bluuebunny/crossref_metadata_2025 huggingface dataset:
3D printed guide-assisted percutaneous screw fixation for minimally displaced scaphoid waist fractures with delayed diagnosis or presentation
Authors: Rong Cunmin , Zhang Qinglin , Zhu Shaobo , Zhang Guanghui , Zeng Junhao , Han Qingluan , Guo Yang
Published: February 2024

Objectives

To Investigate the value of 3D printed guide-assisted percutaneous management of minimally displaced scaphoid waist fractures(Herbert’s B2) with delayed diagnosis or presentation.

Methods

From October 2018 to February 2022, 10 patients with established delayed diagnoses and presentation of minimally displaced scaphoid waist fractures were treated with 3D printed guides assisted with percutaneous internal fixation without bone grafting. This technique was based on the patient’s preoperative CT and imported into the software. Based on Boolean subtraction, the most centralized screw placement position was identified and a customized guide was produced. Intraoperative percutaneous insertion of the guide wire was assisted by the custom guide.

Results

All 10 patients were successful in one attempt. The fractures healed at a mean of 7.7 weeks postoperatively (range 6–10 weeks). At a mean follow-up of 7.7 months (6–13 months), patients had excellent recovery of wrist function with minimal pain reduction. There were no major postoperative complications and the patients all returned to their previous activities before the injury.

Conclusions

Percutaneous internal fixation based on 3D printed guides is a safe and effective technique for delayed diagnosis or presentation of patients with minimally displaced fractures of the scaphoid waist. This method allows for easy insertion of screws and avoids multiple attempts.
Effects of different patterns of movement for correcting a deep curve of Spee with clear aligners on the anterior teeth: a finite element analysis
Authors: Zhu Lin , Liu Lin , Wang Wei , Deng Wen Wen
Published: February 2024

Objective

To analyse the anterior teeth effects of clear aligners on five different patterns of mandibular molar movement and to define the most effective configuration to be implemented with clear aligners through finite element analysis.

Methods

A three-dimensional mandibular model with a deep overbite in the mandible was constructed using cone beam computerized tomography (CBCT) data. The model included the mandibular dentition, mandibular periodontal ligaments, attachments, and aligners. Five models were created: (1) configuration A: second molar distalization (0.25 mm); (2) configuration B: second molar distalization (0.25 mm), first molar extrusion (0.15 mm); (3) configuration C: second molar distalization (0.25 mmm), first and second premolar extrusion(0.15 mm); (4) configuration D: second molar distalization (0.25 mm), first molar and first/second premolar extrusion(0.15 mm); and (5) configuration E: second molar distalization (0.25 mm), first molar and first/second premolar extrusion (0.15 mm), first molar and first/second premolar expansion (0.15 mm).

Results

In all configurations, the anterior teeth exhibited labial tipping and the mandibular central incisor of configuration E showed the highest labial tipping. Configuration E demonstrated a relatively minor impact on mandibular molars distalization compared with configuration A. Configuration A showed the highest distal displacement value, and configuration E produced the lowest displacement value. Configuration E caused the highest periodontal ligament (PDL) pressure of the central and lateral incisors. The differences in the canines between configurations C and D,were not significant, and the stress distribution differed among the five groups.

Conclusions

All patterns utilizing clear aligners facilitated mandibular molar distalization. Extruding the premolars and second molar distalization at the same time had little impact on second molar distalization; When expansion and extrusion were simultaneously performed during the distalization of mandibular molars, our prime consideration was the alveolar bone on the labial side of the anterior teeth to prevent the occurrence of gingival recession, dehiscence, and fenestration. Due to the lack of consideration for periodontal tissues in this study, clinical protocols should be designed based on the periodontal status of the mandibular anterior teeth.
Dental Caries diagnosis from bitewing images using convolutional neural networks
Authors: ForouzeshFar Parsa , Safaei Ali Asghar , Ghaderi Foad , Hashemikamangar Sedighe Sadat
Published: February 2024

Background

Dental caries, also known as tooth decay, is a widespread and long-standing condition that affects people of all ages. This ailment is caused by bacteria that attach themselves to teeth and break down sugars, creating acid that gradually wears away at the tooth structure. Tooth discoloration, pain, and sensitivity to hot or cold foods and drinks are common symptoms of tooth decay. Although this condition is prevalent among all age groups, it is especially prevalent in children with baby teeth. Early diagnosis of dental caries is critical to preventing further decay and avoiding costly tooth repairs. Currently, dentists employ a time-consuming and repetitive process of manually marking tooth lesions after conducting radiographic exams. However, with the rapid development of artificial intelligence in medical imaging research, there is a chance to improve the accuracy and efficiency of dental diagnosis.

