bluuebunny/crossref_metadata_2025 huggingface dataset:
Secreted protein acidic and rich in cysteine (SPARC) induces apoptosis of human brain vascular smooth muscle cells through regulating HK2 in intracranial aneurysm
Authors: Zhou Donglin , Li Tao , Tan Xianjun , Yun Chenping , Jiang Peng , Zhang Tongfu , Kuang Hong , Wang Yunyan
Published: November 2023

Background

Vascular smooth muscle cell (VSMC) dysfunction is one of the crucial pathologic processes in the development of intracranial aneurysm (IA). Secreted protein acidic and rich in cysteine (SPARC), a multifunctional glycoprotein, is overexpressed in many tumor, but its underlying mechanism in vascular disease has not been elucidated. The aim of this study is to evaluate the potential function of SPARC in IA generation and regulation of mitochondrial function in VSMC.

Methods

Human brain vascular smooth muscle cells were treated with recombinant SPARC to detect apoptosis-related markers. The downstream targets affecting mitochondrial dysfunction after SPARC treatment were explored by transcriptome sequencing and bioinformatics analysis, and verified using by immunohistochemistry and western blot. Further in vitro experiments verified the role of downstream targets in regulating VSMC mitochondrial function.

Results

Secreted protein acidic and rich in cysteine (SPARC) expression was associated with the risk of IA rupture. SPARC induces mitochondrial pathway apoptosis in human brain VSMC. We screened 40 differentially expressed genes related to mitochondrial function after SPARC treatment. Hexokinase 2 (HK2) was identified as a downstream target of mitochondrial pathway apoptosis in VSMC induced by SPARC. In addition, immunohistochemical results confirmed that the difference between SPARC and HK2 expression is located mainly in the smooth muscle layer of IA. Overexpression of HK2 reversed the SPARC-induced increase in apoptosis and mitochondrial damage in VSMC.

Conclusion

Secreted protein acidic and rich in cysteine (SPARC) regulated mitochondrial function in VSMC and induced apoptosis through HK2, which plays an important role in the formation and rupture of IA. Targeting SPARC may be a novel strategy to delay the development of intracranial aneurysms.
The WACDT, a modern vigilance task for network defense
Authors: Guidetti Oliver A. , Speelman Craig P. , Bouhlas Peter
Published: November 2023

Vigilance decrement refers to a psychophysiological decline in the capacity to sustain attention to monotonous tasks after prolonged periods. A plethora of experimental tasks exist for researchers to study vigilance decrement in classic domains such as driving and air traffic control and baggage security; however, the only cyber vigilance tasks reported in the research literature exist in the possession of the United States Air Force (USAF). Moreover, existent cyber vigilance tasks have not kept up with advances in real-world cyber security and consequently no longer accurately reflect the cognitive load associated with modern network defense. The Western Australian Cyber Defense Task (WACDT) was designed, engineered, and validated. Elements of network defense command-and-control consoles that influence the trajectory of vigilance can be adjusted within the WACDT. These elements included cognitive load, event rate, signal salience and workload transitions. Two forms of the WACDT were tested. In static trials, each element was adjusted to its maximum level of processing difficulty. In dynamic trials, these elements were set to increase from their minimum to their maximum values. Vigilance performance in static trials was shown to improve over time. In contrast, dynamic WACDT trials were characterized by vigilance performance declines. The WACDT provides the civilian human factors research community with an up-to-date and validated vigilance task for network defense accessible to civilian researchers.
The association between dietary inflammatory index and cognitive function in adults with/without chronic kidney disease
Authors: Wan Biyu , Lin Pinli , Wang Mengya , Zhong Jintao , Peng Lu , Tang Xiaona , Wang Lingzhen , Tang Fang , Liang Yuyan , Liu Xusheng , Deng Lili
Published: November 2023

Background and aims

Cognitive impairment (CI) is a prevalent condition in patients with chronic kidney disease (CKD), who face an elevated risk of developing cognitive decline. The fundamental mechanism underlying CI is linked to chronic inflammation, which can be gauged by the Dietary Inflammatory Index (DII). The DII is categorized into anti-inflammatory diets with lower scores and pro-inflammatory diets with higher scores. Specifically, pro-inflammatory diets may contribute to chronic inflammation. However, the correlation between the inflammatory potential of diet and cognitive function in patients with CKD has not been explored. This study aims to investigate the connection between the inflammatory potential of diet and cognitive function in individuals with or without chronic kidney disease.

Methods

Data from the 2011–2012 and 2013–2014 National Health and Nutrition Examination Survey (NHANES) were utilized. Participants under the age of 60 or lacking DII, CI, CKD, and other essential data were excluded. DII was computed based on a 24-h dietary recall interview for each participant. Cognitive performance was evaluated using three cognitive tests: the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) test, the Animal Fluency Test (AFT), and the Digital Symbol Substitution Test (DSST). Logistic regression analysis and subgroup analysis were conducted to assess the independent relationship between DII score and CI in the CKD and non-CKD populations.

Results

The study included a total of 2069 subjects, with CI prevalence ranging from 21.4 to 23.5%. Multiple regression models showed that after adjusting for all covariates of the three cognitive function tests, higher DII scores were significantly associated with increased risk of CI (CERAD OR = 1.18, 95% CI: 1.1 ~ 1.26, AFT OR = 1.15, 95% CI: 1.08 ~ 1.23, DSST OR = 1.19, 95% CI: 1.11 ~ 1.28). Subgroup analysis indicated that the effect of DII score on CI remained consistent in all subgroups (p > 0.05).

