bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Missense Variants in PAX8 and NKX2-1 Cause Congenital Hypothyroidism
Authors: Li Menglin , Li Zhuo , Chen Miaomiao , Hu Zhiqing , Zhou Miaojin , Wu Lingqian , Zhang Chunhua , Liang Desheng
Published: January 2023

Primary congenital hypothyroidism (CH) is a common neonatal endocrine disorder characterized by elevated concentrations of thyroid stimulating hormone (TSH) and low concentrations of free thyroxine (FT4). PAX8 and NKX2-1 are important transcription factors involved in thyroid development. In this study, we detected three novel variants in PAX8 (c.149A > C and c.329G > A) and NKX2-1 (c.706A > G) by whole exome sequencing (WES) in three unrelated CH patients with variable phenotypes. The results of Western blot and immunofluorescence analysis showed that the three variants had no effect on protein expression and subcellular localization. However, the results of the electrophoretic mobility shift assay (EMSA) and dual-luciferase reporter assay suggested that the three variants in PAX8 and NKX2-1 both affected their DNA-binding ability and reduced their transactivation capacity. Moreover, a dominant-negative effect in K236E−NKX2-1 was identified by dual-luciferase reporter assay. To sum up, our findings extend our knowledge of the current mutation spectrum of PAX8 and NKX2-1 and provide important information for diagnosing, treating, and preventing CH in these families.
Tracking Unauthorized Access Using Machine Learning and PCA for Face Recognition Developments
Authors: Păvăloaia Vasile-Daniel , Husac George
Published: January 2023

In the last two decades there has been obtained tremendous improvements in the field of artificial intelligence (AI) especially in the sector of face/facial recognition (FR). Over the years, the world obtained remarkable progress in the technology that enhanced the face detection techniques use on common PCs and smartphones. Moreover, the steadily progress of programming languages, libraries, frameworks, and tools combined with the great passion of developers and researchers worldwide contribute substantially to open-source AI materials that produced machine learning (ML) algorithms available to any scholar with the will to build the software of tomorrow. The study aims to analyze the specialized literature starting from the first prototype delivered by Cambridge University until the most recent discoveries in FR. The purpose is to identify the most proficient algorithms, and the existing gap in the specialized literature. The research builds a FR application based on simplicity and efficiency of code that facilitates a person’s face detection using a real time photo and validate the access by querying a given database. The paper brings contribution to the field throughout the literature review analysis as well as by the customized code in Phyton, using ML with Principal Component Analysis (PCA), AdaBoost and MySQL for a myriad of application’s development in a variety of domains.
Playing and Socializing—Adults’ Perceptions of the FIFA Digital Game
Authors: Pinheiro Alessandro , Oliveira Abílio , Alturas Bráulio
Published: January 2023

Gamers’ perceptions of using competitive digital games, especially concerning anxiety and socialization, have raised doubts about the benefits of playing such games. Since different studies highlight different results, this research aims to explore these differences by analyzing the perceptions of adults involved in playing a competitive digital game, in this case, FIFA, considering data that were collected during the COVID-19 pandemic period. The main question is ‘How do adults perceive anxiety, stress, and socialization when playing the FIFA digital game?’. The research comprises two studies involving volunteer participants: In the first part, which adopts a qualitative approach, the participants’ perceptions of what they think and feel when playing FIFA were analyzed and interpreted using text mining analysis. In the second, a quantitative study, FIFA users’ perceptions of the gaming experience were statistically analyzed. The results show that adult users tend to refer to positive perceived stress and socialization. The fact that participants identified manipulations and interference in the game and no longer allowed its use to influence their mood reveals that perceptions of attacks of rage were considered possible reactions to the use of the game, interpreted from the interface, and leading to the creation of knowledge.
The Flash Loan Attack Analysis (FAA) Framework—A Case Study of the Warp Finance Exploitation
Authors: Werapun Warodom , Karode Tanakorn , Arpornthip Tanwa , Suaboot Jakapan , Sangiamkul Esther , Boonrat Pawita
Published: January 2023

Decentralized finance (DeFi) has exploded in popularity with a billion-dollar market cap. While uncollateralized lending, known as a flash loan, emerged from DeFi, it has become a primary tool used by attackers to drain investment tokens from DeFi networks. The existing countermeasures seem practical, but no comprehensive quantitative analysis framework was available to test them. This paper proposes the Flash loan Attack Analysis (FAA) framework, which aids security practitioners in understanding the DeFi system’s effects on preventative methods when various factors change. The quantitative predictions can help security professionals in identifying hidden dangers and more efficiently adopting countermeasure strategies. The simulation predicts that the existing strategy, fair reserves, can fully protect the platform in a typical market environment; however, in a highly volatile market where the token price drops by 60% in a single hour, it will be broken, causing more than $8 million in damage.
ANN-Based Assessment of Soft Surface Soil Layers’ Impact on Fault Rupture Propagation and Kinematic Distress of Gas Pipelines
Authors: Makrakis Nikolaos , Psarropoulos Prodromos N. , Tsompanakis Yiannis
Published: January 2023

