bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Surgeon Type on Total Ankle Arthroplasty Readmission, Complication, and Infection Rates
Authors: Nixon Devon , Ko Hyunkyu , Martin Brook
Published: April 2024

Introduction/Purpose:

Total ankle arthroplasty (TAA) remains an attractive surgical option to address end-stage ankle pathology in appropriately selected patients. When successful, TAA can yield high patient satisfaction and marked improvements in patient- reported outcomes. However, surgical complications can lead to significant clinical impairment. TAA can be performed by both orthopedic surgeons and non-orthopedic surgeons – however, no prior study has compared TAA outcomes based on surgeon type.

Methods:

Utilizing Medicare claims from 2016 to 2019, we retrospectively identified patients ≥65 years of age who underwent TAA based on CPT coding. Patients on Medicare HMO, under age 65, and dual-eligible patients were excluded. Within this dataset, provider type was identified, allowing for comparisons between orthopedic and nonorthopedic surgeons. We compared groups based on readmission, all-complication, and infection rates within 1-year of TAA using logistic regressions controlling for age, sex, race, and comorbidity. To help mitigate bias, we also performed a propensity matched model with the same variables. Data were reported as percentage point (PPT) differences (95% CI) between groups, with a positive number indicating higher rate of complications among patients treated by nonorthopedic surgeons.

Results:

During our timeframe, 8,244 Medicare patients underwent TAA – 6,928 performed by orthopedic surgeons and 1,316 performed by non-orthopedic surgeons. There were no differences between groups based on age, sex, or race. Readmission rates were similar between groups (p=0.058). TAA performed by non-orthopedic surgeons had higher all-complication rates (43.4% vs. 36.7%, p< 0.001) and infection rates (8.9% vs. 4.7%, p< 0.001) compared to nonorthopedic surgeons. These differences in all- complication risk in non-orthopedic surgeons were further seen in logistic regression analyses (5.8 ppt (95% CI: 2.3, 9.4), p< 0.001) and propensity matched analyses (5.6 ppt (95% CI: 2.1, 9.2), p< 0.001). Group-differences were also revealed in infection risk through logistic regression analyses (3.9 ppt (95% CI: 2.0, 5.9), p< 0.001) and propensity matched analyses (3.8 ppt (95% CI: 1.8, 5.8), p< 0.001).

Conclusion:

TAA performed by non-orthopedic surgeons had greater all-complication and infection rates as compared to TAA done by orthopedic surgeons. Analyses of complications between orthopedic surgeons and non-orthopedic surgeons performing total ankle arthroplasty
Micro CT Analysis and 3D Modelling of Fluid Permeability of Talar Subchondral Bone After Marrow Stimulation Techniques Demonstrates Superiority of Nanofracture Over Microfracture and Fine Wire Drilling
Authors: Warren James P. , Canden Ahranee , Brockett Claire L. , Farndon Mark A.
Published: April 2024

Introduction/Purpose:

The aim was to compare different bone marrow stimulation techniques and consequent fluid permeability of subchondral bone by assessing flow of radiopaque contrast agent using μCT image analysis and 3D modelling.

Methods:

Donated human tali specimens (n=12) were prepared by creating separate matched 10mm diameter chondral defects in each. Each defect underwent one of three surgical techniques: fine wire drilling, nanofracture or microfracture, addition of radiopaque contrast agent and imaged using a clinical μCT scanner. Using Slicer 3D software each μCT scan was segmented for bone and contrast agent regions in each surgical site of each sample. Each site was resolved into a cylinder and the ratio of segmented pixels of contrast agent against bone calculated.

Results:

μCT analysis indicated that 8/12 nanofracture regions demonstrated enhanced flow of contrast to at least the depth of the fracture site, with some additional lateral flow also observed. 8/12 microfracture regions demonstrated flow of contrast agent localised to the fracture site and preferential flow laterally. Only 1/12 samples with fine wire drilling demonstrated any fluid flow. In 11/12 samples that showed no permeation of contrast agent, a residual layer of contrast agent on the chondral surface was seen. Segmentation of each sample site showed a significant increase (n=12, p< 0.05) in fluid flow of the contrast agent in the nanofracture sites (11%) compared to microfracture (5%) and fine wire drilling (2%).