Methods

This study introduces a data-driven model for accurately diagnosing dental decay through the use of Bitewing radiology images using convolutional neural networks. The dataset utilized in this research includes 713 patient images obtained from the Samin Maxillofacial Radiology Center located in Tehran, Iran. The images were captured between June 2020 and January 2022 and underwent processing via four distinct Convolutional Neural Networks. The images were resized to 100 × 100 and then divided into two groups: 70% (4219) for training and 30% (1813) for testing. The four networks employed in this study were AlexNet, ResNet50, VGG16, and VGG19.

Results

Among different well-known CNN architectures compared in this study, the VGG19 model was found to be the most accurate, with a 93.93% accuracy.

Conclusion

This promising result indicates the potential for developing an automatic AI-based dental caries diagnostic model from Bitewing images. It has the potential to serve patients or dentists as a mobile app or cloud-based diagnosis service (clinical decision support system).
Impact of palliative care at end-of-life Covid-19 patients – a small-scale pioneering experience
Authors: Rodrigues-Ribeiro João Luís , Castro Luísa , Pinto-Ribeiro Filipa , Nunes Rui
Published: February 2024

Background

In March 2020, the outbreak caused by the SARS-CoV-2 virus was declared a pandemic, resulting in numerous fatalities worldwide. To effectively combat the virus, it would be beneficial to involve professionals who specialize in symptom control for advanced illnesses, working closely with other specialties throughout the illness process. This approach can help manage a range of symptoms, from mild to severe and potentially life-threatening. No studies have been conducted in Portugal to analyse the intervention of Palliative Medicine at the end of life of Covid-19 patients and how it differs from other specialties. This knowledge could help determine the importance of including it in the care of people with advanced Covid-19.

Objectives

The objective of this study is to examine potential differences in the care provided to patients with Covid-19 during their Last Hours and Days of Life (LHDOL) between those who received care from Palliative Medicine doctors and those who did not.

Methods

This is a retrospective cohort study spanning three months (Dec 2020 to Feb 2021), the duration of the Support Unit especially created to deal with Covid-19 patients. The database included clinical files from 181 patients admitted to the Support Unit, 27 of which died from Covid-19.

Results

Statistically significant differences were identified in the care provided. Specifically, fewer drugs were administered at the time of death, including drugs for dyspnoea, pain and agitation, suspension of futile devices and use of palliative sedation to control refractory symptoms.

Conclusions

End-of-life care and symptomatic control differ when there’s regular follow-up by Palliative Medicine, which may translate less symptomatic suffering and promote a dignified and humane end of life.
Structured Counselling and Regular Telephonic follow up to improve Referral flow and compliance in Nepal for Diabetic Retinopathy(SCREEN-D Study): a randomised controlled trial
Authors: Bhattarai Binita , Thapa Hari Bahadur , Bashyal Sandip , Thapa Sarasawati Khadka , Chaudhuri Sirshendu , Agiwal Varun , Pant Hira , Singh Samiksha , Mahajan Hemant
Published: February 2024

Background

Diabetic Retinopathy (DR) is an emerging public health issue, leading to severe visual impairment or blindness. Early identification and prompt treatment play a key role in achieving good visual outcomes. The objective of the study was to estimate the effectiveness of SCREEN package on improving referral compliance from peripheral centres to a tertiary eye centre in Nepal.

Methods

In this facility-based cluster-randomized trial, ten out of 19 referring centres of the tertiary eye care centre in Lumbini zone, Nepal were randomized into intervention and control groups. A SCREEN packagewereprovided as intervention for DR patients who require advanced treatment in the tertiary centres and was compared with the current practice of the control arm, where structured counselling and follow-up mechanism are absent. Compliance was estimated by a weekly follow-up between the referring centre and the referred hospital.

Results

We recruited 302 participantsof whom 153 were in the intervention arm. The mean age of the participants was 57.8 years (Standard deviation [SD]±11.7 years). With implementation of SCREEN package71.2% (n=109) in the intervention group and 42.9% (n=64) in the control group were compliant till three months of follow-up (Difference 28.3%, 95% CI: 17.6- 39.0, p<0.05). Compliance was 43% (n=66) with counselling alone, and 66% (n=103) with first telephonic follow-up in the intervention arm. The mean duration to reach the referral centre was 14.7 days (SD± 9.4 days) and 18.2 days (SD± 9.1 days) in the intervention and the control arm, respectively (Difference 3.5 days, 95% CI: 0.7 to 6.4 days).

Conclusions

Counselling& follow-up to patients is the key factor to improve the utilization of the health services by patients with DR. Health systems must be strengthened by optimizing the existing referral structure in Nepal.