Large-scale lifelines in seismic-prone regions very frequently cross areas that are characterized by active tectonic faulting, as complete avoidance might be techno-economically unfeasible. The resulting Permanent Ground Displacements (PGDs) constitute a major threat to such critical infrastructure. The current study numerically investigates the crucial impact of soil deposits, which usually cover the ruptured bedrock, on the ground displacement profile and the kinematic distress of natural gas pipelines. For this purpose, a decoupled numerical methodology, based on Finite Element Method (FEM), is adopted and a detailed parametric investigation is performed for various fault and soil properties. Moreover, the advanced capabilities of Artificial Neural Networks (ANNs) are utilized, aiming to facilitate the fast and reliable assessment of soil response and pipeline strains due to seismic faulting, replacing time-consuming FEM computations. An extensive sensitivity analysis is performed to select the optimal architecture and training algorithm of the employed ANNs for both the geotechnical and structural parts of the decoupled approach, with suitable input and target values related to bedrock offset, fault and soil properties, surface PGDs, and pipeline strains. The proposed ANN-based approach can be efficiently applied by practice engineers in seismic design and route optimization of natural gas pipelines.
Integrative Approaches Establish Colour Polymorphism in the Bamboo-Feeding Leafhopper Mukaria splendida Distant (Hemiptera: Cicadellidae) from India
Authors: Ramaiah Mogili , Meshram Naresh M. , Dey Debjani
Published: January 2023

The leafhopper species, Mukaria splendida Distant, is economically important due to itsstatus as a pest on bamboo and was recently reported to bea vector for phytoplasmal disease. Morphological identification is often difficult and requires a high level of taxonomic expertise, with misidentifications causing problematic false-positive/negative results. In this paper, colour polymorphism was recorded in the bamboo-feedingleafhopper M. splendida (Distant, 1908), which is a major insect pest in the bamboo ecosystem based on explorations conducted in different locations of India. Ten morphs were identified for each sex of M. splendida Distant based on the colour pattern on the pronotum and forewings. However, in view of the economic importance of the species, the morphological studies were integrated with the molecular data for the accurate identification of the species. The morphological characteristics and sequence results of the amplified product of the mitochondrial cytochrome oxidase subunit I (mtCOI) gene confirmed that all the morphs were M. splendida and the pairwise distance matrix showed a negligible genetic distance in the COI mtDNA gene. Simulated future predictions, along with detailed notes on the colour polymorphic forms with illustrations, and additional distribution records as well as thebiology of M. splendida were discussed in light of the available literature, all of which will aid the authentic identification of this species.
Cardiac Amyloidosis: A Rare TTR Mutation Found in an Asian Female
Authors: Mouksian Kristina , Ammon Jessica , Pullen Drenda , Zhang Qiuhua , Yedlapati Neeraja , Jefferies John Lynn
Published: January 2023

Background: Transthyretin cardiac amyloidosis (ATTR) is a life-threatening, debilitating disease caused by abnormal formation and deposit of transthyretin (TTR) protein in multiple tissues, including myocardial extracellular matrix. It can be challenging to diagnose due to the myriad of presenting signs and symptoms. Additionally, numerous TTR mutations exist in certain ethnicities. Interestingly, our patient was discovered to have a very rare Gly67Ala TTR mutation typically not found in individuals of Asian descent. Recent advances in cardiovascular imaging techniques have allowed for earlier recognition and, therefore, management of this disease. Although incurable, there are now new, emerging treatments that are available for symptom control of cardiac amyloidosis, making early diagnosis vital for these patients, specifically their quality of life. Case summary: We outline a case of a 50-year-old Asian female who was initially hospitalized for nausea and vomiting and persistent orthostatic hypotension. She underwent a multitude of laboratory and imaging tests, resulting in a diagnosis of cardiac amyloidosis, which was confirmed to be due to a rare TTR mutation via genetic testing. Conclusions: Our objective is to describe various TTR mutations, existing diagnostic imaging modalities, and available treatments, as well as highlight the importance of early screening and awareness of cardiac amyloidosis, allowing for quicker diagnosis and treatment of this disease.
Polygenic Risk Score Impact on Susceptibility to Age-Related Macular Degeneration in Polish Patients
Authors: Wąsowska Anna , Teper Sławomir , Matczyńska Ewa , Łyszkiewicz Przemysław , Sendecki Adam , Machalińska Anna , Wylęgała Edward , Boguszewska-Chachulska Anna
Published: January 2023

Age-related macular degeneration (AMD) is a common retina degenerative disease with a complex genetic and environmental background. This study aimed to determine the polygenic risk score (PRS) stratification between the AMD case and control patients. The PRS model was established on the targeted sequencing data of a cohort of 471 patients diagnosed with AMD and 167 healthy controls without symptoms of retinal degeneration. The highest predictive value to the target dataset was achieved for a 22-variant model with a p-value lower than threshold PT = 0.0123. The median PRS for cases was higher by 1.1 than for control samples (95% CI: (−1.19; −0.85)). The patients in the highest quantile had a significantly higher relative risk of developing AMD than those in the lowest reference quantile (OR = 35.13, 95% CI: (7.9; 156.1), p < 0.001). The diagnostic ability was investigated using ROC analysis with AUC = 0.76 (95% CI: (0.72; 0.80)). The polygenic susceptibility to AMD may be the starting point to expand AMD diagnostics based on rare highly penetrant variants and investigate associations with disease progression and treatment response in Polish patients in future studies.
Prophylactic Salpingectomy during Hysterectomy for Benign Disease: A Prospective Study to Evaluate High-Grade Serous Ovarian Carcinoma Precursors
Authors: Tchartchian Garri , Bojahr Bernd , Heils Lucas , Krentel Harald , De Wilde Rudy L.
Published: January 2023

