bluuebunny/crossref_metadata_2025 huggingface dataset:
An online self-management program for spinal cord injury: a pilot randomised controlled trial of the SCI&U peer health coaching intervention
Authors: Jaglal Susan B , Allin Sonya J. , Craven B. Catherine , Guilcher Sara J.T. , Linassi A. Gary , McBride Christopher B. , Moineddin Rahim , Mortenson W. Ben , Munce Sarah , Salbach Nancy M. , Shepherd John D. , Sweet Shane N. , Thorson Teri , Tomasone Jennifer R.
Published: December 2024

Background: The spinal cord injury and you (SCI&U) intervention aims to improve self-management skills for persons living with SCI using a web-based, peer health-coaching model. This study assessed the feasibility of conducting a future definitive trial of SCI&U, specifically the feasibility of recruitment and retention, usability and quality of the program, and estimates of effect sizes for a variety of self-management outcomes.
Methods: A two-group, randomised, controlled, pilot trial with prospective recruitment, concealed group allocation, blinded outcome evaluation, and waitlist control was conducted in Canada. We aimed to recruit 60 participants who were 18 years and older living in the community at least six months post-injury, were able to speak and read English, and had a primary care physician. The intervention included online client-coach videoconferencing sessions, goal setting, action planning, and a sortable resource library. Data were collected at baseline, 2, 6 and 12 months post-randomisation. SCI&U was offered to the waitlist group at 12 months. Primary short-term self-management outcome was Skill and Technique Acquisition (STA), a subscale of the Health Education Impact Questionnaire. Primary long-term outcome was cumulative days rehospitalised.
Results: Of 65 eligible individuals, 34 were randomised to waitlist control and 31 to intervention. Mean time since injury was 25.6 years for intervention and 20.2 years for control. Outcome data were gathered for 86% of participants at 6 months and 89% at 12 months. The usability and quality of the program were highly rated. The difference in STA between intervention and control was 0.56 (95% CI -0.41, 1.52) at 6 months and 0.72 (95% CI -0.28, 1.72) at 12 months. Other subscales also had large effect sizes: Self-monitoring and insight 1.51 (95% CI 0.39, 2.69); and Emotional distress -1.40 (95% CI -3.04, 0.23). In the 12 months following recruitment, 5 intervention and 4 control participants spent median 11 (3-19) and 24 (5-95) nights in hospital, respectively.
Conclusions:The trial methodology and procedures were feasible; the SCI&U intervention was acceptable to participants. The program positively impacted an individual’s ability to self-manage. Further research is needed to confirm these findings and evaluate the program on those with recently acquired SCI.
Trial registration: ClinicalTrials.gov, NCT04474171, retrospectively registered 07/13/2020; https://clinicaltrials.gov/study/NCT04474171#study-record-dates
Geometry-encoded molecular dynamics enables deep learning insights into P450 regiospecificity control
Authors: POMPON Denis , GARCIA-ALLES Luis F. , URBAN Philippe
Published: December 2024

Cytochrome P450 1A2, as many isoenzymes, can generate multiple metabolites from a single substrate. A loose coupling between substrate binding and oxygen activation makes possible substrate reorientations at the active site prior to catalysis. In the present work, caffeine oxidation to alternative bioactive compounds was used to decipher this pluripotency. A model involving two interacting subsites capable of sequentially accommodating one or two caffeine molecules was considered. Molecular dynamics was used to characterize subsite interactions and feed a dedicated geometric encoding of trajectories that was coupled to dimensional reductions and differential machine learning. The two subsites differentially control caffeine orientations and can exchange substrate through a phenylalanine gated mechanism. This exchange can be locked by the presence of a second bound molecule. Complementary roles of subsites in progressively determining the caffeine orientation during its approach to active oxygen were examined. Interestingly, substrate face flipping becomes impaired upon entry into the rather flat active site. This makes the mechanisms that define the orientation of caffeine relative to active oxygen dependent on the substrate face oriented toward heme. Globally, this evidenced that P450 1A2 regioselectivity results from local determinants combined with subsite interactions and caffeine face preselection at a longer distance
The neutrophil to lymphocyte ratio as a predictor of major adverse cardiovascular events in patients with non-small cell lung cancer
Authors: Zheng Zhimin , Lin Xueqin , Pan Yuxiong
Published: December 2024

Background: Cancer patients are more susceptible to mortality from cardiovascular disease. This study sought to determine whether the neutrophil to lymphocyte ratio (NLR) could serve as a predictor for major adverse cardiovascular events (MACEs) in patients with non-small cell lung cancer (NSCLC) after surgery.
Methods: A retrospective analysis was conducted on clinicopathological data from 204 NSCLC patients who underwent radical surgery at Longyan First Hospital between January 2019 and December 2021. Follow-up for postoperative MACEs was performed until June 2024. The optimal NLR cut-off point was identified using the receiver operating characteristic (ROC) curve. Survival analysis, including Kaplan-Meier and Cox regression methods, was applied to assess the correlation between NLR and patient prognosis.
Results: The critical NLR value was determined to be 2.86. Univariate Cox regression analysis indicated that gender, tumor size, NLR, platelet to lymphocyte ratio (PLR), and advanced lung cancer inflammation index (ALI) were associated with MACEs (P-values: 0.011, <0.001, <0.001, 0.027, 0.001). Furthermore, multivariate Cox regression analysis demonstrated that NLR (HR: 1.104, 95% CI: 1.032-1.182, P= 0.004), tumor diameter (HR: 1.922, 95% CI: 1.160-3.185, P= 0.011), and gender (HR: 1.873, 95% CI: 1.037-3.378, P= 0.037) were independent predictors of MACEs.
Conclusions: The elevation of NLR is significantly associated with an increased risk of MACEs in patients with non-small cell lung cancer, making it a valuable tool for risk stratification.
Bioinformatics analyses and verification the promoting cancer role of RRM2 in cervical cancer
Authors: Abuduhailili Xieyidai , Lu Ruijiao , Li Yuxia , Feng Yangchun , Wang Senyu
Published: December 2024