Trial registration

ClinicalTrials.gov Protocol Registration and Results System, ClinicalTrials.gov Identifier: NCT04834648, 08/04/2021.
Molecular epidemiology of Enterocytozoon bieneusi from foxes and raccoon dogs in the Henan and Hebei provinces in China
Authors: Chen Minghui , Wang Haidong , Li Xinmiao , Guo Yunan , Lu Ying , Zheng Liping , Liang Guoqing , Sui Yuzhen , Wang Bukang , Dai Hongyu , Dong Haiju , Zhang Longxian
Published: February 2024

Background

Enterocytozoon bieneusi is a zoonotic pathogen widely distributed in animals and humans. It can cause diarrhea and even death in immunocompromised hosts. Approximately 800 internal transcribed spacer (ITS) genotypes have been identified in E. bieneusi. Farmed foxes and raccoon dogs are closely associated to humans and might be the reservoir of E. bieneusi which is known to have zoonotic potential. However, there are only a few studies about E. bieneusi genotype identification and epidemiological survey in foxes and raccoon dogs in Henan and Hebei province. Thus, the present study investigated the infection rates and genotypes of E. bieneusi in farmed foxes and raccoon dogs in the Henan and Hebei provinces.

Result

A total of 704 and 884 fecal specimens were collected from foxes and raccoon dogs, respectively. Nested PCR was conducted based on ITS of ribosomal RNA (rRNA), and then multilocus sequence typing (MLST) was conducted to analyze the genotypes. The result showed that infection rates of E. bieneusi in foxes and raccoon dogs were 18.32% and 5.54%, respectively. Ten E. bieneusi genotypes with zoonotic potential (NCF2, NCF3, D, EbpC, CHN-DC1, SCF2, CHN-F1, Type IV, BEB4, and BEB6) were identified in foxes and raccoon dogs. Totally 178 ITS-positive DNA specimens were identified from foxes and raccoon dogs and these specimens were then subjected to MLST analysis. In the MLST analysis, 12, 2, 7 and 8 genotypes were identified in at the mini-/ micro-satellite loci MS1, MS3, MS4 and MS7, respectively. A total of 14 multilocus genotypes were generated using ClustalX 2.1 software. Overall, the present study evaluated the infection of E. bieneusi in foxes and raccoon dogs in the Henan and Hebei province, and investigated the zoonotic potential of the E. bieneusi in foxes and raccoon dogs.

Conclusions

These findings expand the geographic distribution information of E. bieneusi’ host in China and was helpful in preventing against the infection of E. bieneusi with zoonotic potential in foxes and raccoon dogs.
Subcutaneous application of hyperimmune serum against Histophilus somni recombinant proteins affects serum antibody reactivity in beef calves
Authors: Bajzert Joanna , Jawor Paulina , Baran Rafał , Stefaniak Tadeusz
Published: February 2024

Background

Respiratory tract diseases cause significant economic loss in beef cattle. This study aimed to determine whether the application of hyperimmune serum (HS) containing antibodies against selected antigens of Gram-negative bacteria would improve the health and growth of different breeds of beef calves kept on three farms. Two recombinant protein antigens (Histophilus somni rHsp60 and rOMP40) were used to immunize four cows to produce HS. Eighty seven beef calves (Charolaise n = 36, Limousine n = 34, and crossbreed n = 17) were included into study. One hundred milliliters of serum were administered subcutaneously to 43 beef calves (Charolaise n = 18, Limousine n = 17, and crossbreed n = 8) twice, between 1 and 5 and 21–28 days of life. Calves were examined three times, and blood samples were taken to evaluate immunoglobulin M, G1, and G2, fibrinogen, serum amyloid A, and haptoglobin concentrations and reactivity of these Ig classes of antibodies against H. somni rHsp60 and rOMP40. Average daily weight gain during the first month and until weaning was calculated.

Results

HS showed higher (p ≤ 0.05) reactivity in calf sera against H. somni rHsp60 and OMP40 in IgG1 and IgG2. In experimental calves, compared to control calves, the reactivity of IgG1 against rOMP40 in the second sampling was higher in Limousine calves (p ≤ 0.001) and in the other two herds (p ≤ 0.05). Serum IgG2 antibody activity against H. somni rHsp60 in the second sampling was higher in experimental calves than in control calves in charolaise (p ≤ 0.05) and limousine (p ≤ 0.001) herds. The reactivity of IgG2 against rOMP40 in the second sampling of experimental calves was higher in herds with Charolaise and Limousine calves (p ≤ 0.001) and in crossbred calves (p ≤ 0.05). In the third sampling, serum IgG1 antibody reactivity against rOMP40 in Limousine calves was higher (p ≤ 0.05) in the experimental group. Among the other evaluated parameters, only SAA in the second sampling in the herd with Charolaise calves and heart rate in the herd with Limousine calves were significantly higher in the control calves (p ≤ 0.05).