Recent findings suggest that high-grade serous ovarian cancer can originate in the fallopian tube. Not only has that made the identification of precursor lesions pivotal in early detection and prevention of these cancers, prophylactic salpingectomy alongside hysterectomy for benign indications has been increasingly proposed as well. The present prospective single-center study included 273 women who underwent opportunistic salpingectomy alongside laparoscopic supracervical hysterectomy. Uterine and tubal histopathological results as well as intra- and postoperative complications were evaluated. The complication rate was 3.3%, of which none were caused by salpingectomy. Uterine histopathology diagnosed 181 patients (66.8%) with uterine myomas, 60 patients (22.1%) with adenomyosis, 29 patients (10.7%) with adenomyomatosis, and, 1 patient (0.4%) without pathological abnormality. p53 signatures were detected in 221 right fallopian tubes (80.9%) and in 229 left tubes (83.9%). In total, 8 patients showed bilateral STIL (2.9%), whereas in 1 patient (0.4%) STIL was detected in the left tube only. No STIC were detected. Laparoscopic opportunistic salpingectomy is demonstrated to be both safe and feasible. It appears to be promising to reduce the risk for ovarian cancer, yet more studies are needed to undoubtedly confirm this.
The Emergencies in the Group of Patients with Temporomandibular Disorders
Authors: Pihut Malgorzata , Kulesa-Mrowiecka Malgorzata
Published: January 2023

Temporomandibular disorder is a musculoskeletal disease with complex, multifactorial etiology regarding improper functioning of the stomatognathic system (masticatory muscles, temporomandibular joints, and surrounding structures). This article presents medical emergencies occurring among patients treated for temporomandibular disorders, which tend to constitute a severe difficulty for practitioners during their clinical practice. Examples of the most common emergencies of this type are disc displacement without reduction and a sudden contraction of the inferior part of the lateral pterygoid muscle. The latter occurs in cases of uncontrolled and incorrect use of the anterior repositioning splints and the hypertrophy of the coronoid process of the mandible. The sudden attacks of pain of secondary trigeminal neuralgia are also discussed in this article, together with their specific nature, which is significantly different from the nature of the pain of primary trigeminal neuralgia, yet the two types of neuralgia can be easily confused when the primary one takes the painful form. Subsequent emergencies discussed are myofascial pain syndrome, traumatic and inflammatory states of the temporomandibular joints, subluxation, and the consequences of intense occlusive parafunctions. Finally, the recommended therapeutic methods, which are used as part of the treatment in the cases of aforementioned emergencies, are described in this mini-review article, emphasizing that the implementation of the incorrect treatment and rehabilitation for emergencies of temporomandibular disorders may lead to permanent damage to the soft tissue structures of the temporomandibular joints.
Preliminary Research on the Effect of Hyperbaric Oxygen Therapy in Patients with Post-COVID-19 Syndrome
Authors: Kitala Diana , Łabuś Wojciech , Kozielski Jerzy , Strzelec Przemysław , Nowak Mariusz , Knefel Grzegorz , Dyjas Piotr , Materniak Krzysztof , Kosmala Jolanta , Pająk Jolanta , Czop Jolanta , Janda-Kalus Barbara , Marona Barbara , Nowak-Wróżyna Anna , Gierek Marcin , Szczegielniak Jan , Kucharzewski Marek
Published: January 2023

Negative consequences and medical complications of COVID-19 can persist for up to several months after initial recovery. These consequences can include stroke, diabetes, decreased lung diffusing capacity, sleep apnea, pulmonary fibrosis, arrhythmia, myocarditis, fatigue, headaches, muscle aches, heart rate fluctuations, sleep problems, memory problems, nervousness, anxiety, and other neurological disorders. Thirty-one patients who reported symptoms related to previous COVID-19 disease of both sexes were enrolled in the initial program. The patients underwent compression sessions in a multiplace hyperbaric chamber. Each patient underwent a cycle of 15 compressions. Before the first session, each participant completed a venous blood gas test, a Fullerton test, and two spirometry tests (one before the Fullerton test and one after the test). Patients completed psychotechnical tests, a questionnaire on quality of life (Polish version of EQ-5D-5L), and a questionnaire on specific symptoms accompanying the disease and post-infection symptoms. The results showed significant improvements in areas such as quality of life, endurance and strength, some spirometric parameters, the anion gap and lactate levels, working memory, and attention in the group of treated patients. In contrast, there were no changes in pH, pO2, pCO2, glucose, and excess alkaline values. A follow-up interview confirmed that the beneficial effects were maintained over time. Considering the results obtained, including the apparent improvement in the patient’s clinical condition, it can be concluded that the use of 15 compression sessions was temporarily associated with a noticeable improvement in health and performance parameters as well as improvement in certain blood gas parameters.
Markedly Elevated Aspartate Aminotransferase from Non-Hepatic Causes
Authors: Han Ji-Hee , Kwak Ji-Yoon , Lee Sang-Soo , Kim Hyun-Gyu , Jeon Hankyu , Cha Ra-Ri
Published: January 2023