Conclusion:

Nanofracture showed significantly improved fluid permeability throughout the surrounding trabecular structure, when compared to microfracture and fine wire drilling. Microfracture allowed some fluid flow, but only confined to the immediate area around the fracture site, while fine wire drilling allows very little fluid flow at all. This study suggests that nanofracture should perhaps be the preferred mode of subchondral bone preparation for osteochondral lesions of the talus. Quantitative measurement of contrast permeability into talar subchondral bone by technique Nanofracture showed significantly improved fluid permeability throughout the surrounding trabecular structure, when compared to microfracture and fine wire drilling
The paradox of the safer cigarette: understanding the pulmonary effects of electronic cigarettes
Authors: Allbright Kassandra , Villandre John , Crotty Alexander Laura E. , Zhang Michael , Benam Kambez H. , Evankovich John , Königshoff Melanie , Chandra Divay
Published: April 2024

Electronic cigarette (e-cigarette) use continues to rise globally. E-cigarettes have been presented as safer alternatives to combustion cigarettes that can mitigate the harm associated with tobacco products; however, the degree to which e-cigarette use itself can lead to morbidity and mortality is not fully defined. Herein we describe how e-cigarettes function; discuss the current knowledge of the effects of e-cigarette aerosol on lung cell cytotoxicity, inflammation, antipathogen immune response, mucociliary clearance, oxidative stress, DNA damage, carcinogenesis, matrix remodelling and airway hyperresponsiveness; and summarise the impact on lung diseases, including COPD, respiratory infection, lung cancer and asthma. We highlight how the inclusion of nicotine or flavouring compounds in e-liquids can impact lung toxicity. Finally, we consider the paradox of the safer cigarette: the toxicities of e-cigarettes that can mitigate their potential to serve as a harm reduction tool in the fight against traditional cigarettes, and we summarise the research needed in this underinvestigated area.
Photophobia is associated with lower sleep quality in individuals with migraine: results from the American Registry for Migraine Research (ARMR)
Authors: Sharp Nina , Burish Mark J , Digre Kathleen B , Ailani Jessica , Fani Mahya , Lamp Sophia , Schwedt Todd J.
Published: April 2024

Background

Patients with migraine often have poor sleep quality between and during migraine attacks. Furthermore, extensive research has identified photophobia as the most common and most bothersome symptom in individuals with migraine, second only to headache. Seeking the comfort of darkness is a common strategy for managing pain during an attack and preventing its recurrence between episodes. Given the well-established effects of daily light exposure on circadian activity rhythms and sleep quality, this study aimed to investigate the relationship between photophobia symptoms and sleep quality in a cohort of patients with migraine.

Methods

A cross-sectional observational study was conducted using existing data extracted from the American Registry for Migraine Research (ARMR). Participants with a migraine diagnosis who had completed the baseline questionnaires (Photosensitivity Assessment Questionnaire (PAQ), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-2 (PHQ-2)), and selected questions of the ARMR Sleep questionnaire were included. Models were created to describe the relationship of photophobia and photophilia with various sleep facets, including sleep quality (SQ), sleep disturbance (SDis), sleep onset latency (SOL), sleep-related impairments (SRI), and insomnia. Each model was controlled for age, sex, headache frequency, anxiety, and depression.

Results

A total of 852 patients meeting the inclusion criteria were included in the analysis (mean age (SD) = 49.8 (13.9), 86.6% (n = 738) female). Those with photophobia exhibited significantly poorer sleep quality compared to patients without photophobia (p < 0.001). Photophobia scores were associated with SQ (p < 0.001), SDis (p < 0.001), SOL (p = 0.011), SRI (p = 0.020), and insomnia (p = 0.005) after controlling for age, sex, headache frequency, depression, and anxiety, signifying that higher levels of photophobia were associated with worse sleep-related outcomes. Conversely, photophilia scores were associated with better sleep-related outcomes for SQ (p < 0.007), SOL (p = 0.010), and insomnia (p = 0.014).

Conclusion

Results suggest that photophobia is a significant predictor of poor sleep quality and sleep disturbances in migraine. These results underscore the necessity for comprehensive and systematic investigations into the intricate interplay between photophobia and sleep to enhance our understanding and develop tailored solutions for individuals with migraine.
CRISPR–Cas9 applications in T cells and adoptive T cell therapies
Authors: Chen Xiaoying , Zhong Shuhan , Zhan Yonghao , Zhang Xuepei
Published: April 2024