Conclusion

Higher DII scores were associated with an increased risk of cognitive impairment in people with or without CKD, suggesting that consuming a pro-inflammatory diet may contribute to the impairment of the cognitive function.
Multiomics analysis of metabolic heterogeneity in cervical cancer cell lines with or without HPV
Authors: Liu Xu , Zhu Yaqi , Huang Sheng , Shi Tingyu , Li Tanghua , Lan Yanan , Cao Xiaojian , Wu Yingtao , Ding Jinya , Chen Xiaohua
Published: November 2023

Metabolomics analysis revealed the metabolic heterogeneity of cervical cancer (CC) cell lines C33A and CaSki, and their molecular mechanisms were explored. Using the modified Bligh-Dyer method, the endogenous metabolites of C33A and CaSki cells were divided into polar and nonpolar fractions. The metabolites were analysed by ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Then, the differential metabolites were screened by combining multivariate statistical analysis and volcano maps, and functional enrichment and pathway analysis of the differential metabolites were performed. Finally, association analysis was carried out in combination with transcriptomics, and the important differential metabolisms were experimentally verified by real-time PCR (RT−qPCR) and oil red staining. The results showed that between the C33A and CaSki cell lines, there were significant differences in amino acids, nucleotides and lipids, such as in threonine, arachidonic acid and hypoxanthine, in the metabolic pathways. These compounds could be used as markers of differences in cellular metabolism. The heterogeneity of lipid metabolism accounted for 87.8%, among which C33A cells exhibited higher contents of fatty acid polar derivatives, while CaSki cells showed higher contents of free fatty acids and glycerides. Based on correlation analysis of the above metabolic differences in HPV pathways as well as lipid metabolism-related genes, p53 and the genes involved in lipid metabolism pathways, such as Peroxisome Proliferator Activated Receptor Gamma(PPARG) and stearoyl-CoA desaturase (SCD), are relevant to the metabolic heterogeneity of the cells. The differential expression of some genes was validated by RT−qPCR. CaSki cells showed significantly higher glyceride levels than that of C33A cells, as verified by oil red O staining and glyceride assays. The above results showed that the metabolomic differences between C33A and CaSki cells were relatively obvious, especially in lipid metabolism, which might be related to the decreased expression of PPARG and p53 caused by HPV E6. Further studies on the molecular mechanism of lipid metabolism heterogeneity in cervical cancer cell lines with or without HPV could provide a new reference for the development of CC and individualized treatments of tumour patients.
Standardized construction of a porcine model for acute obstructive jaundice and training of endoscopic ultrasound-guided choledochoduodenostomy
Authors: Zhou Xue , Liu Ziming , Ma Wenzhuang , Sheng Shiyun , Sun Siyu , Ge Nan
Published: November 2023

Background

Endoscopic ultrasound-guided biliary drainage (EUS-BD) is an alternative to endoscopic retrograde cholangiopancreatography (ERCP) for patients with obstructive jaundice. However, it is still a challenge for many endoscopists because of its novelty and complexity. This study aimed to establish an ideal bile duct dilatation model for the training and practice of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS).

Methods

The 34 healthy Bama miniature pigs were divided into the part of developing the standardized EUS-CDS (n=9) and the part of trainees training (n=25). Part one, two different methods were used to clip Vater’s ampulla using metal clips to establish an extrahepatic bile duct dilatation model. Part two, five trainees were trained on EUS-CDS with 25 pigs. Following a 2-week observation period, the feasibility and effectiveness of the technique were evaluated.

Results

In the group with three metal clips perpendicular to the duodenal wall clipping Vater’s ampulla, the success rate of extrahepatic bile duct dilation greater than 1 cm in 24 h was 5/6, whereas the remaining one pig was 48 h. All five trainees can finally complete the EUS-CDS independently. No death occurred during the 2-week observation period.

Conclusion

Clipping Vater’s ampulla with three metal clips perpendicular to the duodenal wall is an effective and stable method to create a porcine bile duct dilatation model.
Hepatoid adenocarcinoma of the lung with PD-L1 expression and the response to anti-PD-1 therapy: a case report
Authors: Li Yan , Liu Lili , Wang Dongfeng , Tan Xiaojing , Sui Yanmin , Yang Honglan
Published: November 2023

Hepatoid adenocarcinoma of the lung (HAL) is extremely rare; a standardized treatment strategy for HAL has not been established. The prognosis of patients with unresectable HAL is extremely poor. Here, we reported a 64-year-old male patient with unresectable alpha-fetoprotein-producing HAL who showed moderate harboring programmed death ligand 1 (PD-L1) expression and no targetable driver mutations. The patient was treated with brain radiotherapy, multiple lines of chemotherapies, and PD-1 inhibitor and achieved a survival rate of 9 months. The patient finally died because of the progression of brain metastasis. The case report provides valuable information for the treatment strategy development of advanced HAL patients and reminds us of the therapeutic particularity of brain metastasis.
Research trends and hotspots in prostate cancer associated exosome: a bibliometric analysis
Authors: Zhu Zhengjia , Zhou Yingjian , Li Hao , Xu Wenchao , Wang Tao , Liu Jihong , Jiang Hongyang
Published: November 2023

Background

Prostate cancer is viewed as the second most common cancer in men worldwide. In our study, we used bibliometric analysis to construct a visual map of the relationship between prostate cancer and exosomes with the intent of uncovering research trends and current hotspots in this field.