Conclusion

The application of HS to calves in all herds had an impact on specific reactivity in IgG1 and IgG2 classes against H. somni rOMP40 and rHsp60, antigens which were used for serum production.
Double diabetes—when type 1 diabetes meets type 2 diabetes: definition, pathogenesis and recognition
Authors: Bielka Weronika , Przezak Agnieszka , Molęda Piotr , Pius-Sadowska Ewa , Machaliński Bogusław
Published: February 2024

Currently, the differentiation between type 1 diabetes (T1D) and type 2 diabetes (T2D) is not straightforward, and the features of both types of diabetes coexist in one subject. This situation triggered the need to discriminate so-called double diabetes (DD), hybrid diabetes or type 1.5 diabetes, which is generally described as the presence of the insulin resistance characteristic of metabolic syndrome in individuals diagnosed with T1D. DD not only raises the question of proper classification of diabetes but is also associated with a significantly greater risk of developing micro- and macroangiopathic complications, which was independent of glycaemic control. When considering the global obesity pandemic and increasing incidence of T1D, the prevalence of DD may also presumably increase. Therefore, it is of the highest priority to discover the mechanisms underlying the development of DD and to identify appropriate methods to prevent or treat DD. In this article, we describe how the definition of double diabetes has changed over the years and how it is currently defined. We discuss the accuracy of including metabolic syndrome in the DD definition. We also present possible hypotheses connecting insulin resistance with T1D and propose possible methods to identify individuals with double diabetes based on indirect insulin resistance markers, which are easily assessed in everyday clinical practice. Moreover, we discuss adjuvant therapy which may be considered in double diabetic patients.
The association between triglyceride glucose-body mass index and all-cause mortality in critically ill patients with atrial fibrillation: a retrospective study from MIMIC-IV database
Authors: Hu Yi , Zhao Yiting , Zhang Jing , Li Chaomin
Published: February 2024

Background

The TyG-BMI index, which is a reliable indicator of insulin resistance (IR), has been found to have a significant correlation with the occurrence of cardiovascular events. However, there still lacks study on the TyG-BMI index and prognosis in patients with atrial fibrillation (AF). The objective of the present study was to evaluate the relationship between TyG-BMI index at admission to ICU and all-cause mortality in critically ill patients with AF.

Methods

The patient’s data were extracted from Medical Information Mart for Intensive Care IV(MIMIC-IV) database. All patients were divided into four groups according to TyG-BMI index. Outcomes include primary and secondary endpoints, with the primary endpoint being the 30-day and 365-day all-cause mortality and the secondary endpoint being the 90-day and 180-day all-cause mortality. TyG-BMI index was quartile and Kaplan-Meier curve was used to compare the outcome of each group. Cox proportional-hazards regression model and restricted cubic splines (RCS) were conducted to assess the relationship between TyG-BMI index and outcomes.

Results

Out of a total of 2509 participants, the average age was 73.26 ± 11.87 years, with 1555 (62.0%) being males. Patients with lower level of TyG-BMI had higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality, according to the Kaplan-Meier curves (log-rank P < 0.001). In addition, cox proportional-hazards regression analysis revealed that the risk of 30-day, 90-day, 180-day and 365-day all-cause mortality was significantly higher in the lowest quartile of TyG-BMI. Meanwhile, the RCS analysis indicated that L-typed relationships between TyG-BMI index and all-cause mortality, with inflection points at 223.60 for 30-day and 255.02 for 365-day all-cause mortality, respectively. Compared to patients with TyG-BMI levels below the inflection points, those with higher levels had a 1.8% lower risk for 30-day all-cause mortality (hazard ratio [HR] 0.982, 95% confidence interval [CI] 0.9676–0.988) and 1.1% lower risk for 365-day all-cause mortality (HR 0.989, 95% CI 0.986–0.991).

Conclusion

In critically ill patients with AF, a lower TyG-BMI level is significantly associated with a higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality. TyG-BMI index could be used as a valid indicator for grading and treating patients with AF in the ICU.
Development and characterization of a novel nanobody with SRMV neutralizing activity
Authors: Sun Miao , Wang Changjiang , Luo Huaye , Chen Yanfei , Qu Guanggang , Chen Jian , Li Ling , Zhang Min , Xue Qinghong
Published: February 2024