There have been no reports on mortality in patients with markedly elevated aspartate aminotransferase (AST) levels from non-hepatic causes to date. This study aimed to determine the etiologies of markedly elevated AST levels > 400 U/L due to non-hepatic causes and to investigate the factors associated with mortality in these cases. This retrospective study included 430 patients with AST levels > 400 U/L unrelated to liver disease at two centers between January 2010 and December 2021. Patients were classified into three groups according to etiology: skeletal muscle damage, cardiac muscle damage, and hematologic disorder. Binary logistic regression analysis was performed to evaluate the factors associated with 30-day mortality. The most common etiology for markedly elevated AST levels was skeletal muscle damage (54.2%), followed by cardiac muscle damage (39.1%) and hematologic disorder (6.7%). The 30-day mortality rates for the skeletal muscle damage, cardiac muscle damage, and hematologic disorder groups were 14.2%, 19.5%, and 65.5%, respectively. The magnitude of the peak AST level significantly correlated with 30-day mortality, with rates of 12.8%, 26.7%, and 50.0% for peak AST levels < 1000 U/L, <3000 U/L, and ≥3000 U/L, respectively. In the multivariate analysis, cardiac muscle damage (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.31–5.80), hematologic disorder (OR = 9.47, 95% CI = 2.95–30.39), peak AST < 3000 U/L (OR = 2.94, 95% CI = 1.36–6.35), and peak AST ≥ 3000 U/L (OR = 9.61, 95% CI = 3.54–26.08) were associated with increased 30-day mortality. Our study revealed three etiologies of markedly elevated AST unrelated to liver disease and showed that etiology and peak AST level significantly affected the survival rate.
Documentation of Drug-Related Problems with ICD-11: Application of the New WHO Code-Set to Clinical Routine Data
Authors: Andrikyan Wahram , Jung-Poppe Lea , Altenbuchner Anna , Nicolaus Hagen , Pfistermeister Barbara , Dormann Harald , Fromm Martin , Maas Renke
Published: January 2023

Drug-related problems (DRPs), i.e., adverse drug reactions (ADRs) and medication errors (MEs), constitute a serious threat to the patient’s safety. DRPs are often insufficiently captured by clinical routine documentation, and thus, they frequently remain unaddressed. The aim of this study was to assess the coverage and usability of the new 11th revision of the WHO International Classification of Diseases (ICD-11) to document DRPs. We refined the ‘Quality and Safety Algorithm’ from the ICD-11 Reference Guide and used it for DRP reporting to code 100 different anonymized DRPs (50 ADRs and 50 MEs) in a German hospital. The ICD-11 three-part model consisting of harm, cause, and mode was used whenever they were applicable. Of 50 ADRs, 15 (30.0%), such as drug-induced osteoporosis, were fully classifiable and codable by the ICD-11, whereas 35 (70.0%), such as drug-induced hypokalaemia, could not be fully classified due to sanctioning rules preventing the postcoordination (i.e., a combination of specific codes, such as drug and diagnosis). However, coding without the loss of information was possible in the 35 of these 35 (100.0%) ADR cases when we were deviating from the cluster code order of the Reference Guide. In all 50 MEs, the mode could be encoded, but for none of the MEs, postcoordination, i.e., the assignment of the ME to a specific drug, was allowed. In conclusion, the ICD-11 three-part model enables us to acquire more detailed documentation of DRPs than the previous ICD versions did. However, the codability, documentation, and reporting of DRPs could be significantly improved by simple modifications of the current ICD-11 sanctioning rules and by the addition of new ICD-11 codes.
Interest of a Commercialized Pneumocystis jirovecii Quantitative PCR to Discriminate Colonization from Pneumocystis Pneumonia according to the Revised EORTC/MSGERC Criteria
Authors: Lussac-Sorton Florian , Fleur Tara , Voisin Thibault , Issa Nahéma , Blanchard Élodie , Charpentier Éléna , Delhaes Laurence
Published: January 2023

Quantitative PCR (qPCR) is highly sensitive to diagnose Pneumocystis jirovecii (Pj) pneumonia (PCP). However, differentiating PCP and colonization remains difficult. This study aimed to establish the performances of the commercialized qPCR MycoGENIE® Pj kit (Ademtech) to distinguish PCP and Pj colonization. Patients with a positive Pj qPCR on bronchoalveolar lavage (BAL) or upper respiratory tract (URT) samples were prospectively included between May 2019 and December 2020 at Bordeaux University Hospital. They were classified in “PCP” or “Pj colonization” groups based on the revised EORTC/MSGERC criteria. The two groups’ results were compared; ROC curves were produced to determine the best thresholds. Excluding the low number of HIV-positive subjects, there were 100 PCP (32 BAL, 68 URT) and 70 Pj colonization (34 BAL, 36 URT). Pj loads were significantly higher in PCP compared to Pj colonization group (p ≤ 0.01). The best cut-offs for PCP diagnosis were 31.45 Cq/8275 copies/mL for BAL and 32.33 Cq/8130 copies/mL for URT (sensitivity = 59.4%, 63.3%, specificity = 82.4%, 88.9%, respectively). Fungal load quantification using MycoGENIE® Pj qPCR helps discriminating PCP from colonization, high fungal loads being indicative of probable PCP. Low load results should be interpreted with caution, in accordance with clinical and radiological signs.
Causal Relationships of General and Abdominal Adiposity on Osteoarthritis: A Two-Sample Mendelian Randomization Study
Authors: Lyu Leifeng , Cai Yuanqing , Xiao Mofan , Liang Jialin , Zhang Guangyang , Jing Zhaopu , Zhang Rupeng , Dang Xiaoqian
Published: January 2023