Method

We searched the Web of Science Core Collection for all publications in the prostate cancer associated with exosome field came out since 2010. With the assistance of bibliometric analysis software such as VOSviewer and CiteSpace, we conducted data extraction and analysis for countries/regions, institutions, authors, journals, references and keywords.

Results

A bibliometric analysis of 990 publications was performed. Since 2010, the published quantity and cited frequency of the prostate cancer-associated exosome field have revealed an increasing tendency. In this field, we visualized the research trends by the means of analyzing the references and keywords. We obtained the statistical data: the total citations of publications have increased to 55,462, the average citation per article has reached 55.3 times, and the H-index has amounted to 110. Our findings supported that USA, China and Italy rank the top countries with both the maximum publications and strongest cooperations. Harvard Medical School, Cedars Sinai Med Ctr, Johns Hopkins University, are top institutions in the center of research as they are held to be. Thery C, Skog J and Taylor DD are the leading and outstanding professors and researchers. And top journals like Prostate, Plos One and Journal of Extracellular Vesicle expressed keen interests in this field. Based on our analysis and research, we believe that this field is attracting more and more attention and will focus on tumor bone metastasis, drug delivery, and tumor suppressor.

Conclusion

In the past 12 years, researchers have dedicated their efforts to prostate cancer associated exosome. On the basis of previous studies, scientists are showing increasingly solicitude for the role of exosome in prostate cancer progression and potential therapy such as drug delivery.
AI-assisted system improves the work efficiency of cytologists via excluding cytology-negative slides and accelerating the slide interpretation
Authors: Du Hui , Dai Wenkui , Zhou Qian , Li Changzhong , Li Shuai Cheng , Wang Chun , Tang Jinlong , Wu Xiangchen , Wu Ruifang
Published: November 2023

Given the shortage of cytologists, women in low-resource regions had inequitable access to cervical cytology which plays an pivotal role in cervical cancer screening. Emerging studies indicated the potential of AI-assisted system in promoting the implementation of cytology in resource-limited settings. However, there is a deficiency in evaluating the aid of AI in the improvement of cytologists’ work efficiency. This study aimed to evaluate the feasibility of AI in excluding cytology-negative slides and improve the efficiency of slide interpretation. Well-annotated slides were included to develop the classification model that was applied to classify slides in the validation group. Nearly 70% of validation slides were reported as negative by the AI system, and none of these slides were diagnosed as high-grade lesions by expert cytologists. With the aid of AI system, the average of interpretation time for each slide decreased from 3 minutes to 30 seconds. These findings suggested the potential of AI-assisted system in accelerating slide interpretation in the large-scale cervical cancer screening.
Multidisciplinary management of pregnancy-associated and early post-partum head and neck cancer patients
Authors: Bergamini Cristiana , Cavalieri Stefano , Resteghini Carlo , Alfieri Salvatore , Nuzzolese Imperia , Colombo Elena , Ottini Arianna , Calareso Giuseppina , Vingiani Andrea , Iacovelli Nicola Alessandro , Franceschini Marzia , Guzzo Marco , Deganello Alberto , Licitra Lisa
Published: November 2023

Background

Pregnancy-associated cancer (PAC) occurs during pregnancy or within 12 months after the delivery. Head and neck cancer (HNC) during pregnancy is infrequent, therefore diagnosis and personalized therapy are intricate.

Methods

We investigated outcomes of 15 PAC patients (5 salivary, 4 nasopharyngeal, 3 thyroid, 2 oral cavity, one HPV-related carcinoma) diagnosed in the period 2005-2019. A literature review on PAC is provided.

Results

Median gestational age at PAC diagnosis was 28 weeks (range: 16–40 weeks) in ten cases, at 5 months after delivery (range: 1 week–6 months) in the remaining five. Treatments included surgery (3 during pregnancy, 5 after childbirth), chemoradiation (8), and 3 patients with upfront metastatic disease received chemotherapy. Median survival was 6.6 years (eight women remain with no evidence of disease six years after diagnosis).

Conclusion

All patients received state-of-the-art therapy, with encouraging long-term results, highlighting treatment safety in women with HNC during pregnancy.
Radiotherapy in the preoperative neoadjuvant treatment of locally advanced rectal cancer
Authors: Yu Zhen , Hao Yuying , Huang Yuhua , Ling Ling , Hu Xigang , Qiao Simiao
Published: November 2023

Radiotherapy and chemotherapy are effective treatments for patients with locally advanced rectal cancer (LARC) and can significantly improve the likelihood of R0 resection. Radiotherapy can be used as a local treatment to reduce the size of the tumor, improve the success rate of surgery and reduce the residual cancer cells after surgery. Early chemotherapy can also downgrade the tumor and eliminate micrometastases throughout the body, reducing the risk of recurrence and metastasis. The advent of neoadjuvant concurrent radiotherapy (nCRT) and total neoadjuvant treatment (TNT) has brought substantial clinical benefits to patients with LARC. Even so, given increasing demand for organ preservation and quality of life and the disease becoming increasingly younger in its incidence profile, there is a need to further explore new neoadjuvant treatment options to further improve tumor remission rates and provide other opportunities for patients to choose watch-and-wait (W&W) strategies that avoid surgery. Targeted drugs and immunologic agents (ICIs) have shown good efficacy in patients with advanced rectal cancer but have not been commonly used in neoadjuvant therapy for patients with LARC. In this paper, we review several aspects of neoadjuvant therapy, including radiation therapy and chemotherapy drugs, immune drugs and targeted drugs used in combination with neoadjuvant therapy, with the aim of providing direction and thoughtful perspectives for LARC clinical treatment and research trials.
Percutaneous transthoracic catheter drainage prior to surgery in treating neonates with congenital macrocystic lung malformation presenting with respiratory distress
Authors: He Taozhen , Sun Xiaoyan , Luo Dengke , Dai Shiyi , Yuan Miao , Yang Gang , Cheng Kaisheng , Xu Chang
Published: November 2023