T cell immunity is central to contemporary cancer and autoimmune therapies, encompassing immune checkpoint blockade and adoptive T cell therapies. Their diverse characteristics can be reprogrammed by different immune challenges dependent on antigen stimulation levels, metabolic conditions, and the degree of inflammation. T cell-based therapeutic strategies are gaining widespread adoption in oncology and treating inflammatory conditions. Emerging researches reveal that clustered regularly interspaced palindromic repeats–associated protein 9 (CRISPR–Cas9) genome editing has enabled T cells to be more adaptable to specific microenvironments, opening the door to advanced T cell therapies in preclinical and clinical trials. CRISPR–Cas9 can edit both primary T cells and engineered T cells, including CAR-T and TCR-T, in vivo and in vitro to regulate T cell differentiation and activation states. This review first provides a comprehensive summary of the role of CRISPR–Cas9 in T cells and its applications in preclinical and clinical studies for T cell-based therapies. We also explore the application of CRISPR screen high-throughput technology in editing T cells and anticipate the current limitations of CRISPR–Cas9, including off-target effects and delivery challenges, and envisioned improvements in related technologies for disease screening, diagnosis, and treatment.
Biomarker discovery with quantum neural networks: a case-study in CTLA4-activation pathways
Authors: Nguyen Phuong-Nam
Published: April 2024

Background

Biomarker discovery is a challenging task due to the massive search space. Quantum computing and quantum Artificial Intelligence (quantum AI) can be used to address the computational problem of biomarker discovery from genetic data.

Method

We propose a Quantum Neural Networks architecture to discover genetic biomarkers for input activation pathways. The Maximum Relevance-Minimum Redundancy criteria score biomarker candidate sets. Our proposed model is economical since the neural solution can be delivered on constrained hardware.

Results

We demonstrate the proof of concept on four activation pathways associated with CTLA4, including (1) CTLA4-activation stand-alone, (2) CTLA4-CD8A-CD8B co-activation, (3) CTLA4-CD2 co-activation, and (4) CTLA4-CD2-CD48-CD53-CD58-CD84 co-activation.

Conclusion

The model indicates new genetic biomarkers associated with the mutational activation of CLTA4-associated pathways, including 20 genes: CLIC4, CPE, ETS2, FAM107A, GPR116, HYOU1, LCN2, MACF1, MT1G, NAPA, NDUFS5, PAK1, PFN1, PGAP3, PPM1G, PSMD8, RNF213, SLC25A3, UBA1, and WLS. We open source the implementation at: https://github.com/namnguyen0510/Biomarker-Discovery-with-Quantum-Neural-Networks.
Prospective, randomized study comparing two different regimens of split-dose polyethylene glycol and their effect on endoscopic outcomes
Authors: Abou Zeid Jawad , Hallit Souheil , Akiki Bassem , Abou Zeid Zeina , Yazbeck Charbel
Published: April 2024

Background

Different split regimens of polyethylene glycol are routinely used and no guidelines are available to select an optimal protocol of ingestion. This study aims to compare the efficacy and side effect profile of two different regimens of polyethylene glycol bowel preparation solution: PEG (3 + 1) vs. PEG (2 + 2).

Methods

240 patients above the age of 18 years were included in the study between June 1st and November 31st, 2023. Patients were randomly assigned either to Group A, consisting of 115 patients receiving a 3 L of PEG the night before the colonoscopy, and 1 L the same morning of the procedure. Or to group B, where 125 patients ingested 2 L the night before the procedure, and the remaining 2 L the same morning. The cleansing efficacy was evaluated by the attending endoscopist using the Boston Bowel Preparation Scale, through a score assigned for each segment of the colon (0–3). Side effects, tolerability, and willingness to retake the same preparation were listed by an independent investigator using a questionnaire administered before the procedure.

Results

A higher percentage of patients had gastric fullness with the 3 + 1 vs. 2 + 2 preparation (58.3% vs. 31.2%; p <.001). A higher Boston bowel preparation score was seen in patients who took the 2 + 2 vs. 3 + 1 preparation (7.87 vs. 7.23). Using the 2 + 2 preparation was significantly associated with higher Boston bowel preparation scores vs. the 3 + 1 preparation (OR = 1.37, p =.001, 95% CI 1.14, 1.64). After adjustment over other variables (age, gender, comorbidities, previous abdominal surgeries, presence of adenoma, and time between last dose and colonoscopy), results remained the same (aOR = 1.34, p =.003, 95% CI 1.10, 1.62).

Conclusion

While both (2 + 2) and (3 + 1) regimens of polyethylene glycol are a good choice for a successful colonoscopy, we recommend the use of (2 + 2) regimen for its superior efficacy in bowel cleansing.
Factors impacting clinical data and documentation quality in Australian aged care and disability services: a user-centred perspective
Authors: Tshering Gap , Troeung Lakkhina , Walton Rebecca , Martini Angelita
Published: April 2024

Background

Research has highlighted a need to improve the quality of clinical documentation and data within aged care and disability services in Australia to support improved regulatory reporting and ensure quality and safety of services. However, the specific causes of data quality issues within aged care and disability services and solutions for optimisation are not well understood.

