bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence factors of medical disputes in Shanghai and implications - from the perspective of doctor, patient and disease
Authors: Liu Yu , Wang Pei , Bai Yonghai
Published: September 2022

Objective

This study aimed to explore the causes and factors behind medical disputes that occurred across eight hospitals in Shanghai over a three-year period (January 2018 to December 2020), thus providing targeted suggestions for amelioration.

Methods

Stratified sampling was employed to collect 561 cases in which medical disputes occurred at two tertiary hospitals, two secondary hospitals, and four primary hospitals in Shanghai. The causes were analyzed using descriptive statistics, while the factors affecting the dispute level (i.e., 1 through 4, with 1 being most severe) were analyzed via one-way ANOVA and logistic regression analyses. 

Results

Doctors and patients variously contributed to the medical disputes; 86.1% were related to doctors, while 13.9% were related to patients. For doctors, there are seventeen factors that influenced medical disputes. In particular, the insufficient communication (28.82%) is the most prominent factor in the doctors’ factors. For patients, there are seven factors that influenced medical disputes. In particular, the misunderstanding of medical behavior (43.48%) is the most prominent factor in the patients’ factors. Of all investigated medical disputes, 406 were level 4 (78%), 95 were level 3 (18%), and 19 were level 2 (4%); there were no level 1 disputes. The reasons for different level placements included the disease classification, treatment effect, diagnosis and treatment regulation violations by doctors, and low technical levels.

Conclusions

In addition to strengthening training about clinical and communication skills, the hospitals should establish quality control mechanisms for case records and construct rapid, standardized referral mechanisms. The doctors should attach great importance to the quality and urgency of treatment given to critically ill patients, who must be informed about their prognoses in a timely manner to avoid medical disputes and physical deterioration. The patients should actively cooperate with their doctors in the treatment process, moderate any unrealistic expectations that patients may have about the outcomes. During the COVID-19 pandemic particularly, doctors and patients should strengthen empathy and mutual trust more, then defeat disease together.
Designing multi-epitope-based vaccine targeting surface immunogenic protein of Streptococcus agalactiae using immunoinformatics to control mastitis in dairy cattle
Authors: Pathak Rajesh Kumar , Lim Byeonghwi , Kim Do-Young , Kim Jun-Mo
Published: September 2022

Background

Milk provides energy as well as the basic nutrients required by the body. In particular, milk is beneficial for bone growth and development in children. Based on scientific evidence, cattle milk is an excellent and highly nutritious dietary component that is abundant in vitamins, calcium, potassium, and protein, among other minerals. However, the commercial productivity of cattle milk is markedly affected by mastitis. Mastitis is an economically important disease that is characterized by inflammation of the mammary gland. This disease is frequently caused by microorganisms and is detected as abnormalities in the udder and milk. Streptococcus agalactiae is a prominent cause of mastitis. Antibiotics are rarely used to treat this infection, and other available treatments take a long time to exhibit a therapeutic effect. Vaccination is recommended to protect cattle from mastitis. Accordingly, the present study sought to design a multi-epitope vaccine using immunoinformatics.

Results

The vaccine was designed to be antigenic, immunogenic, non-toxic, and non-allergic, and had a binding affinity with Toll-like receptor 2 (TLR2) and TLR4 based on structural modeling, docking, and molecular dynamics simulation studies. Besides, the designed vaccine was successfully expressed in E. coli. expression vector (pET28a) depicts its easy purification for production on a larger scale, which was determined through in silico cloning. Further, immune simulation analysis revealed the effectiveness of the vaccine with an increase in the population of B and T cells in response to vaccination.

Conclusion

This multi-epitope vaccine is expected to be effective at generating an immune response, thereby paving the way for further experimental studies to combat mastitis.
Time-series analysis of presentations to four syringe dispensing machines and a needle and syringe programme during COVID-19 lockdowns in Melbourne, Australia
Authors: O’Keefe Daniel , Livingston Michael , Cossar Reece D. , Kerr Phoebe , Jacka David , Dietze Paul
Published: September 2022

Background

Australian harm reduction services are provided via a mix of modalities, including fixed-site needle and syringe programmes (NSP) and syringe-dispensing machines (SDMs). SDMs are cost-effective and provide 24-h anonymous access to needles/syringes, often to underserved geographic areas, and can attract clientele who may choose not to use NSPs. The introduction of COVID-19 control measures saw disruptions and adaptations to the provision of harm reduction services. It is possible that SDMs filled the gap in otherwise disrupted harm reduction services in Melbourne. In this paper, we use data from four SDMs and an NSP to explore changes to harm reduction usage during periods of COVID-19 lockdowns in Melbourne, Australia, in 2020.

Methods

Our data span September 2017–December 2020. We analysed daily counts of SDM use and monthly counts of NSP use, according to unique presentations to both. Auto-regressive integrated moving average (ARIMA) time-series models were fitted to the data with the effects of lockdowns estimated via a step function.