Backgound

It is rarely seen that neonates with congenital macrocystic lung malformation (CMLM) presenting with respiratory distress require emergency intervention. No consensus has been achieved concerning the best policy facing such condition. This study aims to evaluate the efficacy and safety of our strategies in treating neonates with CMLM presenting with respiratory distress.

Methods

We retrospectively reviewed the data of six neonates with CMLM presenting with respiratory distress from April 2020 to October 2022 for whom drainage-prior-to-surgery strategy were adopted and favorable outcomes were obtained. The relevant data was reviewed and analyzed.

Results

All the patients were prenatally diagnosed with congenital lung malformation and postnatally as congenital macrocystic lung malformation via CT scan. Each neonate accepted percutaneous thoracic catheter drainage prior to surgery. The first and fifth neonates with macrocystic lung mass experienced prompt open lobectomy and delayed thoracoscopic surgery due to failure of air drainage, respectively. The other four patients obtained good drainage of the large air-filled cyst, thus gaining the opportunity for elective thoracoscopic surgery within median 45 days.

Conclusions

For neonates with macrocystic lung malformation presenting with respiratory distress due to mediastinal compression, percutaneous thoracic catheter drainage is worth a shot for elective thoracoscopic surgery due to its feasibility and safety.
Prenatal cannabinoid exposure and early language development
Authors: Talavera-Barber Maria M. , Morehead Evlyn , Ziegler Katherine , Hockett Christine , Elliott Amy J.
Published: November 2023

Introduction

The effect of prenatal cannabis exposure (PCE) on childhood neurodevelopment remains poorly understood. There is a paucity of studies describing the neurodevelopment impact of PCE in infancy. The Mullen Scale of Early Learning (MSEL) is a cognitive screening tool that can be used from birth to 68 months and includes language and motor domains. Here we aim to explore the association between PCE during pregnancy and neurodevelopmental outcomes at 12 months of age.

Methods

Participants were pregnant persons/infant pairs enrolled in The Safe Passage Study, a large prospective cohort study. Inclusion criteria included data available on PCE with associated MSEL scores at 12 months of age. Exposed participants were defined as early exposure (1st trimester only) or late exposure (2nd or 3rd trimester) and were randomly matched with unexposed participants. Multiple linear regression models were performed to test associations between prenatal cannabis exposure and the five Mullen subscales: gross motor, fine motor, expressive language, receptive language, and visual reception.

Results

Sixty-nine exposed and 138 randomly matched unexposed infants were included in the analyses. Mothers of children with PCE were younger with the mean age 23.7 years for early exposure (n = 51) and 22.8 years for late exposure (n = 18). Maternal characteristics with prenatal cannabis use include a high-school education, American Indian or Alaska Native descent, lower socioeconomic status and co-use of tobacco. There were no gestational age or sex difference among the groups. Expressive (95% CI: 2.54–12.76; p = 0.0036,) and receptive language scores (95% CI: 0.39–8.72; p = 0.0322) were significantly increased between late-exposed infants compared to unexposed infants following adjustment for covariates. Gross motor scores (95% CI: 1.75–13; p = 0.0105) were also significantly increased for early-exposed infants with no difference in visual reception scores.

Conclusion

Preclinical studies have shown abnormal brain connectivity in offspring exposed to cannabis affecting emotional regulation, hyperactivity, and language development. Results from this study link PCE to altered early language development within the first year of life. Exposed infants demonstrated increased expressive and receptive language scores at 12 months of age, which can translate to better performance in school. However, further research is needed to determine the implications of these results later in childhood.
Optimal timing of surgery for prenatally diagnosed choledochal cysts
Authors: Ho In Geol , Ihn Kyong , Jeon Ho Jong , Lee Dong Eun , Han Seok Joo
Published: November 2023

Objective

Choledochal cysts are increasingly being diagnosed antenatally. The appropriate time of surgical treatment has the greatest impact on the prognosis of choledochal cyst treatment. The purpose of this study was to compare the clinical outcomes of prenatally diagnosed choledochal cysts in infants according to the surgical treatment timing.

Methods

We retrospectively reviewed the medical records of infants who underwent surgery for choledochal cysts with antenatal diagnoses. We investigated each patient's demographic information, type of choledochal cyst, serum liver enzyme levels, and surgical outcomes according to the surgical intervention timing.

Results

Between May 2006 and December 2020, 93 infants underwent surgery to treat choledochal cysts; among them, 68 had antenatally suspected choledochal cysts. Of the 68 patients, 21 developed symptoms directly after birth. While 38 patients remained asymptomatic, 9 developed symptoms before operation. To compare surgical outcomes, asymptomatic patients were divided into early (13 cases) and late (25 cases) operation groups based on an age benchmark of 30 days. The early surgical group experienced longer times to resume a full diet (6.0 ± 1.6 vs. 4.5 ± 0.7, p < 0.001) and longer postoperative hospital stays (11 ± 3.9 vs. 7.5 ± 0.8, p < 0.001). Surgical complications occurred in two patients in the early operation group. Minimally invasive surgery was performed in 12 patients in the late operation group. In both groups, postoperative liver function recovered at 6 months, with no significant difference.