Background: Cervical cancer is one of the most common malignant tumours in women, and is the seventh highest among cancers, cervical cancer main caused by HPV infection; Xinjiang is a high incidence of cervical cancer. Immunotherapy is a new type of tumour therapy based on immune checkpoints, which has made a big breakthrough in the treatment of cancer. Ribonucleotide reductase subunit M2 (RRM2) is expressed at increased levels in cervical cancer and is associated with apoptosis and proliferation of cancer cells. In this study we explore the mechanism of RRM2 regulates the high expression of PD-L1 in cervical cancer through ERK signaling pathway by Bioinformatics analyses and experiments, and also investigate the role of RRM2 in cervical cancer .
Methods: Bioinformatics analyses and experiments were carried out to revealed the promoting cancer role of RRM2 in cervical cancer and verify that RRM2 enhanced PD-L1 expression through activation of the ERK signaling pathway.
Results: RRM2 plays an crucial role in the occurrence and progression of cervical cancer and enhanced the expression of PD-L1 in cancer cells via activating the ERK signaling pathway.
Research on Electromagnetic Tomography Method for Imaging Reinforcement Structures in Concrete Utility Poles Based on an Improved VGG16 Deep Learning Network
Authors: Weng Jia , Wang Peifeng , Qiu Canshu , Wu Chaohang , Wang Juan
Published: December 2024

Concrete utility poles are extensively utilized in the load-bearing structures of low-voltage distribution lines, where the quality of the internal reinforcement directly impacts their reliability and supports the stable operation of the distribution network. Non-destructive testing of these poles aids maintenance personnel in understanding the internal structure of the reinforcements, evaluating the performance of the poles, and ensuring their reliable operation. Addressing this issue, this paper introduces a method for imaging the reinforcement structure of concrete utility poles using electromagnetic tomography. This method involves evenly dis-tributing 32 threaded coils on the surface of the pole, employing adjacent excitation methods to stimulate the coils and measure their voltage. The measurement data from the poles are inputted into an enhanced VGG16 neural network, trained with finite element data, to reconstruct the reinforcement structure. The effectiveness of this method was confirmed through simulation experiments, which demonstrated its ability to accurately image reinforcement structures with varying numbers of rebars, burial depths, diameters, and missing rebars, exhibiting strong generalization capabilities. While the generalizability of the model decreases when the rebar count is fixed during dataset construction, imaging performance improves for specific pole models. The reinforcement imaging method proposed in this paper enhances the efficiency of maintenance operations and offers new perspectives for the inspection of reinforcement structures in concrete utility poles.
The Effect of Selective Decontamination on Antimicrobial Resistance in Intensive Care Patients: A Systematic Review and Meta-analysis
Authors: Eerten Frederique van , Plate Joost , Groenwold Rolf , Schweitzer Valentijn , Kluytmans Jan , Hietbrink Falco
Published: December 2024

Background Selective Digestive Decontamination (SDD) and Selective Oropharyngeal Decontamination (SOD) are applied to prevent infections amongst Intensive Care Unit (ICU) patients and have proven to reduce mortality and infection rates. However, concerns about development of antimicrobial resistance persists, specifically after ICU discharge. The aim of this study was to assess the occurrence of antimicrobial resistance during ICU stay and after ICU discharge in patients who received SDD, or SOD compared to control.Methods A previous systematic review, which included studies on antimicrobial resistance after SDD or SOD from before 01-02-2012, was updated. All studies analyzing antimicrobial resistance during and after ICU stay, were included. Pooled odds ratios and 95% confidence intervals were calculated using the Mantel-Haenszel method with random effects. Analyses were done separately for SDD and SOD.Results Twenty-seven studies were included in the meta-analysis on the occurrence of antimicrobial resistance during ICU stay, yielding a protective association in patients receiving SDD; OR 0.73 (95%-CI 0.54;0.98, I2 75%), less resistance to fluoroquinolones in patients receiving SDD OR 0.29 (95%-CI 0.12;0.68, I2 30%) and less multi-resistant bacteria; OR 0.53 (95%-CI 0.33; 0.87, I2 0%), compared to control treatment. Four studies investigated antimicrobial resistance after ICU discharge of which two were eligible for pooling, which yielded no significant effect; OR 1.20 (95%-CI 0.23;6.36, I2 90%).Conclusion During ICU stay, SDD is associated with reduced antimicrobial resistance to specific antibiotics, in line with a previous review. More specifically combined with intravenous (IV) component, in settings with low prevalence of resistance and in a cluster design. This current review emphasizes the limited amount of data on the long-term effect of antimicrobial decontamination strategies to antimicrobial resistance. Understanding this long-term effect is essential when deciding whether to implement preventative antibiotics in specific subgroups. This could be done by means of a prospective long-term follow-up study.
Active learning algorithm for alleviating the user cold start problem of recommender systems
Authors: De Pessemier Toon , Willems Bruno , Martens Luc
Published: December 2024