Background: Adiposity is closely related to osteoarthritis, but the causal effects of different types of adiposity on osteoarthritis are indistinct. This study conducted a Mendelian Randomization (MR) analysis for the causal effects of general adiposity and abdominal adiposity on knee osteoarthritis (KOA) and hip osteoarthritis (HOA). Methods: The general adiposity was assessed by body mass index (BMI), while the abdominal adiposity was evaluated with waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR). The data used in this two-sample MR analysis originated from genome-wide association studies (GWAS). Significant (p < 5 × 10−8) and independent (r2 < 0.01) single-nucleotide polymorphisms were selected as instrumental variables for the MR analysis. Subsequently, this study used the inverse variance weighted, weighted median, and other methods for the causal inference, and the results were presented as odds ratios (OR). Moreover, sensitivity analyses were conducted to assess the stability and reliability of the results. Results: The MR results revealed positive causal effects of BMI on KOA (OR: 1.694; 95% CI: from 1.492 to 1.923; p = 3.96 × 10−16) and HOA (OR: 1.412; 95% CI: from 1.196 to 1.666; p = 4.58 × 10−5). Additionally, WC and HC both positively and causally related to KOA (WC: OR: 1.827; 95% CI: from 1.564 to 2.134; p = 2.68 × 10−14; HC: OR: 1.610; 95% CI: from 1.357 to 1.912; p = 5.03 × 10−8) and HOA (WC: OR: 1.491; 95% CI: from 1.254 to 1.772; p = 5.85 × 10−6; HC: OR: 1.439; 95% CI: from 1.205 to 1.719; p = 5.82 × 10−5). However, no causal relationship existed between WHR and obesity. These results were robust according to the sensitivity analyses. Conclusions: This study indicated that both general and abdominal obesity had positive causal effects on knee osteoarthritis and hip osteoarthritis.
Impact of Type 2 Diabetes Mellitus on the Prognosis of Non-Small Cell Lung Cancer
Authors: Lu You , Hu Yaohua , Zhao Yi , Xie Shuanshuan , Wang Changhui
Published: January 2023

Objective: Type 2 diabetes mellitus (T2DM) is the most common metabolic disease and is characterized by sustained hyperglycemia. The impact of T2DM on the survival of lung cancer patients remains controversial. The aim of this study was to investigate the associations of type 2 diabetes with lung cancer mortality. Methods: From January 2019 to January 2020, 228 patients with non-small cell lung cancer (NSCLC) staging earlier than IIIA were included. Results: In our study, we found that the overall survival (OS) and progression-free survival (PFS) of lung cancer patients with diabetes was longer than non-diabetes group. Diagnosed T2DM was associated with the prognosis of lung cancer after adjusting for age and covariates. The association between T2DM and OS was influenced by age, stage of cancer and cancer treatment, as well as whether taking metformin was associated with the OS of lung cancer. However, with the adjustment for age and covariates, the relation trended to lose statistical significance. Conclusion: T2DM is an independent prognostic factor for patients with NSCLC staging before IIIA. The patients with both NSCLC and T2DM trended to having a longer OS, possibly due to metformin.
Identification of Three Circulating MicroRNAs in Plasma as Clinical Biomarkers for Breast Cancer Detection
Authors: Wang Shuang , Li Lijuan , Yang Mengmeng , Wang Xiaoyan , Zhang Huan , Wu Nan , Jia Kaichao , Wang Junchao , Li Menghui , Wei Lijuan , Liu Juntian
Published: January 2023

The diagnostic value of microRNAs (miRNAs) for breast cancer (BC) is largely unknown. Here, our research aim was to explore new circulating miRNAs for BC diagnosis. First, we identified 14 common differentially expressed miRNAs in tissues by TCGA_BRCA and GSE97811 datasets and preliminarily validated them in serum by the GSE73002 dataset. Furthermore, we examined three plasma miRNAs in BC patients (n = 108) and healthy subjects (n = 103) by RT–PCR, namely, hsa-miR-100-5p, hsa-miR-191-5p and hsa-miR-342-3p. The levels of these three miRNAs in BC patients were higher than those in healthy controls (p < 0.05). The ROC curve analysis revealed that these three miRNAs had high diagnostic efficacy for BC and early-stage BC. The combination of hsa-miR-100-5p and hsa-miR-191-5p was the optimal combination for the diagnosis of BC and early-stage BC. Additionally, hsa-miR-100-5p was correlated with stage I–II, T1 stage, N0 stage and Luminal A subtype (p < 0.05). Hsa-miR-191-5p and hsa-miR-342-3p were irrelevant to TNM stage, T stage, N stage and molecular subtypes. Meanwhile, the biological function analysis indicated that these three miRNAs are mainly involved in the calcium signaling pathway, MAPK signaling pathway and microRNAs in cancer. In conclusion, these three miRNAs demonstrate a positive effect on detection and discovery in BC.
A Nomogram Based on Preoperative Lab Tests, BMI, ICG-R15, and EHBF for the Prediction of Post-Hepatectomy Liver Failure in Patients with Hepatocellular Carcinoma
Authors: Zhang Deyao , Pan Yangxun , Yang Zhenyun , Zeng Huilan , Wang Xin , Chen Jinbin , Wang Juncheng , Zhang Yaojun , Zhou Zhongguo , Chen Minshan , Hu Dandan
Published: January 2023