Conclusion

The results of this study showed longer hospital stays, increased diet durations, and postoperative complications in early surgery patients. However, liver function recovery was not different between the early and late operation groups. Thus, asymptomatic patients should be closely monitored, and we recommend that definitive surgical intervention be postponed until 4 months of age or until weight reaches 7 kg.
Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy
Authors: Paar Vera , Haslinger Michael , Krombholz-Reindl Philipp , Pittner Stefan , Neuner Matthias , Jirak Peter , Kolbitsch Tobias , Minnich Bernd , Schrödl Falk , Kaser-Eichberger Alexandra , Kopp Kristen , Koller Andreas , Steinwender Clemens , Lichtenauer Michael , Monticelli Fabio C. , Seitelberger Rainald , Hoppe Uta C. , Dinges Christian , Motloch Lukas J.
Published: November 2023

Introduction: Hypertrophies of the cardiac septum are caused either by aortic valve stenosis (AVS) or by congenital hypertrophic obstructive cardiomyopathy (HOCM). As they induce cardiac remodeling, these cardiac pathologies may promote an arrhythmogenic substrate with associated malignant ventricular arrhythmias and may lead to heart failure. While altered calcium (Ca2+) handling seems to be a key player in the pathogenesis, the role of mitochondrial calcium handling was not investigated in these patients to date.

Methods: To investigate this issue, cardiac septal samples were collected from patients undergoing myectomy during cardiac surgery for excessive septal hypertrophy and/or aortic valve replacement, caused by AVS and HOCM. Septal specimens were matched with cardiac tissue obtained from post-mortem controls without cardiac diseases (Ctrl).

Results and discussion: Patient characteristics and most of the echocardiographic parameters did not differ between AVS and HOCM. Most notably, the interventricular septum thickness, diastolic (IVSd), was the greatest in HOCM patients. Histological and molecular analyses showed a trend towards higher fibrotic burden in both pathologies, when compared to Ctrl. Most notably, the mitochondrial Ca2+ uniporter (MCU) complex associated proteins were altered in both pathologies of left ventricular hypertrophy (LVH). On the one hand, the expression pattern of the MCU complex subunits MCU and MICU1 were shown to be markedly increased, especially in AVS. On the other hand, PRMT-1, UCP-2, and UCP-3 declined with hypertrophy. These conditions were associated with an increase in the expression patterns of the Ca2+ uptaking ion channel SERCA2a in AVS (p = 0.0013), though not in HOCM, compared to healthy tissue. Our data obtained from human specimen from AVS or HOCM indicates major alterations in the expression of the mitochondrial calcium uniporter complex and associated proteins. Thus, in cardiac septal hypertrophies, besides modifications of cytosolic calcium handling, impaired mitochondrial uptake might be a key player in disease progression.
Enhancing phase I dose-finding trials design through dynamic borrowing information and handling late-onset toxicity
Authors: Yang Wenyun , He Ruyue , Sun Yuehan , Yan Fangrong , Wang Fei
Published: November 2023

Introduction: In recent years, there has been a growing trend among regulatory agencies to consider the use of historical controls in clinical trials as a means of improving the efficiency of trial design. In this paper, to enhance the statistical operating characteristic of Phase I dose-finding trials, we propose a novel model-assisted design method named “MEM-Keyboard”.

Methods: The proposed design is based on the multisource exchangeability models (MEMs) that allows for dynamic borrowing of information from multiple supplemental data sources, including historical trial data, to inform the dose-escalation process. Furthermore, with the frequent occurrence of delayed toxicity in novel anti-cancer drugs, we extended our proposed method to handle late-onset toxicity by incorporating historical data. This extended method is referred to as “MEM-TITE-Keyboard” and aims to improve the efficiency of early clinical trials.

Results: Simulation studies have indicated that the proposed methods can improve the probability of correctly selecting the maximum tolerated dose (MTD) with an acceptable level of risk, compared to designs that do not account for information borrowing and late-onset toxicity.

Discussion: The MEM-Keyboard and MEM-TITE-Keyboard, easy to implement in practice, provide a useful tool for identifying MTD and accelerating drug development.
Dose-response association of metformin use and risk of age-related macular degeneration among patients with type 2 diabetes mellitus: a population-based study
Authors: Huang Kuang-Hua , Chang Ya-Lan , Lee Chiachi Bonnie , Gau Shuo-Yan , Tsai Tung-Han , Chung Ning-Jen , Lee Chien-Ying
Published: November 2023

Background: Recent studies have demonstrated that patients with type 2 diabetes mellitus (T2DM) who receive metformin have a decreased risk of developing age-related macular degeneration (AMD). However, other studies have also suggested that metformin may increase the risk of AMD development. Therefore, this study investigated the association between treatment with metformin and the risk of AMD in patients with T2DM by using Taiwan’ National Health Insurance Research Database.

Methods: Patients who received a diagnosis of new-onset T2DM between 2002 and 2013 were enrolled in this study. The patients were divided into patients treated and not treated with metformin to evaluate the risk of AMD after 5 years of follow-up. The logistic regression was used to estimate the risk of AMD associated with the intensity of treatment with metformin.