A key challenge in recommender systems is how to profile new users. A popular solution for this problem is to use active learning strategies. These strategies request ratings for a small set of carefully selected items to reveal the preferences of new users. In this paper, we propose a new decision tree-based algorithm for selecting these items. Treating the recommender system as a black box, the ratings collected from interviewing new users are passed on to the recommender system with the intention of improving its performance. Extensive offline evaluation with two data sets and various recommender algorithms shows that our algorithm does indeed improve the performance of the underlying recommender algorithm if users are able to rate most of the items that are presented to them during the interview. However, online evaluation with 50 real users could not prove that our algorithm does indeed have a positive impact on the performance of the underlying recommender algorithm. This reveals the discrepancy between offline and online evaluations of active learning techniques applied in the context of recommender systems. This is due to the fact that real users are not always able to rate the item selected by the active learning algorithm and therefore cannot provide the requested information, in contrast to many machine learning scenarios were the labeling of all samples is possible. Hence, further research is required to provide more certainty regarding the impact of active learning strategies on recommender algorithms.
Predicting Lung Health with High-Performance Machine Learning: Insights from Upper Respiratory Microbiome Biomarkers
Authors: Yaqin Muhammad A , Singgih Euginia L , Utama Revata , Irmayanti Evita , Khanza Shafira M , Intan Novia S , Pramono Ajeng K , Puspitasari Iva , Rahardjo Sofyan B , Farhanah Nur , Handoyo Thomas , Kholis Fathur N , Hapsari Rebriarina , Pramudo Setyo G , Kandowangko Jenny W , Susetyo Rosreri
Published: December 2024

BACKGROUND The major importance of upper respiratory tract (URT) microbiome diversity to the overall aerodigestive tract made it an ideal hotspot to determine lung health. However, the current sampling methods pose a bottleneck for large scale lung examination, as they are either invasive such as bronchoalveolar lavage (BAL), or inconsistent like sputum. As COVID-19 pushes innovation for mass surveillance, the self-collected gargle sampling method gained popularity as it is non-invasive, convenient, and requires minimum sampling skill. Combined by the power of sequencing technology and machine learning (ML) algorithms, gargle specimen analysis could be the novel approach for lung health surveillance. Here, we carried out shotgun metagenomics study to compare microbiome diversity between sputum and gargle specimens from 3 subject’s lung health groups, namely healthy, acute, and chronic. We also discovered biomarkers driving microbiome differences in healthy-chronic subjects and used that insight to develop ML based predictive models.RESULTS We found that influence of specimen types on microbiome diversity is significantly inconsequential compared to that of subjects’ health. Our biomarker analysis revealed higher commensals abundance in healthy samples, as well as pathogens predominance in chronic subjects. By using this insight, our prediction models achieve an excellent discriminatory power to distinguish healthy subjects from chronic patients.CONCLUSION Findings in our study demonstrated feasibility of ML-based gargle analysis as an alternative lung health surveillance approach.
Tumour-derived secreted phosphoprotein 1/SPP1 via activation of microglia contributes to the formation of the breast cancer brain metastatic niche
Authors: Wojnicki Kamil , Poleszak Katarzyna , Kochalska-Les Agata , Roura Adria-Jaume , Matyja Ewa , Czernicki Tomasz , Grajkowska Wiesława , Waśniewski Kacper , Vymolova Barbora , Kaminska Bozena
Published: December 2024

Brain metastases (BrMets) occur in 20%-40% of patients with breast cancer and contribute significantly to morbidity and/or mortality. BrMets are more common in certain breast cancer subtypes, such as human epidermal growth factor receptor 2–positive breast cancer, which has a higher incidence of BrMets. The molecular mechanisms that drive and permit the progression of metastasis in the brain are poorly understood. Identifying components of the metastatic niches and propensities of primary tumors towards the brain microenvironment are essential to improve our understanding of BrMet development, patient management and outcomes. SPP1, a secreted phosphoglycoprotein 1, is a potent activator of microglia (brain resident myeloid cells) in malignant gliomas. SPP1 is elevated in breast cancer and breast cancer brain metastasis. Exploration of public bulk and scRNAseq datasets shows high SPP1 overexpression in breast malignant cells, as well as in the immune cells in BrMets. We found that breast cancer cells with high expression of SPP1 strongly activate microglia in co-cultures, which in turn increases cancer cell invasion. Blocking SPP1-mediated cancer-microglia communication with the 7aaRGD interfering peptide or shRNA mediated knockdown of SPP1 in cancer cells, abolished microglia-dependent cancer cell invasion. Notably, we found that an antibiotic minocycline efficiently reduces the expression of SPP1 in several breast cancer cell lines, and decreases both the basal and microglia-induced invasion of breast cancer cells. The results highlight the important role of breast cancer-derived SPP1 in shaping the permissive microenvironment of BrMet, and indicate a potential of the 7aaRGD peptide or minocycline to be new therapeutics in breast cancer brain metastasis treatment.
Global Warming Exacerbates the Risk of Habitat Loss for Regional Mangrove Species
Authors: Liao Jian , Li Gaocong , Zhang Shuiyuan , Yang Yuanfeng , Li Yiyang , Dong Zhongdian , Guo Yusong , Wang Zhongduo
Published: December 2024