Objectives

This study explored aged care and disability workforce (referred to as ‘data-users’) experiences and perceived root causes of clinical data quality issues at a large aged care and disability services provider in Western Australia, to inform optimisation solutions.

Methods

A purposive sample of n = 135 aged care and disability staff (including community-based and residential-based) in clinical, care, administrative and/or management roles participated in semi-structured interviews and web-based surveys. Data were analysed using an inductive thematic analysis method, where themes and subthemes were derived.

Results

Eight overarching causes of data and documentation quality issues were identified: (1) staff-related challenges, (2) education and training, (3) external barriers, (4) operational guidelines and procedures, (5) organisational practices and culture, (6) technological infrastructure, (7) systems design limitations, and (8) systems configuration-related challenges.

Conclusion

The quality of clinical data and documentation within aged care and disability services is influenced by a complex interplay of internal and external factors. Coordinated and collaborative effort is required between service providers and the wider sector to identify behavioural and technical optimisation solutions to support safe and high-quality care and improved regulatory reporting.
Influence of moderate-to-high intensity physical activity on depression levels: a study based on a health survey of Chinese university students
Authors: Li Bo , Jiang Wei , Han Shan-shan , Ye Yu-peng , Li Ya-xing , Lou Hu , Zhang Jun-yong
Published: April 2024

Objective

The study aims to examine how moderate-to-vigorous physical activity (MVPA) affects the severity of depression symptoms among Chinese college students. Additionally, it seeks to analyze the mediating mechanisms involving self-rated health and general self-efficacy.

Methods

The study utilized data from the 2023 Chinese College Health Tracking Survey and employed multiple linear regression and structural equation modeling techniques to investigate the impacts of MVPA on depression levels and its underlying mediating mechanisms among college students. The primary cohort comprised 49,717 enrolled college students from 106 universities in China.

Results

A total of 41,620 valid questionnaires were collected (response rate: 83.7%), with females accounting for 58.6%. In the past month, approximately 30.2% of college students engaged in MVPA. Self-rated health (B = − 0.282, P < 0.001) and general self-efficacy (B = − 0.133, P < 0.001) significantly influenced college students’ depression scores. Even after controlling for other variables, participating in MVPA remained significantly associated with reduced depression scores (B = − 0.062, P = 0.002). The results of the structural equation model showed that MVPA not only directly decreased college students’ depression scores but also indirectly reduced the likelihood of depression occurrence by improving their physical health status and general self-efficacy.

Conclusion

The lack of physical activity among Chinese college students is evident. Engaging in MVPA can reduce the likelihood of depression among college students. MVPA achieves this reduction by enhancing college students’ general self-efficacy and improving their physical health. The factors influencing depression levels among college students are multifaceted. For future interventions targeting college students’ mental health, comprehensive approaches that incorporate behavioral and psychological factors should be emphasized.
The development and validation of tour guides internalized occupational stigma scale (TIOSS)
Authors: Fan Zhiguang , Shi Xiaoli , Liu Li , Yang Shuhan , Li Li
Published: April 2024

Background

Tour guides’ identification and internalization of occupational stigma may exacerbate their career development, perceived professional reputation and status, and mental health. The current study aimed to develop and verify the Tour guides Internalized Occupational Stigma Scale (TIOSS) to provide an effective tool for relevant quantitative research.

Methods

The study developed an initial questionnaire through literature analysis, expert review, and semi-structured surveys. We conducted item analyses and exploratory factor analyses among 326 tour guides, and confirmatory factor analysis and reliability and validity tests among 315 tour guides.

Results

The TIOSS consists of 21 items and is formed in three dimensions referring to Stigma Perception (SP), Status Loss (SL), and Career Denial (CD). The correlation coefficient values of the TIOSS total scale and dimension scores with the criterion instruments ranged from 0.17 to 0.68. In addition, the Cronbach’s α coefficients for the TIOSS and its dimensions ranged from 0.837 to 0.928, and the split-half reliability coefficients ranged from 0.843 to 0.916. The study also revealed that the TIOSS was consistent across genders.

Conclusion

The TIOSS performed favorable reliability and validity to be a valid instrument to assess tour guides' internalized occupational stigma.
“In our community, we normalize pain”: discussions around menstruation and uterine fibroids with Black women and Latinas
Authors: Orellana Minerva , DSouza Karen. N , Yap Jane Q. , Sriganeshan Abhirami , Jones M. Elena , Johnson Charis , Allyse Megan , Venable Sateria , Stewart Elizabeth A. , Enders Felicity , Balls-Berry Joyce E.
Published: April 2024

Background

Uterine fibroids are non-cancerous neoplasms that arise from the uterus affecting over 75% of women. However, there is a disparity with Black women having an increased prevalence of nearly 80%. Black women also experience increased symptom burden, including younger age at the time of diagnosis and increased number and volume of fibroids. Less is known about other ethnoracially diverse women such as Latinas and the potential cultural impacts on fibroid burden and treatment.