Result: A total of 7 517 patients (103.16 patients per 10,000 people) developed AMD in 5 years after DM diagnosis. After adjusting for the relevant variables, patients with T2DM treated with <5 defined daily dose (DDD)/month of metformin had a lower risk of AMD (odds ratios [OR]: 0.93; 95% confidence interval [CI]: 0.88 0.99). Patients treated with >25 DDD/month of metformin had a higher risk of AMD (OR: 1.39; 95% CI: 1.08-1.78).

Conclusion: Metformin use may be associated with a risk of AMD among patients with T2DM in a dose-dependent association manner, with the greater benefit at lower DDD/month. However, higher DDD/month exhibited an increased risk of AMD.
Case report: Severe respiratory failure caused by licorice
Authors: Taniguchi Hiroaki , Terayama Takero , Kiriu Nobuaki , Kato Hiroshi , Seno Soichiro , Sekine Yasumasa , Tanaka Yoshihiro , Kiyozumi Tetsuro
Published: November 2023

Licorice, one of the most commonly used herbs, can cause hypokalemia, metabolic alkalosis, and apparent mineralocorticoid excess, also known as pseudoaldosteronism. Herein, we present a case of diaphragmatic dysfunction caused by licorice administration. An 80-year-old woman who had been taking dietary supplements and following a restricted diet for approximately 6 months was brought to the emergency department with impaired consciousness. Chronic respiratory acidosis was observed, and hypertension and hypokalemia became more prominent during hospitalization. History revealed that she was taking herbal medicines containing licorice. Based on the results of hormone tests, the patient was diagnosed with pseudoaldosteronism. Chest radiography and pulmonary function tests confirmed the clinical diagnosis of diaphragmatic dysfunction. The metabolic alkalosis resulting from licorice administration may have contributed to the impairment of the respiratory muscles. This case suggests that caution should be exercised when using licorice in patients with preexisting health or medical issues such as advanced age, malnutrition, and electrolyte imbalance.
Comparing efficacy of first-line treatment of metastatic castration resistant prostate cancer: a network meta-analysis of randomized controlled trials
Authors: Liu Yang , Deng Xianzhong , Wen Zhi , Huang Jing , Wang Chongjian , Chen Caixia , Bao Erhao , Wang Jiahao , Yang Xuesong
Published: November 2023

Background: Metastatic castration-resistant prostate cancer (mCRPC) presents significant treatment selection challenges due to limited therapeutic options. This study aimed to comprehensively assess the efficacy of multiple treatment regimens for mCRPC through a network meta-analysis (NMA) of randomized controlled trials (RCTs).

Methods: A systematically comprehensive search for randomized controlled trials (RCTs) was performed in Pubmed, Cochrane Library, Embase, and Web of Science databases. The network meta-analysis was employed to compare the overall survival (OS), progression-free survival (PFS), and radiographic progression-free survival (rPFS) among different interventions at specific time points. This study was prospectively registered with PROSPERO (CRD42023422823).

Results: A total of 29 RCTs, involving 12,706 patients and investigating 16 interventions, were included in the analysis. Chempretarget ((capivasertib or cabozantinib) + docetaxel + prednisone)) and PARP (Olaparib or rucaparib) inhibitors emerged as interventions that significantly improved survival outcomes compared to first-line treatment in mCRPC patients. Chempretarget demonstrated superior overall survival starting from the 12th month, while PARP inhibitors showed a clear advantage in progression-free survival within the 3–18 months range. Notably, chempre ((Docetaxel or Cabazitaxel) + prednisone) exhibited favorable performance in radiographic progression-free survival during the 3–18 month period.

Conclusion: Our findings underscore the efficacy of chempretarget, PARP inhibitors, and chempre in enhancing survival outcomes for mCRPC patients. Further head-to-head comparisons are warranted to validate these results. These findings carry important implications for treatment decision-making in mCRPC and may guide the development of more effective therapeutic strategies.
From heart failure and kidney dysfunction to cardiorenal syndrome: TMAO may be a bridge
Authors: Zhang Jialun , Zhu Peining , Li Siyu , Gao Yufei , Xing Yue
Published: November 2023

The study of trimethylamine oxide (TMAO), a metabolite of gut microbiota, and heart failure and chronic kidney disease has made preliminary achievements and been summarized by many researchers, but its research in the field of cardiorenal syndrome is just beginning. TMAO is derived from the trimethylamine (TMA) that is produced by the gut microbiota after consumption of carnitine and choline and is then transformed by flavin-containing monooxygenase (FMO) in the liver. Numerous research results have shown that TMAO not only participates in the pathophysiological progression of heart and renal diseases but also significantly affects outcomes in chronic heart failure (CHF) and chronic kidney disease (CKD), besides influencing the general health of populations. Elevated circulating TMAO levels are associated with adverse cardiovascular events such as HF, myocardial infarction, and stroke, patients with CKD have a poor prognosis as well. However, no study has confirmed an association between TMAO and cardiorenal syndrome (CRS). As a syndrome in which heart and kidney diseases intersect, CRS is often overlooked by clinicians. Here, we summarize the research on TMAO in HF and kidney disease and review the existing biomarkers of CRS. At the same time, we introduced the relationship between exercise and gut microbiota, and appropriately explored the possible mechanisms by which exercise affects gut microbiota. Finally, we discuss whether TMAO can serve as a biomarker of CRS, with the aim of providing new strategies for the detection, prognostic, and treatment evaluation of CRS.
Efficacy and safety of tocilizumab and baricitinib among patients hospitalized for COVID-19: a systematic review and meta-analysis
Authors: Zhang Jin , Fan Xiongxiong , Zhang Xiaoyu , Jiang Fengli , Wu Yiping , Yang Beibei , Li Xinghuan , Liu Dong
Published: November 2023

Introduction: Tocilizumab and baricitinib are recommended treatment options for COVID-19 patients with hyperinflammatory response; however, there is a lack of systematic review directly evaluating their efficacy and safety.