Background: Liver cancer is one of the most common malignant tumors, and worldwide, its incidence ranks sixth, and its morality third. Post-hepatectomy liver failure (PHLF) is the leading cause of death in patients who have undergone liver resection. This retrospective study investigated the risk factors for PHLF by predicting and constructing an index to evaluate the risk. This was achieved by combining the lab tests with an indocyanine green (ICG) clearance test. Methods: The study analyzed 1081 hepatocellular carcinoma (HCC) patients who had received liver resection at Sun Yat-sen University Cancer Center between 2005 and 2020. The patients were divided into a PHLF group (n = 113) and a non-PHLF group (n = 968), according to the International Study Group of Liver Surgery (ISGLS) criteria. Receiver operating characteristics (ROC) curves were then used to estimate the optimal cut-off values. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors. Finally, a nomogram was constructed where the calibration plot, the areas under the ROC curve (AUC), and the decision curve analysis (DCA) showed good predictive ability. Results: Correlation analysis revealed that body mass index (BMI) was positively correlated with ICG-R15 and with effective hepatic blood flow (EHBF). Univariate and multivariate logistics regression analysis revealed that BMI, ICG-R15, international normalized ratio (INR), tumor size, hepatic inflow occlusion (HIO) time, and operation method were independent predictive factors for PHLF. When these factors and EHBF were included in the nomogram, the nomogram showed a good predictive value, with a C-index of 0.773 (95% Confidence Interval [CI]: 0.729–0.818). The INR had the largest ROC areas (AUC INR = 0.661). Among the variables, ICG-R15 (AUC ICG-R15 = 0.604) and EHBF (AUC EHBF = 0.609) also showed good predictive power. Conclusions: The risk of PHLF in HCC patients can be precisely predicted by this model prior to the operation. By integrating EHBF into the model, HCC patients at higher risk for PHLF can be identified more effectively.
The Outcome of Discontinuing Tyrosine Kinase Inhibitors in Advanced Sarcoma Following a Favorable Tumor Response to Antiangiogenics Therapy
Authors: Zhang Zhusheng , Bao Qiyuan , Fu Yucheng , Wen Junxiang , Li Meng , Liu Zhuochao , He Guoyu , Wang Beichen , Shen Yuhui , Zhang Weibin
Published: January 2023

(1) Background: The use of antiangiogenic TKIs (AA-TKIs) has recently emerged as a major paradigm shift in the treatment of advanced sarcoma. However, the feasibility of drug holidays for patients demonstrating a very favorable response remains unknown. (2) Methods: We aim to explore the outcomes of patients with advanced sarcoma who discontinued AA-TKIs after a (near-) complete remission or were long-term responders. Patients with advanced disease were included if they had bilateral or multiple lung metastases, extrapulmonary recurrence, a short disease-free interval, etc., at the initiation of AA-TKIs. (3) Results: A total of 22 patients with AA-TKI discontinuation were analyzed, with a median follow-up of 22.3 months post-discontinuation. Prior to discontinuation, there were four drug-induced complete remissions (CRs), twelve surgical CRs, and six long-term responders. Disease progression was observed in 17/22 (77.3%) patients, with a median of 4.2 months. However, since the majority were still sensitive to the original AA-TKIs and amenable to a second surgical remission, 7 out of these 17 patients achieved a second CR after disease progression and were thus considered as relapse-free post-discontinuation (pd-RFS). Therefore, the pd-RFS and post-discontinuation overall survival (pd-OS) in the last follow-up were 12/22 (54.5%) and 16/22 (72.7%), respectively. Remarkably, surgical CR and drug tapering off (versus abrupt stopping) were associated with a greater pd-RFS and pd-OS (p < 0.05). Furthermore, higher necrosis rates (p = 0.040) and lower neutrophil-to-lymphocyte ratios (NLR) (p = 0.060) before discontinuation tend to have a better pd-RFS. (4) Conclusions: Our results suggest that AA-TKI discontinuation with a taper-off strategy might be safe and feasible in highly selected patients with advanced sarcoma. Surgical CR, NLR, and tumor necrosis rates before discontinuation were potential biomarkers for AA-TKI withdrawal.
Anterior Segment Parameter Changes after Cataract Surgery in Open-Angle and Angle-Closure Eyes: A Prospective Study
Authors: Yang Kangyi , Liang Zhiqiao , Lv Kun , Ma Yao , Hou Xianru , Wu Huijuan
Published: January 2023