Methods

Community engagement studios were conducted to facilitate discussions with stakeholders on their uterine fibroid and menstruation experience. We recruited Black women (n = 6) diagnosed with uterine fibroids and Latinas (n = 7) without uterine fibroids. We held two virtual community engagement studios split by uterine fibroid diagnosis. The studios were not audio recorded and notes were taken by four notetakers. The notes were thematically analyzed in Atlas.ti using content analysis.

Results

Participants felt there was a lack of discussion around menstruation overall, whether in the home or school settings. This lack of menstruation education was pronounced when participants had their first menstruation experience, with many unaware of what to expect. This silence around menstruation led to a normalization of painful menstruation symptoms. When it came to different treatment options for uterine fibroids, some women wanted to explore alternative treatments but were dismissed by their healthcare providers. Many participants advocated for having discussions with their healthcare provider about life goals to discuss different treatment options for their uterine fibroids.

Conclusion

Despite uterine fibroid diagnosis, there is silence around menstruation. Menstruation is a normal biological occurrence and needs to be discussed to help prevent delayed diagnosis of uterine fibroids and possibly other gynecological disorders. Along with increased discussions around menstruation, further discussion is needed between healthcare providers and uterine fibroid patients to explore appropriate treatment options.
Nutritional management recommendation systems in polycystic ovary syndrome: a systematic review
Authors: Shahmoradi Leila , Azadbakht Leila , Farzi Jebraeil , Kalhori Sharareh Rostam Niakan , Yazdipour Alireza Banaye , Solat Fahimeh
Published: April 2024

Background

People with polycystic ovary syndrome suffer from many symptoms and are at risk of developing diseases such as hypertension and diabetes in the future. Therefore, the importance of self-care doubles. It is mainly to modify the lifestyle, especially following the principles of healthy eating. The purpose of this study is to review artificial intelligence-based systems for providing management recommendations, especially food recommendations.

Materials and methods

This study started by searching three databases: PubMed, Scopus, and Web of Science, from inception until 6 June 2023. The result was the retrieval of 15,064 articles. First, we removed duplicate studies. After the title and abstract screening, 119 articles remained. Finally, after reviewing the full text of the articles and considering the inclusion and exclusion criteria, 20 studies were selected for the study. To assess the quality of articles, we used criteria proposed by Malhotra, Wen, and Kitchenham. Out of the total number of included studies, seventeen studies were high quality, while three studies were moderate quality.

Results

Most studies were conducted in India in 2021. Out of all the studies, diagnostic recommendation systems were the most frequently researched, accounting for 86% of the total. Precision, sensitivity, specificity, and accuracy were more common than other performance metrics. The most significant challenge or limitation encountered in these studies was the small sample size.

Conclusion

Recommender systems based on artificial intelligence can help in fields such as prediction, diagnosis, and management of polycystic ovary syndrome. Therefore, since there are no nutritional recommendation systems for these patients in Iran, this study can serve as a starting point for such research.
Healthcare team resilience during COVID-19: a qualitative study
Authors: Ambrose John W. , Catchpole Ken , Evans Heather L. , Nemeth Lynne S. , Layne Diana M. , Nichols Michelle
Published: April 2024

Background

Resilience, in the field of Resilience Engineering, has been identified as the ability to maintain the safety and the performance of healthcare systems and is aligned with the resilience potentials of anticipation, monitoring, adaptation, and learning. In early 2020, the COVID-19 pandemic challenged the resilience of US healthcare systems due to the lack of equipment, supply interruptions, and a shortage of personnel. The purpose of this qualitative research was to describe resilience in the healthcare team during the COVID-19 pandemic with the healthcare team situated as a cognizant, singular source of knowledge and defined by its collective identity, purpose, competence, and actions, versus the resilience of an individual or an organization.

Methods

We developed a descriptive model which considered the healthcare team as a unified cognizant entity within a system designed for safe patient care. This model combined elements from the Patient Systems Engineering Initiative for Patient Safety (SEIPS) and the Advanced Team Decision Making (ADTM) models. Using a qualitative descriptive design and guided by our adapted model, we conducted individual interviews with healthcare team members across the United States. Data were analyzed using thematic analysis and extracted codes were organized within the adapted model framework.

