authors: De Silva Megan , Chadwick William , Naidoo Navindhra
Published: November 2023

Background

Sepsis is a life-threatening condition that contributes significantly to protracted hospitalisations globally. The unique positioning of paramedics and other emergency care cadres in emergency contexts enable the prospect of early identification and management of sepsis, however, a standardised screening tool still does not exist in the emergency setting. The objective of this review was to identify and recommend the most clinically ideal sepsis screening tool for emergency contexts such as emergency departments and out-of-hospital emergency contexts.

Methods

A rapid review of five databases (Medline, Embase, the Cochrane Library, CINAHL, and ProQuest Central) was undertaken, with searches performed on February 10, 2022. Covidence software was used by two authors for initial screening, and full text review was undertaken independently by each reviewer, with conflicts resolved by consensus-finding and a mediator. Systematic reviews, meta-analyses, randomised controlled trials, and prospective observational studies were eligible for inclusion. Data extraction used an a priori template and focused on sensitivity and specificity, with ROBINS-I and ROBIS bias assessment tools employed to assess risk of bias in included studies. Study details and key findings were summarised in tables. The a priori review protocol was registered on Open Science Framework (https://doi.org/10.17605/OSF.IO/3XQ5T).

Results

The literature search identified 362 results. After review, 18 studies met the inclusion criteria and were included for analysis. There were five systematic reviews, with three including meta-analysis, eleven prospective observational studies, one randomised controlled trial, and one validation study.

Conclusions

The review recognised that a paucity of evidence exists surrounding standardised sepsis screening tools in the emergency context. The use of a sepsis screening tool in the emergency environment may be prudent, however there is currently insufficient evidence to recommend a single screening tool for this context. A combination of the qSOFA and SIRS may be employed to avoid ‘practice paralysis’ in the interim. The authors acknowledge the inherent potential for publication and selection bias within the review due to the inclusion criteria.
Early-life gut microbiota in food allergic children and its impact on the development of allergic disease
Authors: Yan Xiumei , Yan Jingbin , Xiang Qiangwei , Dai Huan , Wang Yinghui , Fang Lingjuan , Huang Kaiyu , Zhang Weixi
Published: November 2023

Background

The prevalence of food allergies (FA) has been steadily increasing over 2 to 3 decades, showing diverse symptoms and rising severity. These long-term outcomes affect children’s growth and development, possibly linking to inflammatory bowel disease. However, the cause remains unclear. Previous studies reveal that early infancy significantly impacts FA development through gut microbiota. Yet, a consistent view on dysbiosis characteristics and its connection to future allergies is lacking. We explored how early-life gut microbiota composition relates to long-term clinical signs in children with FA through longitudinal research.

Methods

We employed high-throughput 16S rDNA gene sequencing to assess gut microbiota composition in early-life FA children in southern Zhejiang. Follow-up of clinical manifestations over 2 years allowed us to analyze the impact of early-life gut microbiota dysbiosis on later outcomes.

Results

While the diversity of gut microbiota in FA children remained stable, there were shifts in microbiota abundance. Abundant Akkermansia, Parabacteroides, Blautia, and Escherichia-Shigella increased, while Bifidobacterium and Clostridium decreased. After 2 years, two of ten FA children still showed symptoms. These two cases exhibited increased Escherichia-Shigella and reduced Bifidobacterium during early childhood. The other eight cases experienced symptom remission.