Peste des petits ruminants (PPR) is an acute, contact infectious disease caused by the small ruminant morbillivirus (SRMV), and its morbidity in goats and sheep can be up to 100% with significant mortality. Nanobody generated from camelid animals such as alpaca has attracted wide attention because of its unique advantages compared with conventional antibodies. The main objective of this study was to produce specific nanobodies against SRMV and identify its characteristics. To obtain the coding gene of SRMV-specific nanobodies, we first constructed an immune phage-displayed library from the VHH repertoire of alpaca that was immunized with SRMV-F and -H proteins. By using phage display technology, the target antigen-specific VHHs can be obtained after four consecutive rounds of biopanning. Results showed that the size of this VHH library was 2.26 × 1010 CFU/mL and the SRMV-F and -H specific phage particles were greatly enriched after four rounds of biopanning. The positive phage clones were selected and sequenced, and total of five independent different sequences of SRMV-specific nanobodies were identified. Subsequently, the DNA fragments of the five nanobodies were cloned into E. coli BL21(DE3), respectively, and three of them were successfully expressed and purified. Specificity and affinity towards inactivated SRMV of these purified nanobodies were then evaluated using the ELISA method. Results demonstrated that NbSRMV-1-1, NbSRMV-2-10, and NbSRMV-1-21 showed no cross-reactivity with other antigens, such as inactivated BTV, inactivated FMDV, His-tag labeled protein, and BSA. The ELISA titer of these three nanobodies against inactivated SRMV was up to 1:1000. However, only NbSRMV-1-21 displayed SRMV neutralizing activity at a maximum dilution of 1:4. The results indicate that the nanobodies against SRMV generated in this study could be useful in future applications. This study provided a novel antibody tool and laid a foundation for the treatment and detection of SRMV.
A cuproptosis score model and prognostic score model can evaluate clinical characteristics and immune microenvironment in NSCLC
Authors: Tang Yijie , Wang Tianyi , Li Qixuan , Shi Jiahai
Published: February 2024

Background

Cuproptosis-related genes (CRGs) are associated with lung adenocarcinoma. However, the links between CRGs and non-small-cell lung cancer (NSCLC) are not clear. In this study, we aimed to develop two cuproptosis models and investigate their correlation with NSCLC in terms of clinical features and tumor microenvironment.

Methods

CRG expression profiles and clinical data from NSCLC and normal tissues was obtained from GEO (GSE42127) and TCGA datasets. Molecular clusters were classified into three patterns based on CRGs and cuproptosis cluster-related specific differentially expressed genes (CRDEGs). Then, two clinical models were established. First, a prognostic score model based on CRDEGs was established using univariate/multivariate Cox analysis. Then, through principal component analysis, a cuproptosis score model was established based on prognosis-related genes acquired via univariate analysis of CRDEGs. NSCLC patients were divided into high/low risk groups.

Results

Eighteen CRGs were acquired, all upregulated in tumor tissues, 15 of which significantly (P < 0.05). Among the three CRG clusters, cluster B had the best prognosis. In the CRDEG clusters, cluster C had the best survival. In the prognostic score model, the high-risk group had worse prognosis, higher tumor mutation load, and lower immune infiltration while in the cuproptosis score model, a high score represented better survival, lower tumor mutation load, and high-level immune infiltration.

Conclusions

The cuproptosis score model and prognostic score model may be associated with NSCLC prognosis and immune microenvironment. These novel findings on the progression and immune landscape of NSCLC may facilitate the provision of more personalized immunotherapy interventions for NSCLC patients.
Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer
Authors: Xie Tianlei , Peng Shan , Liu Shujun , Zheng Minghao , Diao Wenli , Ding Meng , Fu Yao , Guo Hongqian , Zhao Wei , Zhuang Junlong
Published: February 2024

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore’s independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.
Associations of the triglyceride-glucose index and remnant cholesterol with coronary artery disease: a retrospective study
Authors: Wu Xiaosheng , Qiu Weiping , He Houlin , Zhao Guojun , Liu Jianling
Published: February 2024

Background

Remnant cholesterol (RC) represents a low-cost and readily measured lipid index that contributes significantly to residual cardiovascular disease risk. The triglyceride-glucose (TyG) index exhibits a significant correlation with cardiovascular disease occurrence. However, RC and the TyG index have rarely been examined for their potentials in predicting coronary artery disease (CAD). Accordingly, the study was designed to validate the correlations of these two biomarkers with CAD and to compare the forecasted values of these two biomarkers for newly diagnosed CAD.

Methods

Totally 570 subjects firstly administered coronary angiography were enrolled, including 431 newly diagnosed CAD cases and 139 individuals without CAD. The individuals were classified into two groups according to CAD diagnosis. RC was derived as total cholesterol content (mmol/L) – (high density lipoprotein cholesterol content + low density lipoprotein cholesterol content; both in mmol/L). The TyG index was determined as ln (fasting triglyceride level [mg/dL] × fasting plasma glucose level [mg/dL])/2.

Results

Baseline feature analysis revealed significant differences in RC and the TyG index between the CAD and non-CAD groups (both P < 0.001). RC and the TyG index were independent risk factors for CAD in accordance with logistic regression analysis (both P < 0.05). Moreover, spearman correlation analysis elucidated CAD had a more remarkable correlation with the TyG index compared with RC (both P < 0.001). Furthermore, according to receiver operating characteristic curve analysis, the TyG index was better than RC in predicting CAD.