Objective: This review was conducted to evaluate the efficacy and safety of tocilizumab and baricitinib in the treatment of hospitalized patients with COVID-19.

Methods: Relevant databases were searched for studies that compared the effect or safety of baricitinib or tocilizumab in hospitalized patients with COVID-19. The mortality was the main outcome. The hospital length of stay or adverse drug reactions were taken into consideration as secondary endpoints. The analyses were performed in Revman 5.3 or Stata 16.0. The protocol and analysis plan were pre-registered in PROSPERO, with the registration number CRD42023408219.

Results: In total, 10 studies with 2,517 patients were included. The overall pooled data demonstrated that, there was no statistically significant difference in the 28-day mortality rate and the hospital length of stay between the tocilizumab and baricitinib (OR = 1.10, 95% CI = 0.80–1.51, p = 0.57; OR = −0.68, 95% CI = −2.24–0.87, p = 0.39). The adverse reactions including secondary infection rate, thrombotic and bleeding events, and acute liver injury of tocilizumab were significantly higher than that of baricitinib. (OR = 1.49, 95% CI = 1.18–1.88, p < 0.001,OR = 1.52, 95% CI = 1.11–2.08, p = 0.009; OR = 1.52, 95% CI = 1.11–2.08, p = 0.009; OR = 2.24, 95% CI = 1.49–3.35, p < 0.001).

Conclusion: In patients hospitalized with COVID-19, no discernible difference in therapeutic efficacy was observed between tocilizumab and baricitinib; however, the group treated with baricitinib demonstrated a significantly lower incidence of adverse effects.
Relation of leg phase angle from bioelectrical impedance analysis with voluntary and evoked contractile properties of the plantar flexors
Authors: Hirata Kosuke , Yamada Yosuke , Iida Natsuki , Kanda Akihiro , Shoji Mikio , Yoshida Tsukasa , Akagi Ryota
Published: November 2023

Introduction: Bioelectrical impedance analysis (BIA) can noninvasively and quickly assess electrical properties of the body, such as the phase angle. Phase angle is regarded as the quantity and/or quality of skeletal muscle and is associated with exercise performance, such as jump height and walking speed. Although the phase angle derived from BIA is assumed to be a useful way to assess muscle function, the relationship between the phase angle and neuromuscular properties has not been fully investigated. The purpose of this study was to investigate the association of phase angle with voluntary and evoked contractile properties in 60 adults (age, 21–83 years; 30 females and 30 males).

Methods: The phase angle of the right leg at 50 kHz was evaluated using BIA. The twitch contractile properties (peak twitch torque [PTtwitch], rate of twitch torque development [RTDtwitch], and time-to-PTtwitch [TPTtwitch]) of the plantar flexors were measured using tibial nerve electrical stimulation. Maximal voluntary isometric contractions (MVICs) were performed to measure the maximal muscle strength and explosive muscle strength, from which the peak MVIC torque (PTMVIC) and rate of torque development (RTD) over a time interval of 0–200 ms were assessed, respectively. The root mean square (RMS) values of electromyographic (EMG) activity during the PTMVIC and RTD measurements (EMG-RMSMVIC and EMG-RMSRTD, respectively) were calculated. The RTD and EMG-RMSRTD were normalized using PTMVIC and EMG-RMSMVIC, respectively.

Results and discussion: Phase angle significantly correlated with twitch contractile properties (|r| ≥ 0.444, p < 0.001), PTMVIC (r = 0.532, p < 0.001), and RTD (r = 0.514, p < 0.001), but not with normalized RTD (r = 0.242, p = 0.065) or normalized EMG-RMSRTD (r = −0.055, p = 0.676). When comparing measurement variables between the low- and high-phase angle groups while controlling for sex and age effects, the high-phase angle group showed greater PTtwitch, RTDtwitch, PTMVIC, and RTD (p < 0.001) and shorter TPTtwitch (p < 0.001) but not normalized RTD (p = 0.184) or normalized EMG-RMSRTD (p = 0.317). These results suggest that the leg phase angle can be an indicator of voluntary and evoked muscle contractile properties but not the neuromuscular activity of the plantar flexors, irrespective of sex and age.
Comparative gut proteomics study revealing adaptive physiology of Eurasian spruce bark beetle, Ips typographus (Coleoptera: Scolytinae)
Authors: Ashraf Muhammad Zubair , Mogilicherla Kanakachari , Sellamuthu Gothandapani , Siino Valentina , Levander Fredrik , Roy Amit
Published: November 2023