Conclusions

Our study suggests that FA and its prognosis might not correlate with early-life gut microbiota diversity. Further experiments are needed due to the small sample size, to confirm these findings.
Moving toward a contemporary classification of drug-induced kidney disease
Authors: Karimzadeh Iman , Barreto Erin F. , Kellum John A. , Awdishu Linda , Murray Patrick T. , Ostermann Marlies , Bihorac Azra , Mehta Ravindra L. , Goldstein Stuart L. , Kashani Kianoush B. , Kane-Gill Sandra L.
Published: November 2023

Drug-induced kidney disease (DIKD) accounts for about one-fourth of all cases of acute kidney injury (AKI) in hospitalized patients, especially in critically ill setting. There is no standard definition or classification system of DIKD. To address this, a phenotype definition of DIKD using expert consensus was introduced in 2015. Recently, a novel framework for DIKD classification was proposed that incorporated functional change and tissue damage biomarkers. Medications were stratified into four categories, including “dysfunction without damage,” “damage without dysfunction,” “both dysfunction and damage,” and “neither dysfunction nor damage” using this novel framework along with predominant mechanism(s) of nephrotoxicity for drugs and drug classes. Here, we briefly describe mechanisms and provide examples of drugs/drug classes related to the categories in the proposed framework. In addition, the possible movement of a patient’s kidney disease between certain categories in specific conditions is considered. Finally, opportunities and barriers to adoption of this framework for DIKD classification in real clinical practice are discussed. This new classification system allows congruencies for DIKD with the proposed categorization of AKI, offering clarity as well as consistency for clinicians and researchers.
Estimating genome-wide DNA methylation heterogeneity with methylation patterns
Authors: Lin Pei-Yu , Chang Ya-Ting , Huang Yu-Chun , Chen Pao-Yang
Published: November 2023

Background

In a heterogeneous population of cells, individual cells can behave differently and respond variably to the environment. This cellular diversity can be assessed by measuring DNA methylation patterns. The loci with variable methylation patterns are informative of cellular heterogeneity and may serve as biomarkers of diseases and developmental progression. Cell-to-cell methylation heterogeneity can be evaluated through single-cell methylomes or computational techniques for pooled cells. However, the feasibility and performance of these approaches to precisely estimate methylation heterogeneity require further assessment.

Results

Here, we proposed model-based methods adopted from a mathematical framework originally from biodiversity, to estimate genome-wide DNA methylation heterogeneity. We evaluated the performance of our models and the existing methods with feature comparison, and tested on both synthetic datasets and real data. Overall, our methods have demonstrated advantages over others because of their better correlation with the actual heterogeneity. We also demonstrated that methylation heterogeneity offers an additional layer of biological information distinct from the conventional methylation level. In the case studies, we showed that distinct profiles of methylation heterogeneity in CG and non-CG methylation can predict the regulatory roles between genomic elements in Arabidopsis. This opens up a new direction for plant epigenomics. Finally, we demonstrated that our score might be able to identify loci in human cancer samples as putative biomarkers for early cancer detection.

Conclusions

We adopted the mathematical framework from biodiversity into three model-based methods for analyzing genome-wide DNA methylation heterogeneity to monitor cellular heterogeneity. Our methods, namely MeH, have been implemented, evaluated with existing methods, and are open to the research community.
Rspo2 exacerbates rheumatoid arthritis by targeting aggressive phenotype of fibroblast-like synoviocytes and disrupting chondrocyte homeostasis via Wnt/β-catenin pathway
Authors: Guo Dong , Pan Haoyan , Lu Xueying , Chen Zhong , Zhou Laixi , Chen Shuxin , Huang Jin , Liang Xinzhi , Xiao Zhisheng , Zeng Hua , Shao Yan , Qi Weizhong , Xie Denghui , Lin Chuangxin
Published: November 2023

Background

The aggressive phenotype of fibroblast-like synoviocytes (FLS) has been identified as a contributing factor to the exacerbation of rheumatoid arthritis (RA) through the promotion of synovitis and cartilage damage. Regrettably, there is currently no effective therapeutic intervention available to address this issue. Recent research has shed light on the crucial regulatory role of R-spondin-2 (Rspo2) in cellular proliferation, cartilage degradation, and tumorigenesis. However, the specific impact of Rspo2 on RA remains poorly understood. We aim to investigate the function and mechanism of Rspo2 in regulating the aggressive phenotype of FLS and maintaining chondrocyte homeostasis in the context of RA.