Conclusions

The TyG index and RC have significant associations with CAD. Compared with RC, the TyG index possesses a closer correlation with CAD and a higher predictive value for CAD.
Hydrogel-mediated extracellular vesicles for enhanced wound healing: the latest progress, and their prospects for 3D bioprinting
Authors: Zheng Yi , Pan Chuqiao , Xu Peng , Liu Kai
Published: February 2024

Extracellular vesicles have shown promising tissue recovery-promoting effects, making them increasingly sought-after for their therapeutic potential in wound treatment. However, traditional extracellular vesicle applications suffer from limitations such as rapid degradation and short maintenance during wound administration. To address these challenges, a growing body of research highlights the role of hydrogels as effective carriers for sustained extracellular vesicle release, thereby facilitating wound healing. The combination of extracellular vesicles with hydrogels and the development of 3D bioprinting create composite hydrogel systems boasting excellent mechanical properties and biological activity, presenting a novel approach to wound healing and skin dressing. This comprehensive review explores the remarkable mechanical properties of hydrogels, specifically suited for loading extracellular vesicles. We delve into the diverse sources of extracellular vesicles and hydrogels, analyzing their integration within composite hydrogel formulations for wound treatment. Different composite methods as well as 3D bioprinting, adapted to varying conditions and construction strategies, are examined for their roles in promoting wound healing. The results highlight the potential of extracellular vesicle-laden hydrogels as advanced therapeutic tools in the field of wound treatment, offering both mechanical support and bioactive functions. By providing an in-depth examination of the various roles that these composite hydrogels can play in wound healing, this review sheds light on the promising directions for further research and development. Finally, we address the challenges associated with the application of composite hydrogels, along with emerging trends of 3D bioprinting in this domain. The discussion covers issues such as scalability, regulatory considerations, and the translation of this technology into practical clinical settings. In conclusion, this review underlines the significant contributions of hydrogel-mediated extracellular vesicle therapy to the field of 3D bioprinting and wound healing and tissue regeneration. It serves as a valuable resource for researchers and practitioners alike, fostering a deeper understanding of the potential benefits, applications, and challenges involved in utilizing composite hydrogels for wound treatment.

Graphical abstract
Computational design and engineering of self-assembling multivalent microproteins with therapeutic potential against SARS-CoV-2
Authors: Qin Qin , Jiang Xinyi , Huo Liyun , Qian Jiaqiang , Yu Hongyuan , Zhu Haixia , Du Wenhao , Cao Yuhui , Zhang Xing , Huang Qiang
Published: February 2024

Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the “3-RBD-up” conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses.

Graphical Abstract
An integrated multi-tissue approach for endometriosis candidate biomarkers: a systematic review
Authors: Brulport Axelle , Bourdon Mathilde , Vaiman Daniel , Drouet Christian , Pocate-Cheriet Khaled , Bouzid Kheira , Marcellin Louis , Santulli Pietro , Abo Carole , Jeljeli Maxime , Chouzenoux Sandrine , Chapron Charles , Batteux Frédéric , Berthelot Camille , Doridot Ludivine
Published: February 2024

Biomarker identification could help in deciphering endometriosis pathophysiology in addition to their use in the development of non invasive diagnostic and prognostic approaches, that are essential to greatly improve patient care. Despite extensive efforts, no single potential biomarker or combination has been clinically validated for endometriosis.

Many studies have investigated endometriosis-associated biological markers in specific tissues, but an integrative approach across tissues is lacking. The aim of this review is to propose a comprehensive overview of identified biomarkers based on tissue or biological compartment, while taking into account endometriosis phenotypes (superficial, ovarian or deep, or rASRM stages), menstrual cycle phases, treatments and symptoms.

We searched PubMed and Embase databases for articles matching the following criteria: 'endometriosis' present in the title and the associated term 'biomarkers' found as Medical Subject Headings (MeSH) terms or in all fields. We restricted to publications in English and on human populations. Relevant articles published between 01 January 2005 (when endometriosis phenotypes start to be described in papers) and 01 September 2022 were critically analysed and discussed.

Four hundred forty seven articles on endometriosis biomarkers that included a control group without endometriosis and provided specific information on endometriosis phenotypes are included in this review. Presence of information or adjustment controlling for menstrual cycle phase, symptoms and treatments is highlighted, and the results are further summarized by biological compartment. The 9 biological compartments studied for endometriosis biomarker research are in order of frequency: peripheral blood, eutopic endometrium, peritoneal fluid, ovaries, urine, menstrual blood, saliva, feces and cervical mucus. Adjustments of results on disease phenotypes, cycle phases, treatments and symptoms are present in 70%, 29%, 3% and 6% of selected articles, respectively. A total of 1107 biomarkers were identified in these biological compartments. Of these, 74 were found in several biological compartments by at least two independent research teams and only 4 (TNF-a, MMP-9, TIMP-1 and miR-451) are detected in at least 3 tissues with cohorts of 30 women or more.