Results

Five themes were identified from the interviews with acute care professionals across the US (N = 22): teamwork in a pressure cooker, consistent with working in a high stress environment; healthcare team cohesion, applying past lessons to present challenges, congruent with transferring past skills to current situations; knowledge gaps, and altruistic behaviors, aligned with sense of duty and personal responsibility to the team. Participants’ described how their ability to adapt to their environment was negatively impacted by uncertainty, inconsistent communication of information, and emotions of anxiety, fear, frustration, and stress. Cohesion with co-workers, transferability of skills, and altruistic behavior enhanced healthcare team performance.

Conclusion

Working within the extreme unprecedented circumstances of COVID-19 affected the ability of the healthcare team to anticipate and adapt to the rapidly changing environment. Both team cohesion and altruistic behavior promoted resilience. Our research contributes to a growing understanding of the importance of resilience in the healthcare team. And provides a bridge between individual and organizational resilience.
Chromosome-level genome assembly of Hippophae tibetana provides insights into high-altitude adaptation and flavonoid biosynthesis
Authors: Zhang Guoyun , Song Yating , Chen Ning , Wei Jihua , Zhang Jianguo , He Caiyun
Published: April 2024

Background

As an endemic shrub of the Qinghai-Tibetan Plateau (QTP), the distribution of Hippophae tibetana Schlecht. ranges between 2800 and 5200 m above sea level. As the most basal branch of the Hippophae genus, H. tibetana has an extensive evolutionary history. The H. tibetana is a valuable tree for studying the ecological evolution of species under extreme conditions.

Results

Here, we generated a high-quality chromosome-level genome of H. tibetana. The total size of the assembly genome is 917 Mb. The phylogenomic analysis of 1064 single-copy genes showed a divergence between 3.4 and 12.8 Mya for H. tibetana. Multiple gene families associated with DNA repair and disease resistance were significantly expanded in H. tibetana. We also identified many genes related to DNA repair with signs of positive selection. These results showed expansion and positive selection likely play important roles in H. tibetana’s adaptation to comprehensive extreme environments in the QTP. A comprehensive genomic and transcriptomic analysis identified 49 genes involved in the flavonoid biosynthesis pathway in H. tibetana. We generated transgenic sea buckthorn hairy root producing high levels of flavonoid.

Conclusions

Taken together, this H. tibetana high-quality genome provides insights into the plant adaptation mechanisms of plant under extreme environments and lay foundation for the functional genomic research and molecular breeding of H. tibetana.
PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer
Authors: Li Mingzhou , Xiao Jianbiao , Song Shasha , Han Fangyi , Liu Hongling , Lin Yang , Ni Yunfei , Zeng Sisi , Zou Xin , Wu Jieqiong , Wang Feifei , Xu Shaowan , Liang You , Xu Peishuang , Hong Huirong , Qiu Junfeng , Cao Jianing , Zhu Qin , Liang Li
Published: April 2024

Background

Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear.

Methods

RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models.

Results

PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy.

Conclusions

PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.
Quantitative measurement of cell-surface displayed proteins based on split-GFP assembly
Authors: Zhang Li , Tan Ling , Liu Meizi , Chen Yunhong , Yang Yu , Zhang Yanfei , Zhao Guoping
Published: April 2024

Background

Microbial cell surface display technology allows immobilizing proteins on the cell surface by fusing them to anchoring motifs, thereby endowing the cells with diverse functionalities. However, the assessment of successful protein display and the quantification of displayed proteins remain challenging. The green fluorescent protein (GFP) can be split into two non-fluorescent fragments, while they spontaneously assemble and emit fluorescence when brought together through complementation. Based on split-GFP assembly, we aim to: (1) confirm the success display of passenger proteins, (2) quantify the number of passenger proteins displayed on individual cells.

Results

In this study, we propose two innovative methods based on split-green fluorescent protein (split-GFP), named GFP1-10/GFP11 and GFP1-9/GFP10-11 assembly, for the purpose of confirming successful display and quantifying the number of proteins displayed on individual cells. We evaluated the display efficiency of SUMO and ubiquitin using different anchor proteins to demonstrate the feasibility of the two split-GFP assembly systems. To measure the display efficiency of functional proteins, laccase expression was measured using the split-GFP assembly system by co-displaying GFP11 or GFP10-11 tags, respectively.