Methods

The expression of Rspo2 in knee joint synovium and cartilage were detected in RA mice with antigen-induced arthritis (AIA) and RA patients. Recombinant mouse Rspo2 (rmRspo2), Rspo2 neutralizing antibody (Rspo2-NAb), and recombinant mouse DKK1 (rmDKK1, a potent inhibitor of Wnt signaling pathway) were used to explore the role and mechanism of Rspo2 in the progression of RA, specifically in relation to the aggressive phenotype of FLS and chondrocyte homeostasis, both in vivo and in vitro.

Results

We indicated that Rspo2 expression was upregulated both in synovium and articular cartilage as RA progressed in RA mice and RA patients. Increased Rspo2 upregulated the expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), as the ligand for Rspo2, and β-catenin in FLS and chondrocytes. Subsequent investigations revealed that intra-articular administration of rmRspo2 caused striking progressive synovitis and articular cartilage destruction to exacerbate RA progress in mice. Conversely, neutralization of Rspo2 or inhibition of the Wnt/β-catenin pathway effectively alleviated experimental RA development. Moreover, Rspo2 facilitated FLS aggressive phenotype and disrupted chondrocyte homeostasis primarily through activating Wnt/β-catenin pathway, which were effectively alleviated by Rspo2-NAb or rmDKK1.

Conclusions

Our data confirmed a critical role of Rspo2 in enhancing the aggressive phenotype of FLS and disrupting chondrocyte homeostasis through the Wnt/β-catenin pathway in the context of RA. Furthermore, the results indicated that intra-articular administration of Rspo2 neutralizing antibody or recombinant DKK1 might represent a promising therapeutic strategy for the treatment of RA.
CSF biomarker analysis of ABCA7 mutation carriers suggests altered APP processing and reduced inflammatory response
Authors: Duchateau Lena , Küҫükali Fahri , De Roeck Arne , Wittens Mandy M. J. , Temmerman Joke , Weets Ilse , Timmers Maarten , Engelborghs Sebastiaan , Bjerke Maria , Sleegers Kristel
Published: November 2023

Background

The Alzheimer’s disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism of action remains unclear. By studying CSF biomarkers reflecting different types of AD-related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.

Methods

The study population consisted of 229 AD patients for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. This included 28 PTC mutation and 16 pathogenic expansion carriers. CSF levels of Aβ1–42, Aβ1–40, P-tau181, T-tau, sAPPα, sAPPβ, YKL-40, and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers and the Aβ ratio between AD patients with or without an ABCA7 PTC mutation or expansion using linear regression on INT-transformed data with APOE-status, age and sex as covariates.

Results

Carriers of ABCA7 expansion mutations had significantly lower Aβ1–42 levels (P = 0.022) compared with non-carrier patients. The effect of the presence of ABCA7 mutations on CSF levels was especially pronounced in APOE ε4-negative carriers. In addition, VNTR expansion carriers had reduced Aβ1–40 (P = 0.023), sAPPα (P = 0.047), sAPPβ (P = 0.016), and YKL-40 (P = 0.0036) levels.

Conclusions

Our results are suggestive for an effect on APP processing by repeat expansions given the changes in the amyloid-related CSF biomarkers that were found in carriers. The decrease in YKL-40 levels in expansion carriers moreover suggests that these patients potentially have a reduced inflammatory response to AD damage. Moreover, our findings suggest the existence of a mechanism, independent of lowered expression, affecting neuropathology in expansion carriers.
Continuous symmetry and chirality measures: approximate algorithms for large molecular structures
Authors: Alon Gil , Ben-Haim Yuval , Tuvi-Arad Inbal
Published: November 2023