Integrative analysis is a crucial step to highlight potential pitfalls behind the lack of success in the search for clinically relevant endometriosis biomarkers, and to illuminate the physiopathology of this disease.

Graphical Abstract
COSMIC-based mutation database enhances identification efficiency of HLA-I immunopeptidome
Authors: Wang Fangzhou , Zhang Zhenpeng , Mao Mingsong , Yang Yudai , Xu Ping , Lu Shichun
Published: February 2024

Background

Neoantigens have emerged as a promising area of focus in tumor immunotherapy, with several established strategies aiming to enhance their identification. Human leukocyte antigen class I molecules (HLA-I), which present intracellular immunopeptides to T cells, provide an ideal source for identifying neoantigens. However, solely relying on a mutation database generated through commonly used whole exome sequencing (WES) for the identification of HLA-I immunopeptides, may result in potential neoantigens being missed due to limitations in sequencing depth and sample quality.

Method

In this study, we constructed and evaluated an extended database for neoantigen identification, based on COSMIC mutation database. This study utilized mass spectrometry-based proteogenomic profiling to identify the HLA-I immunopeptidome enriched from HepG2 cell. HepG2 WES-based and the COSMIC-based mutation database were generated and utilized to identify HepG2-specific mutant immunopeptides.

Result

The results demonstrated that COSMIC-based database identified 5 immunopeptides compared to only 1 mutant peptide identified by HepG2 WES-based database, indicating its effectiveness in identifying mutant immunopeptides. Furthermore, HLA-I affinity of the mutant immunopeptides was evaluated through NetMHCpan and peptide-docking modeling to validate their binding to HLA-I molecules, demonstrating the potential of mutant peptides identified by the COSMIC-based database as neoantigens.

Conclusion

Utilizing the COSMIC-based mutation database is a more efficient strategy for identifying mutant peptides from HLA-I immunopeptidome without significantly increasing the false positive rate. HepG2 specific WES-based database may exclude certain mutant peptides due to WES sequencing depth or sample heterogeneity. The COSMIC-based database can effectively uncover potential neoantigens within the HLA-I immunopeptidomes.
Killing capacity analysis of tumor-infiltrating cytotoxic lymphocytes and impact on lymph node metastasis in differentiated papillary carcinoma of thyroid with the BRAF V600E mutation
Authors: Liu Xiaogang , Liu Honggang , Wang Lu , Han Yubing , Kong Linghong , Zhang Xinpeng
Published: February 2024

Background

Cytotoxic lymphocytes (CLs) express potent toxins, including perforin (P) and granzyme-B (G), which brings about target cell death. The purpose of this study was to evaluate the killing capacity of tumor-infiltrating CLs by means of P and G analysis, and explore the association with lymph node metastasis in papillary carcinoma of thyroid (PTC) without Hashimoto’s thyroiditis (HT).

Methods

Infiltration of lymphocytes in PTC was observed in frozen sections. Both fresh tumor tissues and paracancerous tissues with lymphocyte infiltration were collected and prepared into a single cell suspension. Flow cytometry was used to detect the percentages of CD3+P+, CD3+G+, CD8+P+, and CD8+G+ T lymphocytes (TLs) and CD16-CD56+P+ and CD16-CD56+G+ natural killer (NK) cells. Finally, we investigated differential expression of P and G in NK cells and cytotoxic T lymphocytes (CTLs) in paired tumor tissues (group T, n = 44) and paracancerous tissues (group N, n = 44) from patients with PTC with the BRAF V600E mutation. Furthermore, patients were divided into two groups according to whether cervical central lymph node metastasis (CCLNM) existed: group A (with lymph node metastases, n = 27) and group B (with nonlymph node metastases, n = 17). Patients were also divided into three groups according to the total number of positive CCLNM: group B, group C (with low-level lymph node metastases, less than 5, n = 17) and group D (with high-level lymph node metastases, no less than 5, n = 10).

Results

The percentage of CD3+P+ CTLs was significantly higher in group N than in group T (P < 0.05). The percentage of CD8+G+ CTLs was significantly higher in group T than in group N (P < 0.05). The percentages of CD3+G+, CD16-CD56+P+and CD16-CD56+G+ NK cells showed no significant difference in either group T or group N (P > 0.05). The percentages of CD3+P+ CTLs in group A and group C were significantly higher in the paracancerous tissue than in the tumor tissue (P < 0.05). The percentages of CD8+G+ CTLs in group A and group C were significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05). The percentage of CD16-CD56+G+ NK cells in group D was significantly higher in the tumor tissues than in the paracancerous tissues (P < 0.05).