Conclusions

Our study provides two split-GFP based methods that enable qualitative and quantitative analyses of individual cell display efficiency with a simple workflow, thus facilitating further comprehensive investigations into microbial cell surface display technology. Both split-GFP assembly systems offer a one-step procedure with minimal cost, simplifying the fluorescence analysis of surface-displaying cells.
Immersed in a reservoir of potential: amniotic fluid-derived extracellular vesicles
Authors: Atukorala Ishara , Hannan Natalie , Hui Lisa
Published: April 2024

This review aims to encapsulate the current knowledge in extracellular vesicles extracted from amniotic fluid and amniotic fluid derived stem/stromal cells. Amniotic fluid (AF) bathes the developing fetus, providing nutrients and protection from biological and mechanical dangers. In addition to containing a myriad of proteins, immunoglobulins and growth factors, AF is a rich source of extracellular vesicles (EVs). These vesicles originate from cells in the fetoplacental unit. They are biological messengers carrying an active cargo enveloped within the lipid bilayer. EVs in reproduction are known to play key roles in all stages of pregnancy, starting from fertilisation through to parturition. The intriguing biology of AF-derived EVs (AF-EVs) in pregnancy and their untapped potential as biomarkers is currently gaining attention. EV studies in numerous animal and human disease models have raised expectations of their utility as therapeutics. Amniotic fluid stem cell and mesenchymal stromal cell-derived EVs (AFSC-EVs) provide an established supply of laboratory-made EVs. This cell-free mode of therapy is popular as an alternative to stem cell therapy, revealing similar, if not better therapeutic outcomes. Research has demonstrated the successful application of AF-EVs and AFSC-EVs in therapy, harnessing their anti-inflammatory, angiogenic and regenerative properties. This review provides an overview of such studies and discusses concerns in this emerging field of research.
Nigrostriatal degeneration determines dynamics of glial inflammatory and phagocytic activity
Authors: Ayerra Leyre , Abellanas Miguel Angel , Basurco Leyre , Tamayo Ibon , Conde Enrique , Tavira Adriana , Trigo Amaya , Vidaurre Clara , Vilas Amaia , San Martin-Uriz Patxi , Luquin Esther , Clavero Pedro , Mengual Elisa , Hervás-Stubbs Sandra , Aymerich Maria S.
Published: April 2024

Glial cells are key players in the initiation of innate immunity in neurodegeneration. Upon damage, they switch their basal activation state and acquire new functions in a context and time-dependent manner. Since modulation of neuroinflammation is becoming an interesting approach for the treatment of neurodegenerative diseases, it is crucial to understand the specific contribution of these cells to the inflammatory reaction and to select experimental models that recapitulate what occurs in the human disease. Previously, we have characterized a region-specific activation pattern of CD11b+ cells and astrocytes in the α-synuclein overexpression mouse model of Parkinson´s disease (PD). In this study we hypothesized that the time and the intensity of dopaminergic neuronal death would promote different glial activation states. Dopaminergic degeneration was induced with two administration regimens of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), subacute (sMPTP) and chronic (cMPTP). Our results show that in the sMPTP mouse model, the pro-inflammatory phenotype of striatal CD11b+ cells was counteracted by an anti-inflammatory astrocytic profile. In the midbrain the roles were inverted, CD11b+ cells exhibited an anti-inflammatory profile and astrocytes were pro-inflammatory. The overall response generated resulted in decreased CD4 T cell infiltration in both regions. Chronic MPTP exposure resulted in a mild and prolonged neuronal degeneration that generated a pro-inflammatory response and increased CD4 T cell infiltration in both regions. At the onset of the neurodegenerative process, microglia and astrocytes cooperated in the removal of dopaminergic terminals. With time, only microglia maintained the phagocytic activity. In the ventral midbrain, astrocytes were the main phagocytic mediators at early stages of degeneration while microglia were the major phagocytic cells in the chronic state. In this scenario, we questioned which activation pattern recapitulates better the features of glial activation in PD. Glial activation in the cMPTP mouse model reflects many pathways of their corresponding counterparts in the human brain with advanced PD. Altogether, our results point toward a context-dependent cooperativity of microglia/myeloid cells and astrocytes in response to neuronal damage and the relevance of selecting the right experimental models for the study of neuroinflammation.

Graphical abstract
Birthweight trends and their explanatory factors in Hungary between 1999 and 2018: an analysis of the Hungarian Tauffer registry
Authors: Zsirai László , Kun Attila , Visolyi Gergely Á. , Svébis Márk M. , Domján Beatrix A. , Tabák Ádám
Published: April 2024

Background

The increasing birthweight trend stopped and even reversed in several high income countries in the last 20 years, however the reason for these changes is not well characterized. We aimed to describe birthweight trends of term deliveries in Hungary between 1999 and 2018 and to investigate potential maternal and foetal variables that could drive these changes.

Methods

We analysed data from the Hungarian Tauffer registry, a compulsory anonymized data collection of each delivery. We included all singleton term deliveries in 1999–2018 (n = 1,591,932). We modelled birthweight trends separately in 1999–2008 and 2008–2018 in hierarchical multiple linear regression models adjusted for calendar year, newborn sex, maternal age, gestational age at delivery, and other important determinants.