Mangroves, as a salt-tolerant evergreen broad-leaved vegetation ecosystem, are widely distributed along the coastlines of tropical and subtropical regions. In the field of ecology, scholars generally agree that climatic drivers, particularly temperature and precipitation patterns, play a crucial role in regulating the global distribution, structure, and functions of mangroves. However, significant gaps and challenges remain in the research quantifying the direct relationship between climate and mangroves. This study focused on two dominant mangrove species in the northern margin of the South China Sea: Kandelia obovata and Avicennia Marina. By compiling reported data, utilizing database information, and integrating our field observations, we employed species distribution models to simulate the distribution areas of these two species and their habitat changes under global warming scenarios. Our results indicate that bio18 serves as the primary climatic factor shaping their distribution patterns. Specifically, K. obovata is primarily distributed in the Northern Hemisphere, while A. Marina exhibits a much broader distribution range, encompassing over 40 times the area of K. obovata. The niche overlap between these two species is relatively low, and global warming is further promoting the separation of their niches. Notably, the continued warming of the climate in the future is not expected to pose a significant threat to K. obovata. However, it significantly increases the risk of habitat loss for A. Marina. This study underscores the urgent need to implement conservation measures for mangrove ecosystems, with particular priority given to those species that are currently experiencing or are vulnerable to habitat loss.
Local Anesthesia with Monitored Anesthesia Care for Cephalomedullary Nailing of Proximal Femur Fractures: A Minimally Invasive Approach for High-Risk Surgical Candidates
Authors: Hajializade Mikaiel
Published: December 2024

Background
Proximal femur fractures are common orthopedic injuries, particularly in the elderly population, and present significant challenges due to high comorbidity and elevated risk of anesthesia. Traditional management often involves general or spinal anesthesia, which carries a considerable risk of morbidity and mortality in these high-risk patients. This study aimed to evaluate the safety and efficacy of local anesthesia combined with monitored anesthesia care (MAC) as an alternative to general anesthesia in elderly patients with intertrochanteric fractures.
Methods
In this retrospective study, we included patients aged ≥ 65 years with displaced intertrochanteric fractures who underwent cephalomedullary nailing under local anesthetic infiltration with MAC. Data on demographics, safety outcomes (complications and mortality), and efficacy measures (blood loss, surgical time, anesthesia induction-to-incision time, and length of stay) were collected.
Results
A total of 35 patients were included, with a mean age of 76.6 years. Major complications occurred in 6 patients (17.1%), with a 90-day mortality rate of 2.8%. The mean blood loss was 108 cc, surgical time averaged 33.6 minutes, anesthesia induction-to-incision time was 6.4 minutes, and the mean length of hospital stay was 2 days.
Conclusion
Local anesthesia combined with MAC is a safe alternative to general or spinal anesthesia for managing high-risk patients with proximal femur fractures. This approach reduces morbidity and mortality rates while effectively decreasing surgical time and length of hospital stay.
Tumor-derived Extracellular Vesicles-mediated Oxidative Stress Transfer Activates Glycometabolic Reprogramming of CAFs
Authors: Jiang Erhui , Li Xiang , Dou Xinyu , Xu Yuming , Shao Zhe , Shang Zhengjun
Published: December 2024

Background
Stressed by the adverse conditions of the tumor microenvironment (TME), hyperproliferation of tumor cells is accompanied by high production of reactive oxygen species (ROS). Tumor-derived extracellular vesicles (TEVs) exert a variety of biological functions in the interaction between the tumor cells and cancer-associated fibroblasts (CAFs). However, the intercellular transmission of ROS and its role in tumor-stroma communication remain unclear.
Method
The human gingival fibroblasts (HGFs), paracancerous normal fibroblasts (PNFs) and CAFs were isolated from the healthy gingival tissues of volunteers and six patients with OSCC. HGFs were treated with CAL27/SCC25 TEVs. In vitro, we assessed the level of autophagy and glycometabolism in PNFs/CAFs and HGFs/TEVs-treated HGFs by immunofluorescence and Western blot. Blockage or activation of autophagy was employed to investigate its effects on glycometabolism. Flow cytometry was used to detect whether TEVs play a crucial role in inducing fibroblast autophagy and glycolysis through ROS transfer. In vivo, xenograft models were established to validated the effect of TEVs.
Results
CAFs exhibited higher level in autophagy compared with PNFs. Treatment with autophagy inhibitors diminished autophagy-dependent glycometabolic reprogramming induced by TEVs, whereas activation of autophagy enhanced glycolysis in CAFs. Furthermore, ROS transferred by TEVs was confirmed to drive glycometabolic reprogramming through both autophagy-dependent mechanisms and the HIF-1α/PFKFB3 axis. In vivo, TEVs consistently promoted autophagy and glycometabolic reprogramming.
Conclusion
TEVs-induced intercellular transmission of ROS and the regulatory role of ROS-mediated autophagy in the glycometabolic reprogramming of CAFs, providing a novel rationale for the oxidative stress transfer model in tumor-stroma crosstalk.
A Heart Failure Classification Model from Radial Artery Pulse Wave Using LSTM Neural Networks
Authors: Lyu Yi , Huang Wen-Yue , Wu Hai-Mei , Hong Jing , Wang Yi-Qin , Yan Hai-Xia , Xu Jin
Published: December 2024