Conclusions

The killing capacity of infiltrating CLs in PTC differed between tumor tissues and paracancerous tissues. In cases with CCLNM, higher expression of CD16-CD56+G+ NK cells in tumor tissues may be associated with a high risk of lymph node metastasis.
A roadmap for sustainable implementation of vocational rehabilitation for people with mental disorders and its outcomes: a qualitative evaluation
Authors: Noteboom Yvonne , van Nassau Femke , Bosma Astrid R. , van der Hijden Eric J. E. , Huysmans Maaike A. , Anema Johannes R.
Published: February 2024

Background

People suffering from mental health disorders have lower work participation compared to people without mental challenges. To increase work participation within this group vocational rehabilitation interventions are often offered. Collaboration between the mental health care and social security sectors is needed to enable professionals to perform optimally when carrying out these interventions. Yet, regulatory and financial barriers often hinder sustainable implementation. To overcome these barriers an experimental roadmap for sustainable funding based on a shared savings strategy was piloted in four regions. The aim of the present qualitative study was to gain understanding of the uses of this roadmap and the factors that were important in the experiment’s process.

Method

The roadmap consisted of five steps based upon insights from shared savings strategies and implementation science knowledge, and was initiated by a national steering board. The roadmap aimed to make sustainable funding agreements (based on shared savings) for the implementation of a vocational rehabilitation intervention. In four regions, stakeholders from the mental health care and social security services sector followed the roadmap. We conducted interviews (n = 16) with involved participants and project leaders of the experiment and collected 54 sets of field notes and documents to evaluate the roadmap process. A thematic analysis was used to analyse the data.

Results

Regions perceived improved stakeholder collaboration around vocational rehabilitation after they were guided by the roadmap. Three regions made, or intended to make, agreements on collaboration and funding, yet not based on shared savings. Moreover, going through the roadmap took more time than anticipated. Stakeholder collaboration depended on factors like personal and organizational interests and collaboration conditions and values. Financial legislation and politics were regarded as barriers and personal motives were mentioned as a facilitator in this process.

Conclusions

Our study showed that the roadmap supported stakeholders to establish a more sustainable collaboration, even though no sustainable financial agreements were made yet. Although participants acknowledged the function of financial insights and the need for financial resources, the driver for collaboration was found to be more on improving clients’ perspectives than on solving unfair financial distribution issues. This suggests modifying the focus of the roadmap from financial benefits to improving clients’ perspectives.
A low-input high resolution sequential chromatin immunoprecipitation method captures genome-wide dynamics of bivalent chromatin
Authors: Seneviratne Janith A. , Ho William W. H. , Glancy Eleanor , Eckersley-Maslin Melanie A.
Published: February 2024

Background

Bivalent chromatin is an exemplar of epigenetic plasticity. This co-occurrence of active-associated H3K4me3 and inactive-associated H3K27me3 histone modifications on opposite tails of the same nucleosome occurs predominantly at promoters that are poised for future transcriptional upregulation or terminal silencing. We know little of the dynamics, resolution, and regulation of this chromatin state outside of embryonic stem cells where it was first described. This is partly due to the technical challenges distinguishing bone-fide bivalent chromatin, where both marks are on the same nucleosome, from allelic or sample heterogeneity where there is a mix of H3K4me3-only and H3K27me3-only mononucleosomes.

Results

Here, we present a robust and sensitive method to accurately map bivalent chromatin genome-wide, along with controls, from as little as 2 million cells. We optimized and refined the sequential ChIP protocol which uses two sequential overnight immunoprecipitation reactions to robustly purify nucleosomes that are truly bivalent and contain both H3K4me3 and H3K27me3 modifications. Our method generates high quality genome-wide maps with strong peak enrichment and low background, which can be analyzed using standard bioinformatic packages. Using this method, we detect 8,789 bivalent regions in mouse embryonic stem cells corresponding to 3,918 predominantly CpG rich and developmentally regulated gene promoters. Furthermore, profiling Dppa2/4 knockout mouse embryonic stem cells, which lose both H3K4me3 and H3K27me3 at approximately 10% of bivalent promoters, demonstrated the ability of our method to capture bivalent chromatin dynamics.

Conclusions

Our optimized sequential reChIP method enables high-resolution genome-wide assessment of bivalent chromatin together with all required controls in as little as 2 million cells. We share a detailed protocol and guidelines that will enable bivalent chromatin landscapes to be generated in a range of cellular contexts, greatly enhancing our understanding of bivalent chromatin and epigenetic plasticity beyond embryonic stem cells.
Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis
Authors: Kim Daeun , Song Jaeseung , Mancuso Nicholas , Mangul Serghei , Jung Junghyun , Jang Wonhee
Published: February 2024

Background

Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear.

Methods

To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk.

Results

We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13+BHLHE40+ TH cells which are significantly associated with JIA risks.

Conclusion

Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.