Quantifying imperfect symmetry of molecules can help explore the sources, roles and extent of structural distortion. Based on the established methodology of continuous symmetry and chirality measures, we develop a set of three-dimensional molecular descriptors to estimate distortion of large structures. These three-dimensional geometrical descriptors quantify the gap between the desirable symmetry (or chirality) and the actual one. They are global parameters of the molecular geometry, intuitively defined, and have the ability to detect even minute structural changes of a given molecule across chemistry, including organic, inorganic, and biochemical systems. Application of these methods to large structures is challenging due to countless permutations that are involved in the symmetry operations and have to be accounted for. Our approach focuses on iteratively finding the approximate direction of the symmetry element in the three-dimensional space, and the relevant permutation. Major algorithmic improvements over previous versions are described, showing increased accuracy, reliability and structure preservation. The new algorithms are tested for three sets of molecular structures including pillar[5]arene complexes with Li+, C100 fullerenes, and large unit cells of metal organic frameworks. These developments complement our recent algorithms for calculating continuous symmetry and chirality measures for small molecules as well as protein homomers, and simplify the usage of the full set of measures for various research goals, in molecular modeling, QSAR and cheminformatics.
Intranasal administration of induced pluripotent stem cell-derived cortical neural stem cell-secretome as a treatment option for Alzheimer’s disease
Authors: Mo Hyunkyung , Kim Juryun , Kim Jennifer Yejean , Kim Jang Woon , Han Heeju , Choi Si Hwa , Rim Yeri Alice , Ju Ji Hyeon
Published: November 2023

Background

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly, resulting in gradual destruction of cognitive abilities. Research on the development of various AD treatments is underway; however, no definitive treatment has been developed yet. Herein, we present induced pluripotent stem cell (iPSC)-derived cortical neural stem cell secretome (CNSC-SE) as a new treatment candidate for AD and explore its efficacy.

Methods

We first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation. Then to confirm the efficacy in vivo, CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity (5 μg/g, once a week, 4 weeks). The cell-mediated effects on nerve recovery, amyloid beta (Aβ) plaque aggregation, microglial and astrocyte detection in the brain, and neuroinflammatory responses were investigated. Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects.

Results

Human iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro. Furthermore, CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts. The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aβ plaque accumulation.

Conclusions

Our findings suggest that the iPSC-derived CNSC-SE may serve as a potential, non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.
The significance of goat milk in enhancing nutrition security: a scientiometric evaluation of research studies from 1966 to 2020
Authors: Idamokoro Emrobowansan Monday
Published: November 2023

Background

The present study aimed to reveal scientific findings on goat milk as an instrument to combat food and nutrition insecurity, while considering the recurrent challenge posed by food dearth and high rise of hunger among susceptible people of numerous nations.

Results

A sum of 9206 research outputs were extracted in a BibTeX design for evaluation by means of bibliometric package in R studio software. The generated result included, but not restricted to authors, citations, affiliations, journals and key words. Published research findings on goat milk as related to nutrition security retrieved from web of science (WOS) and Scopus data bases were used with an increase in scientific findings of an annual growth of 14.42% during the period of study. From the result of the study, Spain was rated in first position with a total of publications (n = 953), and a massive global scientific influence with the highest article citations (n = 17,035). The most commonly referred authors’ keywords in this research field were goat/s (n = 1605), milk (n = 920), dairy goat/s (n = 372), fatty acid/s (n = 307), cheese (n = 251), milk production (n = 220), milk consumption (n = 173), which all together gave a hint on associated research studies on goat milk and nutrition security.

Conclusions

The current study presented a global picture that covers the pool of scientific knowledge on goat milk research and its relevance in nutrition security, while giving a direction for more studies in this research area. It is of utmost importance to stress that the present findings only addressed prime areas of goat milk production as linked to nutrition security research, therefore, it is proposed that novel empirical study and potential research outcomes would give new understanding and insight on goat milk utilization as an avenue to tackle nutrition security issues as new findings emerges.
Root-associated symbiotic fungi enhance waterlogging tolerance of peach seedlings by increasing flavonoids and activities and gene expression of antioxidant enzymes
Authors: Liang Sheng-Min , Hashem Abeer , Abd-Allah Elsayed Fathi , Wu Qiang-Sheng
Published: November 2023