Results

Across the study period, we estimated 85,851 SDM presentations and 29,051 NSP presentations. Usage across both the SDMs and the NSP declined during the COVID-19 lockdowns, but only the decline in SDM usage was significant in ARIMA analysis.

Conclusions

The slight, but significant decline in SDM use suggests barriers to access, though this may have been mitigated by SDM users acquiring needles/syringes from other sources. The decline, however, may be a concern if it led to lowered needle/syringe coverage and a subsequent increase in injecting risk. Further work is needed to properly explore potential changes in preference for needle/syringe acquisition site and associated barriers. Importantly, this work adds to the body of literature around the impacts of COVID-19 on harm reduction provision and potential areas of improvement.
Pancreaticoduodenal and choledochal hemangiomatosis with vascular variation in a child: a rare disease with challenge starts from diagnosis—a case report
Authors: Tian Daguang , Zhu Hong , Wei Xiaoping
Published: September 2022

Background

Visceral hemangiomatosis is a benign tumor (rarer than hemangioma) that has not been reported to occur in the pancreas, duodenum, or choledoch. It can be easily confused with other pancreatic tumors or choledocholithiasis. Herein, we describe a case of a child with pancreaticoduodenal and choledochal hemangiomatosis and the key characteristics for the accurate diagnosis of pancreatic tumors based on previous reports and our findings.

Case presentation

We report a case of a 2-year and 9-month-old child who presented with repeated and fluctuating jaundice for 3 months with a history of endoscopic stone removal in a local hospital, following the diagnosis of choledocholithiasis. An abdominal computed tomography revealed a previously undiagnosed pancreatic head tumor and celio-mesenteric trunk (a rare vascular variation). This was misdiagnosed as a pancreatic neuroendocrine tumor. Since the patient’s parents refused FNA biopsy and insisted on surgery, pancreaticoduodenectomy was performed; however, postoperatively, the child was correctly diagnosed with pancreaticoduodenal and choledochal hemangiomatosis. Although the patient was in good condition and had gained 4 kg in weight 3 months postoperatively, pancreaticoduodenectomy could have been avoided if an accurate diagnosis had been established before or during the operation.

Conclusion

Our report highlights the difficulty in diagnosing visceral hemangiomatosis. Radiologists, endoscopists, and surgeons should consider this possibility in cases of repeated and fluctuating jaundice that cannot be explained by choledocholithiasis alone.
Mitochondria transfer restores fibroblasts-like synoviocytes (FLS) plasticity in LPS-induced, in vitro synovitis model
Authors: Kornicka-Garbowska K. , Groborz S. , Lynda B. , Galuppo L. , Marycz K.
Published: September 2022

Background

Synovitis (SI) is one of the most common and serious orthopedic diseases in horses of different age, breed and sex, which contributes to the development of osteoarthritis. The burden of SI includes economic loss and represents a real challenge for current veterinary health care. At the molecular level, fibroblasts-like synoviocytes (FLS) are recognized as major cell populations involved in SI pathogenesis. In the course of SI, FLSs are losing their protective and pro-regenerative cytological features, become highly proliferative and initiate various stress signaling pathways.

Methods

Fibroblast-like synoviocytes were treated with LPS in order to generate SI in vitro model. Mitochondria were isolated from peripheral blood derived mononuclear cells and co-cultured with FLS. After 24 h of culture, cells were subjected to RT-qPCR, western blot, cytometric and confocal microscopy analysis.

Results

Mitochondrial transfer (MT) was observed in vitro studies using confocal microscopy. Further studies revealed, that MT to LPS-treated FLS reduced cell proliferation, modulated apoptosis and decreased inflammatory response. Overall, MT Resulted in the considerable recovery of recipient cells cytophysiological properties.

Conclusions

Presented data provides evidence that mitochondria transfersignificantly modulate FLS proliferative and metabolic activity through improved mitochondrial biogenesis and dynamics in activated FLS. Obtained results for the first time demonstrate that horizontal MT might be considered as a therapeutic tool for synovitis treatment; however, further clinical studies are strongly required.
Identification and analysis of mitochondria-related key genes of heart failure
Authors: Yu Haozhen , Yu Mujun , Li Zhuang , Zhang Enhu , Ma Heng
Published: September 2022