Background The pressing global health issue of heart failure (HF) demands innovative approaches for early detection. Non-invasive, rapid, and cost-effective deep learning (DL)-based techniques offer a promising avenue for addressing this challenge.
Methods A total of 462 participants were categorized into three groups: healthy, coronary artery disease (CAD), and heart failure (HF). Raw radial artery pulse wave data were collected from each participant, followed by preprocessing steps including denoising, normalization, and balancing. Subsequently, four deep learning (DL) algorithms were applied to the processed data: Long Short-Term Memory (LSTM), Convolutional Neural Network (CNN), Gated Recurrent Unit (GRU), and Bidirectional Long Short-Term Memory (Bi-LSTM).
Results LSTM achieved the highest classification performance, with an accuracy of 0.8587, precision of 0.87448, recall of 0.82164, F1-score of 0.83773, specificity of 0.92369, and AUC of 0.93365. Given its superior performance across all metrics, LSTM emerges as the preferred DL model for this study.
Conclusion By employing LSTM to analyze radial artery pulse wave, we can accurately distinguish between healthy individuals, patients with CAD, and those with HF. This simple, non-invasive, and cost-effective method presents a potential strategy for early detection of HF.
Global, regional, and national burdens of pancreatitis in children and adolescents aged 0–24 years from 1992 to 2021: a trend analysisbased on the Global Burden of Disease Study 2021
Authors: Deng Ying-han , Qiu Huabin , Huang Kangming , Huang Yanbin , Lian Fuming , Chen Yun , Chen Hongbin
Published: December 2024

Background:Younger onset of pancreatitis poses a significant public health challenge, this study aims to analyze the global burden of pancreatitis in young populations based on Global Burden of Disease 2021.
Methods:This study uses Incidence and Disability-adjusted life-years (DALYs) to assess the pancreatitis burden. Using Joinpoint modeling to assess the trend of the burden. Using Age-Period-Cohort (APC) modeling to assess age annual percentage changes as well as period and cohort relative risks. Using Norpred modeling to predict the burden through 2040.
Results:Globally, the incidence of pancreatitis among younger individuals is 9.16/100,000(95%UI 5.74 to 13.85) in 2021, AAPC 0.13 (95%CI 0.12-0.14); the DALYs is 6.36/100,000(95%UI 5.21-7.97) in 2021, AAPC -0.93 [95%CI (-1.01 to -0.85)]. Global incidence rates of pancreatitis have risen notably since 1999, and the overall burden of DALYs has declined over the 30 years. In the APC model, different age group experienced different risks. According to the Norpred predictive model, by 2040, the global incidence of pancreatitis among younger individuals is projected to reach 313,567 cases, with an rate of 9.07/100,000.
Conclusion:Globally, the incidence of pancreatitis in younger individuals has risen over the past three decades. Urgent policy interventions are needed to address healthcare inequities to alleviate this burden.
Dose-dependent effects of curcumin on 22Rv1 prostate cancer cell line
Authors: Tossetta Giovanni , Fantone Sonia , Busilacchi Elena Marinelli , Marzioni Daniela , Mazzucchelli Roberta
Published: December 2024

Background
Prostate cancer (PCa) is the second most frequent cancer type in male population over 66 years. Curcumin is a polyphenolic natural compound extract from the rhizomes of Curcuma longa Linn (Zingiberaceae family) which showed important anticancer effects by inhibiting cell proliferation and inducing apoptosis in several cancer types. Recently, some studies reported that the oral curcumin lowered PSA levels, but it did not modify the clinical outcomes in patients with prostate cancer who received intermittent androgen deprivation (IAD). Other studies reported that high concentrations of curcumin were toxic for patients.
Methods and results
In this study we showed that low doses of curcumin can induce senescence-like effects in 22rv1 cell line while higher concentrations have cytotoxic effects. Five,15 and 30 µM curcumin blocked cell cycle in G2/M phase but only 15 and 30 µM curcumin induced cell death. In addition, an increased expression of p21, a known senescence marker, was detected in 22Rv1cells treated with curcumin in every experimental condition.
Conclusion
In the context of personalized approach in PCa care, we suggest that the appropriate concentration of curcumin used in combination with radiotherapy or with androgen deprivation therapy (ADT) could take into consideration.
Ultra-Hypermutation Driven by POLE Mutation in Metastatic Colorectal Cancer: A Case for Immunotherapy Without dMMR
Authors: Li Xiaozhuang , Tang Chuanyun , Zhang Hongli , Zhou Zhiyong , Ma Junpeng , Yuan Xin , Zhong Ziwei , Chen Jing , Peng Huiyun , Zhang Chengsheng
Published: December 2024

Colorectal cancer (CRC) is among the leading causes of cancer-related mortality globally. Metastatic colorectal cancer (mCRC) with ultra-hypermutation is uncommon and its underlying pathogenesis remains incompletely characterized. Additionally, the response to immunotherapy in ultra-hypermutated mCRC is not well defined. Here we report a unique case of a 33-year-old Chinese woman with right-sided colon adenocarcinoma harboring somatic mutations in the POLE (p.A465V), MSH6 (p.G237*), and MSH2 (p.T934M) genes. Despite the presence of MSH6 and MSH2 mutations, immunohistochemistry (IHC) did not show mismatch repair deficiency (dMMR). Genomic analysis revealed high microsatellite instability (MSI-H) and an markedly elevated tumor mutational burden (TMB) of 275.25 Mut/Mb. The patient was initially treated with a combination of nivolumab, capecitabine, and oxaliplatin. Following a favorable response observed through CT and MRI scans after the first treatment cycle, the patient has commenced a second cycle of therapy. To our knowledge, this is the first reported case of ultra-hypermutated mCRC with rare mutations in POLE (p.A465V), MSH6 (p.G237*), and MSH2 (p.T934M) without dMMR, evaluating the efficacy of immune checkpoint inhibitors in this setting.
Physical Activity, Sedentary Behavior and Risk of Inflammatory Bowel Disease
Authors: Xia Siqin , Zhang Jie , Zhang Zixing , Wang Xiang , Ye Dongqing , Fang Xinyu
Published: December 2024