Results

Median birthweights increased from 3250/3400 g (girl/boy) to 3300/3440 g from 1999 to 2008 and decreased to 3260/3400 g in 2018. When we adjusted for gestational age at delivery the increase in the first period became more pronounced (5.4 g/year). During the second period, similar adjustment substantially decreased the rate of decline from 2.5 to 1.4 g/year. Further adjustment for maternal age halved the rate of increase to 2.4 g/year in the first period. During the second period, adjustment for maternal age had little effect on the estimate.

Conclusions

Our findings of an increasing birthweight trend (mostly related to the aging of the mothers) in 1999–2008 may forecast an increased risk of cardiometabolic diseases in offsprings born in this period. In contrast, the decreasing birthweight trends after 2008 may reflect some beneficial effects on perinatal morbidity. However, the long-term effect cannot be predicted, as the trend is mostly explained by the shorter pregnancies.
Role of germinal center and CD39highCD73+ B cells in the age-related tonsillar involution
Authors: Pastor Rocío , Puyssegur Juliana , de la Guardia M. Paula , Varón Lindybeth Sarmiento , Beccaglia Gladys , Spada Nicolás , de Lima Andrea Paes , Collado M. Soledad , Blanco Andrés , Scetti Isabel Aspe , Arabolaza M. Elena , Paoli Bibiana , Chirdo Fernando , Arana Eloísa
Published: April 2024

Background

The tonsils operate as a protection ring of mucosa at the gates of the upper aero-digestive tract. They show similarities with lymph nodes and participate as inductive organs of systemic and mucosal immunity. Based on the reduction of their size since puberty, they are thought to experience involution in adulthood. In this context, we have used tonsillar mononuclear cells (TMC) isolated from patients at different stages of life, to study the effect of ageing and the concomitant persistent inflammation on these immune cells.

Results

We found an age-dependent reduction in the proportion of germinal center B cell population (BGC) and its T cell counterpart (T follicular helper germinal center cells, TfhGC). Also, we demonstrated an increment in the percentage of local memory B cells and mantle zone T follicular helper cells (mTfh). Furthermore, younger tonsils rendered higher proportion of proliferative immune cells within the freshly isolated TMC fraction than those from older ones. We demonstrated the accumulation of a B cell subset (CD20+CD39highCD73+ cells) metabolically adapted to catabolize adenosine triphosphate (ATP) as patients get older. To finish, tonsillar B cells from patients at different ages did not show differences in their proliferative response to stimulation ex vivo, in bulk TMC cultures.

Conclusions

This paper sheds light on the changing aspects of the immune cellular landscape, over the course of time and constant exposure, at the entrance of the respiratory and digestive systems. Our findings support the notion that there is a re-modelling of the immune functionality of the excised tonsils over time. They are indicative of a transition from an effector type of immune response, typically oriented to reduce pathogen burden early in life, to the development of an immunosuppressive microenvironment at later stages, when tissue damage control gets critical provided the time passed under immune attack. Noteworthy, when isolated from such histologic microenvironment, older tonsillar B cells seem to level their proliferation capacity with the younger ones. Understanding these features will not only contribute to comprehend the differences in susceptibility to pathogens among children and adults but would also impact on vaccine developments intended to target these relevant mucosal sites.
Urate-lowering therapy, serum urate, inflammatory biomarkers, and renal function in patients with gout following pegloticase discontinuation
Authors: Holladay Emily E. , Mudano Amy S. , Xie Fenglong , Zhang Jingyi , Mikuls Ted R. , LaMoreaux Brian , Padnick-Silver Lissa , Curtis Jeffrey R.
Published: April 2024

Background/Purpose

Little is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation.

Methods

We conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment.

Results

Of the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (− 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL.

Conclusion

Pegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation.
Subclinical epileptiform discharges in Alzheimer’s disease are associated with increased hippocampal blood flow
Authors: Musaeus Christian Sandøe , Kjaer Troels Wesenberg , Lindberg Ulrich , Vestergaard Mark B. , Bo Henrik , Larsson Wiberg , Press Daniel Zvi , Andersen Birgitte Bo , Høgh Peter , Kidmose Preben , Hemmsen Martin Christian , Rank Mike Lind , Hasselbalch Steen Gregers , Waldemar Gunhild , Frederiksen Kristian Steen
Published: April 2024

Background

In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer’s disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer’s disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus.

Methods

A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG.

Results

No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC.

Conclusions

Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD.

Trial registration

The study is registered at clinicaltrials.gov (NCT04436341).