Root-associated symbiotic fungi can enhance the host plant’s ability to tolerate adverse environmental conditions, but it’s unclear whether and how they enhance waterlogged peach plants. This study aimed to investigate the effects of Funneliformis mosseae (Fm), an arbuscular mycorrhizal fungus, and Serendipita indica (Si), an endophytic fungus, on plant growth, root development, reactive oxygen species (ROS) levels, total flavonoids, ROS scavenging activity of flavonoids, and activities and gene expression of antioxidant enzymes in roots of waterlogged peach seedlings. Although waterlogging treatment had little effect on root development, Fm and Si, particularly Fm, improved root development variables to varying degrees. Waterlogging significantly promoted superoxide anion radicals (O2•−) and hydrogen peroxide (H2O2) levels, whereas Fm and Si distinctly reduced O2•− and H2O2 levels under waterlogging. Waterlogging triggered an increase in total flavonoids in fungi-inoculated seedlings, and the two fungi also significantly increased total flavonoid concentrations and the scavenging activity of total flavonoids to hydroxyl radical, O2•−, and 2,2-diphenyl-1-picrylhydrazyl radical. In addition, root fungal colonization rate was negatively and significantly correlated with O2•− and H2O2, but positively with total flavonoids. Under waterlogging conditions, Fm significantly raised root superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities, and Si likewise elevated root SOD, CAT, GPX, and peroxidase (POD) activities, compared with uninoculated treatment. Although the expression of various antioxidant enzyme genes in roots remained mostly unchanged or were inhibited by the waterlogging, Fm up-regulated the expression of PpSOD3 and PpSOD7, whereas Si up-regulated the expression of PpSOD3, PpCAT1, PpGPX6, PpGPX8, and PpPOD1. In conclusion, low oxidative bursts in Fm- and Si-inoculated peach plants exposed to waterlogging were associated with an increase in total flavonoids as well as activities and gene expression of antioxidant enzymes.

Graphical Abstract
A deep learning model for predicting multidrug-resistant organism infection in critically ill patients
Authors: Wang Yaxi , Wang Gang , Zhao Yuxiao , Wang Cheng , Chen Chen , Ding Yaoyao , Lin Jing , You Jingjing , Gao Silong , Pang Xufeng
Published: November 2023

Background

This study aimed to apply the backpropagation neural network (BPNN) to develop a model for predicting multidrug-resistant organism (MDRO) infection in critically ill patients.

Methods

This study collected patient information admitted to the intensive care unit (ICU) of the Affiliated Hospital of Qingdao University from August 2021 to January 2022. All patients enrolled were divided randomly into a training set (80%) and a test set (20%). The least absolute shrinkage and selection operator and stepwise regression analysis were used to determine the independent risk factors for MDRO infection. A BPNN model was constructed based on these factors. Then, we externally validated this model in patients from May 2022 to July 2022 over the same center. The model performance was evaluated by the calibration curve, the area under the curve (AUC), sensitivity, specificity, and accuracy.

Results

In the primary cohort, 688 patients were enrolled, including 109 (15.84%) MDRO infection patients. Risk factors for MDRO infection, as determined by the primary cohort, included length of hospitalization, length of ICU stay, long-term bed rest, antibiotics use before ICU, acute physiology and chronic health evaluation II, invasive operation before ICU, quantity of antibiotics, chronic lung disease, and hypoproteinemia. There were 238 patients in the validation set, including 31 (13.03%) MDRO infection patients. This BPNN model yielded good calibration. The AUC of the training set, the test set and the validation set were 0.889 (95% CI 0.852–0.925), 0.919 (95% CI 0.856–0.983), and 0.811 (95% CI 0.731–0.891), respectively.

Conclusions

This study confirmed nine independent risk factors for MDRO infection. The BPNN model performed well and was potentially used to predict MDRO infection in ICU patients.