Background: Evidence linking physical activity (PA) and sedentary behavior (SB) to the development of inflammatory bowel disease (IBD) is inconsistent, and their joint associations with disease remain to be determined.
Objective: This study aimed to examine the separate and joint association of PA and SB with IBD risk.
Methods: The research contained 355,021 people with no IBD at baseline in the UK biobank. Information on PA (measured using the International Physical Activity Questionnaire) and SB (sum of computer using, television watching, and driving behavior) were collected. Using Cox proportional hazard models to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD, Crohn’s disease (CD) and ulcerative colitis (UC) risks, while restricted cubic splines (RCS) assessing nonlinear relationships.
Results: During 13.6 years of follow-up, 2,242 incident IBD cases (664 CD and 1,481 UC) were recorded. Compared to the low level of PA, IBD risk was found to be lower for moderate and high PA, with HRs of 0.80 (95% CI: 0.72-0.89, p<0.001) and 0.87 (95% CI: 0.78-0.98, p=0.02), respectively. We also found a nonlinear correlation of PA with IBD risk (p<0.05 for nonlinearity), with a moderate level of PA (~2000 MET min/wk) offering the lowest risk. Besides, each additional hour of SB per day increased IBD risk (HR: 1.03; 95% CI: 1.01-1.05; p<0.001). The risk reduction from moderate and high levels of PA attenuated the adverse effects of long SB (≥6 hours/day), decreasing the risk by 18% and 27%, respectively. The results of PA and SB together on IBD risk showed that participants with low PA and long SB have the highest IBD risk.
Conclusions: The results revealed that promoting PA and reducing SB are beneficial for attenuating the risk of IBD. Individuals combining high PA with lowest SB time are at the lowest probability of developing IBD.
Clinical Utility of a Risk Scoring System for Individualized Treatment of Cesarean Scar Pregnancy
Authors: Sun Haiying , Wang Juan , Zhou Ting , Wang Shixuan , Liu Ronghua
Published: December 2024

Background Cesarean scar pregnancy (CSP) is a condition closely associated with previous cesarean section scars, and improper diagnosis or treatment may result in massive hemorrhage and life-threatening risks. Currently, there is a lack of standardized treatment guidelines or consensus for CSP, leading to a chaotic array of treatment methods. The objective of this study is to formulate a novel CSP scorecard model to aid in the selection of treatment plans for CSP.
Methods A cohort comprising 1,248 patients diagnosed with CSP was examined over a period from January 2013 to January 2023. Univariate and multivariate logistic regression analyses were employed to identify high-risk factors predictive of CSP risk, which served as the foundation for constructing a nomogram. The predictive efficacy of the nomogram was assessed through the application of receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA) curves.
ResultsSix risk factors—gestational age, gestational sac (GS) area, residual myometrial thickness, the relationship between the GS and scar, preoperative hemoglobin levels, and preoperative HCG—were evaluated as predictor variables in the nomogram. The nomogram demonstrated excellent discriminative ability, as evidenced by an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84. Furthermore, the calibration curves and decision curve analysis indicated that the nomogram exhibited strong consistency and substantial clinical utility.
Conclusion This newly developed risk scoring system offers an effective tool for clinicians to tailor individualized CSP treatment plans.
A 7-year retrospective study：Comparison of the efficacy between rotational osteotomy at the base of femoral neck and vascularized iliac bone flap transfer in the treatment of osteonecrosis of the femoral head
Authors: Xia Tianwei , Sun Jiahao , Wang Lu , Zheng Shanbin , Liu Jinzhu , Chen Zhiyuan , Li Muzhe , Guo Yang , Shen Jirong , Ma Yong
Published: December 2024

Objective: To compare the clinical efficacy of rotational osteotomy at the base of femoral neck and iliac bone flap transfer with ascending branch of lateral femoral circumflex artery(vascularized iliac bone flap transfer) in the treatment of ARCO III stage, CJFH-L type osteonecrosis of femoral head.
Methods: We compared 25 cases (Group A), in which 25 hips underwent rotational osteotomy at the base of femoral neck and 25 cases (Group B) , in which 25 hips underwent vascularized iliac bone flap transfer in our hospital from September 2017 to March 2024.The operative time and hospitalization time were compared, the collapse and repair of femoral head and the healing of osteotomy were evaluated, and the reasons of failure were analyzed.
Results: All operations were conducted successfully in both groups. The follow-up time was 36.2 ± 21.62 months. The operation time in Group A was (215.20 ± 56.80) minutes, which was longer than that in Group B (190.21 ± 54.40) minutes (P <0.05) . There was no significant difference in the hospitalization time between the two groups. There was no significant difference in Harris scores between Group A and group B before operation (P<0.05). However, there was significant difference in Harris scores after 3 months, 6 months and at the last follow-up (P <0.05) . In Group A and Group B, there were significant differences 3 months after operation, 6 months after operation and at the last follow-up (P <0.05) . The excellent and good rate of Group A was 36% (9 hips) , the good rate of Group B was 44% (11 hips) . During the longest 7-year follow-up period, 6 hips in Group A and 4 hips in Group B underwent arthroplasty. In addition, one hip in group A underwent total hip exclusion because of infection. DCE-MRI showed that abnormal hyperperfusion of the repaired area was alleviated, and the blood supply of the necrotic area was restored.
Conclusion: Both rotational osteotomy of the base of the femoral neck under surgical dislocation and vascularized iliac bone flap transfer can obtain satisfactory short-term results in the treatment of CJFH-L type，ARCO III stage osteonecrosis of the femoral head. Rotational osteotomy at the base of femoral neck under surgical dislocation can be chosen to delay the collapse process for CJFH-L2 type、ARCOⅢB stage ONFH. Vascularized iliac bone flap transfer has the advantage of short operation time. It is easier and suitable for CJFH-L1 type、ARCOⅢA stage ONFH.
Efficacy and safety of nivolumab plus cabozantinib in octogenarian patients with advanced renal cell carcinoma
Authors: Nemoto Yuki , Endo Takanori , Segawa Hogara , Nakamura Kazutaka , Nishimura Koichi , Horiuchi Toshihide , Toki Daisuke , Kobayashi Hirohito , Takagi Toshio , Kondo Tsunenori
Published: December 2024