Background: To investigate the anterior segment parameters before and after cataract surgery in open-angle eyes and different subtypes of primary angle-closure glaucoma (PACG) eyes and to further explore the potential relationship between the anterior rotation of the ciliary process and crystalline lens. Methods: An observational, prospective study was performed on 66 patients who had cataract surgery including 22 chronic PACG patients, 22 acute PACG patients, and 22 open-angle cataract patients. Anterior segment parameters including the trabecular-ciliary process distance, ciliary process area, trabecular-ciliary angle (TCA), maximum ciliary body thickness (CBTmax), and so on, were measured using ultrasound biomicroscopy preoperatively and 3 months postoperatively. Results: After the surgery, there were significant increases in TCA (p < 0.001) and CBTmax (p < 0.05) in all three groups, while there was no significant change in the trabecular-ciliary process distance (p > 0.05) in all three groups. No significant difference in the changes of ciliary process area, TCA, and CBTmax (p > 0.05) pre- and postoperatively among the three groups were identified. Conclusions: Extractions of crystalline lenses played similar roles in terms of decreasing the anterior rotation of ciliary processes in open-angle eyes and angle-closure eyes. A natural anatomical abnormality may be a more important factor in the anterior rotation of ciliary processes in PACG patients.
Response to Immune Checkpoint Inhibitors Is Affected by Deregulations in the Antigen Presentation Machinery: A Systematic Review and Meta-Analysis
Authors: Rasmussen Maria , Durhuus Jon Ambæk , Nilbert Mef , Andersen Ove , Therkildsen Christina
Published: January 2023

Immune checkpoint inhibitors (ICI) targeting programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) have shown promising results against multiple cancers, where they reactivate exhausted T cells primed to eliminate tumor cells. ICI therapies have been particularly successful in hypermutated cancers infiltrated with lymphocytes. However, resistance may appear in tumors evading the immune system through alternative mechanisms than the PD-1/PD-L1 or CTLA-4 pathways. A systematic pan-cancer literature search was conducted to examine the association between alternative immune evasion mechanisms via the antigen presentation machinery (APM) and resistance towards ICI treatments targeting PD-1 (pembrolizumab and nivolumab), PD-L1 (durvalumab, avelumab, and atezolizumab), and CTLA-4 (ipilimumab). The APM proteins included the human leucocyte antigen (HLA) class I, its subunit beta-2 microglobulin (B2M), the transporter associated with antigen processing (TAP) 1, TAP2, and the NOD-like receptor family CARD domain containing 5 (NLRC5). In total, 18 cohort studies (including 21 original study cohorts) containing 966 eligible patients and 9 case studies including 12 patients were reviewed. Defects in the APM significantly predicted poor clinical benefit with an odds ratio (OR) of 0.39 (95% CI 0.24–0.63, p < 0.001). The effect was non-significant, when considering complete and partial responses only (OR = 0.52, 95% CI 0.18–1.47, p = 0.216). In summary, the APM contains important targets for tumorigenic alterations which may explain insensitivity towards ICI therapy.
Case Report: “Spontaneous Descemet Membrane Detachment”
Authors: Moramarco Antonio , Iannetta Danilo , Cimino Luca , Romano Vito , Gardini Lorenzo , Fontana Luigi
Published: January 2023

Introduction: We report a case and discuss the clinical characteristics and treatment of spontaneous Descemet membrane detachment (DMD). Case description: We describe a rare case of spontaneous DMD in a patient with prior anterior uveitis and provide a review of the current literature. A 20-year-old woman with a prior history of anterior uveitis presented with vision loss in the left eye. The slit-lamp examination showed corneal edema secondary to DMD, confirmed by anterior segment optical coherence tomography (AS-OCT). The patient underwent an intracameral injection of 20% sulphur hexafluoride (SF6) with complete resolution of the DMD. Although rare, several cases of spontaneous DMD have been reported in the literature, mostly occurring after intraocular surgery. We searched the Pubmed database (1949–2021) for peer-reviewed publications relevant to the topic of spontaneous DMD. Discussion: The pathogenesis of spontaneous DMD is complex and depends on several factors. It can occur due to anatomical anomalies, inflammatory disease, trauma, chemical injuries, and surgical or laser procedures. In most cases, early diagnosis and appropriate management led to resolution.
Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease
Authors: Antequera-González Borja , Faiges Marta , Martínez-Micaelo Neus , Galian-Gay Laura , Ligero Carmen , Ferré-Vallverdú María , Masana Lluís , Amigó Núria , Evangelista Arturo , Alegret Josep M.
Published: January 2023

Introduction: The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. Methods: Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. Results: Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. Conclusions: Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter.
Left Ventricular Adverse Remodeling in Ischemic Heart Disease: Emerging Cardiac Magnetic Resonance Imaging Biomarkers
Authors: Calvieri Camilla , Riva Alessandra , Sturla Francesco , Dominici Lorenzo , Conia Luca , Gaudio Carlo , Miraldi Fabio , Secchi Francesco , Galea Nicola
Published: January 2023