The bark beetle, Ips typographus (L.), is a major pest of Norway spruce, Picea abies (L.), causing enormous economic losses globally. The adult stage of the I. typographus has a complex life cycle (callow and sclerotized); the callow beetles feed ferociously, whereas sclerotized male beetles are more aggressive and pioneers in establishing new colonies. We conducted a comparative proteomics study to understand male and female digestion and detoxification processes in callow and sclerotized beetles. Proteome profiling was performed using high-throughput liquid chromatography-mass spectrometry. A total of >3000 proteins were identified from the bark beetle gut, and among them, 539 were differentially abundant (fold change ±2, FDR <0.05) between callow and sclerotized beetles. The differentially abundant proteins (DAPs) mainly engage with binding, catalytic activity, anatomical activity, hydrolase activity, metabolic process, and carbohydrate metabolism, and hence may be crucial for growth, digestion, detoxification, and signalling. We validated selected DAPs with RT-qPCR. Gut enzymes such as NADPH-cytochrome P450 reductase (CYC), glutathione S-transferase (GST), and esterase (EST) play a crucial role in the I. typographus for detoxification and digesting of host allelochemicals. We conducted enzyme activity assays with them and observed a positive correlation of CYC and GST activities with the proteomic results, whereas EST activity was not fully correlated. Furthermore, our investigation revealed that callow beetles had an upregulation of proteins associated with juvenile hormone (JH) biosynthesis and chitin metabolism, whereas sclerotized beetles exhibited an upregulation of proteins linked to fatty acid metabolism and the TCA cycle. These distinctive patterns of protein regulation in metabolic and functional processes are specific to each developmental stage, underscoring the adaptive responses of I. typographicus in overcoming conifer defences and facilitating their survival. Taken together, it is the first gut proteomic study comparing males and females of callow and sclerotized I. typographus, shedding light on the adaptive ecology at the molecular level. Furthermore, the information about bark beetle handling of nutritionally limiting and defence-rich spruce phloem diet can be utilized to formulate RNAi-mediated beetle management.
Forest stand spectrum reconstruction using spectrum spatial feature gathering and multilayer perceptron
Authors: Wang Fan , Song Linghan , Liu Xiaojie , Zhong Shuangwen , Wang Jiawei , Zhang Yao , Wu Yun
Published: November 2023

Introduction

Three-dimensional spectral distributions of forest stands can provide spatial information on the physiological and biochemical status of forests, which is vital for forest management. However, three-dimensional spectral studies of forest stands are limited.

Methods

In this study, LiDAR and multispectral data were collected from Masson pine stands in southern Fujian Province, China, and a method was proposed for inverting forest spectra using point clouds as a unit. First, multispectral values were mapped to a point cloud, and the isolated forest algorithm combined with K-means clustering was applied to characterize fusion data. Second, five deep learning algorithms were selected for semantic segmentation, and the overall accuracy (oAcc) and mean intersection ratio (mIoU) were used to evaluate the performance of various algorithms on the fusion data set. Third, the semantic segmentation model was used to reconfigure the class 3D spectral distribution, and the model inversion outcomes were evaluated by the peaks and valleys of the curve of the predicted values and distribution gaps.

Results

The results show that the correlations between spectral attributes and between spatial attributes were both greater than 0.98, while the correlation between spectral and spatial attributes was 0.43. The most applicable method was PointMLP, highest oAcc was 0.84, highest mIoU was 0.75, peak interval of the prediction curve tended to be consistent with the true values, and maximum difference between the predicted value and the true value of the point cloud spectrum was 0.83.

Discussion

Experimental data suggested that combining spatial fusion and semantic segmentation effectively inverts three-dimensional spectral information for forest stands. The model could meet the accuracy requirements of local spectral inversion, and the NIR values of stands in different regions were correlated with the vertical height of the canopy and the distance from the tree apex in the region. These findings improve our understanding of the precise three-dimensional spectral distribution of forests, providing a basis for near-earth remote sensing of forests and the estimation of forest stand health.
Compost application boosts soil restoration in highly disturbed hillslope vineyard
Authors: Lucchetta Marco , Romano Alessandro , Alzate Zuluaga Monica Yorlady , Fornasier Flavio , Monterisi Sonia , Pii Youry , Marcuzzo Patrick , Lovat Lorenzo , Gaiotti Federica
Published: November 2023

A field trial was carried out to investigate the effects of compost application on a young Cabernet sauvignon vineyard located in a hilly area in the North-East of Italy and subjected to land terracing before plantation. The use of a compost based on manure, pruning residues and pomace at a rate of 65 t ha-1 was compared to the mineral fertilization regime recommended for the vineyards in the area (NPK: 80, 50, 200 kg ha-1). A multi-factorial approach that considered soil chemical properties, microbial community structure and function, vine nutritional and vegetative indexes, yield and quality parameters was applied in the attempt of depict interrelated effects of compost on all these factors. Results of this study show that the application of compost for three consequent years greatly increased soil organic matter content and improved the mineral nutrient availability in the soil. Soil biological fertility showed a slow but significant response to compost addition as from the second year of treatment microbial growth and enzyme activity were increased compared to those of the inorganic fertilization, with special regard to enzymes involved in P cycle. A shift in the soil microbial community structure was also observed in compost-treated soil, with higher presence of copiotrophic bacteria, indicators of soil quality, and phosphorus solubilizing bacteria. A decrease of pathogenic fungal strains was also observed. Organic fertilization increased plant nutrient uptake and vegetative growth compared to those observed in chemically fertilized vines. A trend toward increased yield and improvements for some grape quality parameters such as acidity and pH were observed in the first year of production. These results provide evidence that compost can boost soil fertility restoration in vineyard disturbed by land terracing, allowing for agronomic performances comparable or even improved than those of chemically fertilized vines.