Purpose
To clarify the efficacy and safety profile of nivolumab plus cabozantinib combination therapy in advanced renal cell carcinoma patients older than 80 years.
Methods
We retrospectively evaluated 42 patients with advanced renal cell carcinoma treated with nivolumab plus cabozantinib as the first-line therapy at our institution. The patients were categorized according to age as those aged ≥ 80 years and those aged < 80 years. Efficacy was analysed by comparing the progression-free survival, overall survival, objective response rate, and disease control rate between the two groups. Safety was assessed by comparing the incidence of adverse events.
Results
Ten patients (31%) were classified as age ≥ 80 group. No significant differences were observed in the progression-free survival (p = 0.682), the overall survival (p = 0.627), objective response rate (p = 0.195), and disease control rate (p = 0.070) between the two groups. There was no significant difference in the incidence of all grades of adverse events(p = 1.000), but there was a trend toward a higher incidence of grade 3 or higher adverse events in the group of patients aged < 80 years (p = 0.066).
Conclusions
The efficacy and safety of nivolumab plus cabozantinib combination therapy were comparable between the patients aged ≥ 80 years and those aged < 80 years. Thus, chronological age alone is not a contraindication for nivolumab plus cabozantinib combination therapy for advanced renal cell carcinoma.
Sampling frequency matters: mapping of the healthy infants' gut microbiome during the first year of life
Authors: Micenková Lenka , Smetanová Soňa , Marciniak Jacek , Brodíková Kristýna , Kleknerová Dominika Polaštík , Lakotová Barbora , Zwinsová Barbora , Thon Vojtěch , Vídeňská Petra , Budinská Eva
Published: December 2024

Background
Previous studies described the impact of various early life events on the developing gut environment of infants. Nevertheless, a comprehensive understanding of the time frame of the response of the healthy microbiome to specific factors, such as vaccination, introduction of solid foods etc., and the duration of these changes is currently lacking. Hence, determining the optimal sampling frequency to effectively monitor the complex development of the gut microbiome remains a challenge.
Methods
To address these gaps, we monitored the plasticity of the gut microbiome using 16S rRNA gene sequencing almost on a daily basis in one infant (infant A) and weekly in twelve other infants (B-M) during their first year of life. We associated these changes with external factors and monitored their length.
Results
With respect to the first occurrence and dynamics of changes in the abundance of bacterial genera in all infants, three dominant groups of bacteria emerged, comprising "Early-life colonizers", "Re-appearing colonizers" and "Later-colonizers". Supporting the hypothesis that weekly sampling may not capture microbiota changes accurately, we found that a range of individual samples analyzed within a week varied by over 1 Shannon index, with coefficients of variation exceeding 10% in 19 weeks. While alpha diversity indicators showed decreased variability with age, beta diversity variability remained high at the end of the first year. In particular, the introduction of solid food and probiotics led to gradual but significant changes in bacterial composition, with the duration and extent of the changes varying between infants.
Conclusions
In our unique study, for the first time, we described in detail the mode of bacterial stages and colonizers in infants during the first year of life, finding that a similar colonization motif was observed regardless of sampling frequency. We showed that sparse weekly sampling hindered a comprehensive understanding of how key factors - such as the maternal microbiome, probiotics, diet, vaccinations, and unforeseen variables - affect the child's microbiome over time and in response to specific events early in life. Analysis of weekly variability in alpha and beta diversity suggests that such rare sampling may not be sufficient in terms of the outcomes of interest.
Prenatal Exome Sequencing of Fetuses with Central Nervous System Anomalies Based on Prenatal Ultrasound and Magnetic Resonance Imaging Diagnosis — A Retrospective Cohort Study and System Review
Authors: Yao Miss Jia , Wang Yan , Li Gang , Zhang Zhitao , Lv Yuan , Chen Lizhu
Published: December 2024