Post-ischemic left ventricular (LV) remodeling is a biologically complex process involving myocardial structure, LV shape, and function, beginning early after myocardial infarction (MI) and lasting until 1 year. Adverse remodeling is a post-MI maladaptive process that has been associated with long-term poor clinical outcomes. Cardiac Magnetic Resonance (CMR) is the best tool to define adverse remodeling because of its ability to accurately measure LV end-diastolic and end-systolic volumes and their variation over time and to characterize the underlying myocardial changes. Therefore, CMR is the gold standard method to assess in vivo myocardial infarction extension and to detect the presence of microvascular obstruction and intramyocardial hemorrhage, both associated with adverse remodeling. In recent times, new CMR quantitative biomarkers emerged as predictive of post-ischemic adverse remodeling, such as T1 mapping, myocardial strain, and 4D flow. Additionally, CMR T1 mapping imaging may depict infarcted tissue and assess diffuse myocardial fibrosis by using surrogate markers such as extracellular volume fraction, which may predict functional recovery or risk stratification of remodeling. Finally, there is emerging evidence supporting the utility of intracavitary blood flow kinetic energy and hemodynamic features assessed by the 4D flow CMR technique as early predictors of remodeling.
Neonatal Hepatic Myeloid Progenitors Expand and Propagate Liver Injury in Mice
Authors: Alkhani Anas , Korsholm Cathrine , Levy Claire S. , Mohamedaly Sarah , Duwaerts Caroline C. , Pietras Eric M. , Nijagal Amar
Published: January 2023

Background: Biliary atresia (BA) is a progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to liver failure in children with BA suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) reside in the fetal liver and are known to serve as central hubs of inflammation. We hypothesized that HSPCs are critical for the propagation of perinatal liver injury (PLI). Methods: Newborn BALB/c mice were injected with rhesus rotavirus (RRV) to induce PLI or with PBS as control. Livers were compared using histology and flow cytometry. To determine the effects of HSPCs on PLI, RRV-infected neonatal mice were administered anti-CD47 and anti-CD117 to deplete HSPCs. Results: PLI significantly increased the number of common myeloid progenitors and the number of CD34+ hematopoietic progenitors. Elimination of HSPCs through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 36.4% vs. RRV+myeloablation 77.8%, Chi-test = 0.003). Conclusions: HSPCs expand as a result of RRV infection and propagate PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver such as BA.
Variables That Could Influence Healing Time in Patients with Diabetic Foot Osteomyelitis
Authors: Tardáguila-García Aroa , Álvaro-Afonso Francisco Javier , García-Madrid Marta , López-Moral Mateo , Sanz-Corbalán Irene , Lázaro-Martínez José Luis
Published: January 2023

Aim: To compare the healing time in patients with diabetic foot osteomyelitis according to the presence or absence of clinical signs of infection, variation of blood parameters, the presence of different radiological signs, and the treatment received for the management of osteomyelitis. Methods: A prospective observational study was carried out in a specialised Diabetic Foot Unit between November 2014 and November 2018. A total of 116 patients with osteomyelitis were included in the study (treated by either a surgical or medical approach). During the baseline visit, we assessed the diagnosis of osteomyelitis, demographic characteristics and medical history, vascular and neurological examination, clinical signs of infection, increased blood parameters, radiological signs of osteomyelitis, and the treatment to manage osteomyelitis. We analysed the association between the presence of clinical signs of infection, variation of blood parameters, presence of radiological signs, and treatment received for management of osteomyelitis with the healing time. Results: The mean time to ulcer healing was 15.8 ± 9.7 weeks. Concerning healing times, we did not find an association with the presence of clinical signs of infection or with the increase in blood parameters, except in the case of eosinophils, which with higher values appear to increase the healing time (U = 66, z = −2.880, p = 0.004). Likewise, no relationship has been found between healing time and the appearance of the different radiological signs of osteomyelitis, nor depending on the treatment administered for the management of osteomyelitis. Conclusion: High levels of eosinophils are associated with a longer healing time of diabetic foot ulcers complicated with osteomyelitis, finding no other factors related to increased healing time.
The Causal Effect of Reproductive Factors on Breast Cancer: A Two-Sample Mendelian Randomization Study
Authors: Jia Lijun , Lv Wei , Liang Liang , Ma Yuguang , Ma Xingcong , Zhang Shuqun , Zhao Yonglin
Published: January 2023

Several studies have shown that female reproductive factors are associated with breast cancer (BC), but the results differ. We conducted two-sample MR in the present work. The raw data applied in the MR study were all from the Genome-wide association study (GWAS) database. The causal effect of reproductive factors on breast cancer were mainly estimated by the standard inverse variance weighted (IVW) method. Cochran’s Q test and I2 statistics were used to assess heterogeneity. The pleiotropy was evaluated by MR-Egger intercept test and MR-PRESSO. Finally, the leave-one-out analysis was performed to evaluate the robustness of the MR results. We found that there was a negative causal effect of the age at last live birth on BC (OR = 0.687, 95%CI = 0.539–0.875, p = 0.002) and positive effect of the age at menopause on BC (OR = 1.054, 95%CI = 1.034–1.075, p = 8.010 × 10−8). Additionally, there were null effects of the age at menarche (OR = 0.977, 95%CI = 0.915–1.043, p = 0.484), the age at first sexual intercourse (OR = 1.053, 95%CI = 0.958–1.157, p = 0.284) and the age at first birth (OR = 0.981, 95%CI = 0.936–1.027, p = 0.404) on BC. All these results were reliable and stable. In conclusion, the present study showed that younger age at last birth and older age at menopause could increase the risk of BC.