Background
Assessing the incremental yield of prenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) in the diagnosis of central nervous system (CNS) anomalies based on prenatal ultrasound and magnetic resonance imaging (MRI) diagnoses.
Methods
In this retrospective cohort study, we collected the ES results of fetuses diagnosed with CNS anomalies through prenatal ultrasound and MRI between 2019 and 2023, who also had negative CMA results. We performed subgroup analyses to assess detection rates for different phenotypes in order to identify associated genes and variants. A meta-analysis combining our study with relevant research was performed to further explore the association between phenotype and ES.
Results
In the cohort study of 219 cases, ES identified pathogenic/likely pathogenic single nucleotide variations in 36 cases (16%). The highest detection rate was observed in cases with multisystem malformations (25%, 14/55), followed by multiple CNS anomalies (15%, 2/13) and isolated CNS anomaly (13%, 20/151). The most commonly identified isolated CNS anomaly was agenesis of the corpus callosum (31%, 5/16). Neural tube defects with urogenital anomalies were strongly linked to positive ES results (57%, 4/7). The meta-analysis of 989 cases from 22 studies showed a pooled ES diagnostic yield of 27% [(95% (CI), 21–34%)]. The highest detection rates were in cases of corpus callosum anomalies with facial abnormalities (75%, 8/11) and neural tube defects with urogenital malformations (80%, 12/15). The detection rate for three or more types of complex central nervous system (CNS) abnormalities was 43% (95% confidence interval, 31%-58%), which was significantly higher than that for only two abnormalities, which was 10% [(95% (CI), 4%-18%). No significant difference in diagnostic yield was found between cases identified by prenatal MRI combined with ultrasound [27% (95% confidence interval, 20–36%)] and those identified by ultrasound alone [25% (95% confidence interval, 17–35%)].
Conclusions
ES provided a significantly higher diagnostic yield than CMA for fetuses with CNS abnormalities. Additionally, diagnostic rates for variants varied across different phenotypic abnormalities.
Construction of high protein-producing mutant yeast strains via point and structural mutageneses and their use for carotenoid production
Authors: Yamada Ryosuke , Inoue Yoshifumi , Karitani Yukino , Sakaguchi Rumi , Matsumoto Takuya , Ogino Hiroyasu
Published: December 2024

Yeast Saccharomyces cerevisiae is a safe microorganism with established industrial-scale culture techniques, making it a useful host for protein and chemical production through metabolic engineering. Therefore, S. cerevisiae platform strains with high protein production are needed. In this study, we aimed to develop mutant S. cerevisiae strains with high protein production using techniques to introduce point and structural mutations. Point and structural mutations were introduced into the YPH499/pEUPGGFP strain, which expresses green fluorescent protein (GFP) in S. cerevisiae YPH499, and mutant strains were selected based on their fluorescence intensity. Consequently, YPH499/pEUPGGFP/Mu10G39, with a GFP fluorescence intensity 2.5-fold higher than that of the parent strain, was successfully obtained. Then, GFP expression plasmid was removed from the mutant and a carotenoid-producing plasmid was introduced to construct YPH499Mu10G39/pEU20Beta3. YPH499Mu10G39/pEU20Beta3 produced 6.74 mg/g-dry cell carotenoids after 72 h of culture, which was 2.9-fold higher than that produced by the parent strain. Transcriptome analysis suggested that YPH499Mu10G39 exhibited improved energy production, amino acid precursor supply, ribosome function, and stress tolerance, which may have contributed to its high protein production. In conclusion, by introducing point and structural mutations, we successfully developed the platform strain, YPH499Mu10G39, which is useful for the high production of various proteins. In the future, various proteins and useful chemicals can be produced through metabolic engineering using YPH499Mu10G39 as a platform strain.
High resolution data reveal fundamental steps and turning points in animal movements
Authors: Gunner Richard , Wilson Rory , Lurgi Miguel , Borger Luca , Redcliffe James , Shepard Emily , Holton Mark , Crofoot Margaret , Alagaili Abdulaziz , Andrzejaczek Samantha , Ariano-Sánchez Daniel , Barbedette-Gerard Thomas , Bennett Nigel , Bernard Alice , Brown Rowan , Cole Nik , Creel Scott , Cruz-Neto Ariovaldo , Virgilio Agustina di , Duarte Carlos M , Eizaguirre Christophe , Elliott Kyle , Faltusova Monika , Garel Mathieu , Gillies Natasha , Gleiss Adrian , Göppert Aoife , Grémillet David , de Grissac Sophie , Guilford Tim , Hoareau Maxime , Jessopp Mark , Gomez-Laich Agustina , Miloš Ježek , Lambertucci Sergio , Marchand Pascal , Marks Nikki , Martins Andréia , Meekan Mark , Mizutani Yuichi , Mortensen Rasmus Mohr , Norman Brad , Ortega Josué , Padget Oliver , Painter Michael , Ponchon Aurore , Provost Pascal , Ponchon Aurore , Quintana Flavio , Reinhardt Stefanie , Reynolds Samantha , Rosell Frank , Ruiz-Miranda Carlos , Ryan Peter , Scantlebury Michael , Schoombie Stefan , Scott Rebecca , Silovský Václav , Tatayah Rabindra Vikash , Toïgo Carole , Torrez Lucia , Tremblay Fred , Twining Joshua , Yoda Ken , Weimerskirch Henri , Whelan Shannon , Morales Juan , Potts Jonathan
Published: December 2024

Animal movement paths display substantial complexity and variability, leading researchers to seek underlying rules that govern these patterns and mathematical models that best describe them. Using high-resolution (≥ 10 Hz) movement from 43 vertebrate species across diverse taxa, mass, and lifestyles, we show that movement paths are universally composed of straight-line steps interspersed with sharp turns, echoing a pattern documented for lower taxa such as bacteria. We report how these vertebrate ‘fundamental step lengths’ and ‘fundamental turn angles’, which are intrinsically different from the straight-line paths detailed in studies using low resolution position data, vary with species’ mass, lifestyle, behaviour, and environmental context. To explain these, we posit that animals inherently move in a straight line until sensory information signals a perceived better heading, which instigates a turn. The constellation of fundamental step lengths and turn angles over varying time intervals affects how well different models of animal movement (such as random walk or Lévy flight) fit lower resolution data. By examining turns as decision points, we can seek drivers of animal movement patterns and thereby work to predict future paths under varying conditions.