Mitochondria-induced cell death is a vital mechanism of heart failure (HF). Thus, identification of mitochondria-related genes (Mito-RGs) based on transcriptome sequencing data of HF might provide novel diagnostic markers and therapeutic targets for HF. First, bioinformatics analysis was conducted on the GSE57338, GSE76701, GSE136547, and GSE77399 datasets in the Gene Expression Omnibus. Next, we analyzed HF-Mito differentially expressed genes (DEGs) using the protein–protein interaction (PPI) network for obtaining critical genes and exploring their functions. Subsequently, immune cell scores of the HF and normal groups were compared. The potential alteration mechanisms of the key genes were investigated by constructing a competing endogenous RNA network. Finally, we predicted potential therapeutic agents and validated the expression levels of the key genes. Twenty-three HF-Mito DEGs were acquired in the GSE57338 dataset, and the PPI network obtained four key genes, including IFIT3, XAF1, RSAD2, and MX1. According to gene set enrichment analysis, the key genes showed high enrichment in myogenesis and hypoxia. Immune cell analysis demonstrated that aDCs, B cells, and 20 other immune cell types varied between the HF and normal groups. Moreover, we observed that H19 might affect the expression of IFIT3, AXF1, and RSAD2. PCGEM1 might regulate RSAD2 expression. A total of 515 potential therapeutic drugs targeting the key genes, such as tretinoin, silicon dioxide, and bisphenol A, were acquired. Finally, IFIT3, RSAD2, and MX1 expression increased in HF samples compared with normal samples in the GSE76701 dataset, conforming to the GSE57338 dataset analysis. This work screened four key genes, namely, IFIT3, XAF1, RSAD2, and MX1, which can be further explored in subsequent studies for their specific molecular mechanisms in HF.
Immunoadsorption versus double-dose methylprednisolone in refractory multiple sclerosis relapses
Authors: Pfeuffer Steffen , Rolfes Leoni , Wirth Timo , Steffen Falk , Pawlitzki Marc , Schulte-Mecklenbeck Andreas , Gross Catharina C. , Brand Marcus , Bittner Stefan , Ruck Tobias , Klotz Luisa , Wiendl Heinz , Meuth Sven G.
Published: September 2022

Objective

Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing.

Methods

In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030).

Results

42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption (p = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients (p = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors.

Interpretation

Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.
Cross-validation of predictive models for functional recovery after post-stroke rehabilitation
Authors: Campagnini Silvia , Liuzzi Piergiuseppe , Mannini Andrea , Basagni Benedetta , Macchi Claudio , Carrozza Maria Chiara , Cecchi Francesca
Published: September 2022

Background

Rehabilitation treatments and services are essential for the recovery of post-stroke patients’ functions; however, the increasing number of available therapies and the lack of consensus among outcome measures compromises the possibility to determine an appropriate level of evidence. Machine learning techniques for prognostic applications offer accurate and interpretable predictions, supporting the clinical decision for personalised treatment. The aim of this study is to develop and cross-validate predictive models for the functional prognosis of patients, highlighting the contributions of each predictor.

Methods

A dataset of 278 post-stroke patients was used for the prediction of the class transition, obtained from the modified Barthel Index. Four classification algorithms were cross-validated and compared. On the best performing model on the validation set, an analysis of predictors contribution was conducted.

Results

The Random Forest obtained the best overall results on the accuracy (76.2%), balanced accuracy (74.3%), sensitivity (0.80), and specificity (0.68). The combination of all the classification results on the test set, by weighted voting, reached 80.2% accuracy. The predictors analysis applied on the Support Vector Machine, showed that a good trunk control and communication level, and the absence of bedsores retain the major contribution in the prediction of a good functional outcome.

Conclusions

Despite a more comprehensive assessment of the patients is needed, this work paves the way for the implementation of solutions for clinical decision support in the rehabilitation of post-stroke patients. Indeed, offering good prognostic accuracies for class transition and patient-wise view of the predictors contributions, it might help in a personalised optimisation of the patients’ rehabilitation path.
Soybean cyst nematode detection and management: a review
Authors: Arjoune Youness , Sugunaraj Niroop , Peri Sai , Nair Sreejith V. , Skurdal Anton , Ranganathan Prakash , Johnson Burton
Published: September 2022

Soybeans play a key role in global food security. U.S. soybean yields, which comprise $$32\%$$

32
%

of the total soybeans planted in the world, continue to experience unprecedented grain loss due to the soybean cyst nematode (SCN) plant pathogen. SCN remains one of the primary disruptive pests despite the existence of advanced management techniques such as crop rotation and SCN-resistant varieties. SCN detection is a key step in managing this disease; however, early detection is challenging because soybeans do not show any above ground symptoms unless they  are significantly damaged. Direct soil sampling remains the most common method for SCN detection, however, this method has several problems. For example, the threshold damage methods—adopted by most of the laboratories to make recommendations—is not reliable as it does not consider soil pH, N, P, and K values and relies solely on the egg count instead of assessment of the root infection. To overcome the challenges of manual soil sampling methods, deep learning and hyperspectral imaging are important current topics in precision agriculture for plant disease detection and have been proposed as cost-effective and efficient detection methods that can work at scale. We have reviewed more than 150 research papers focusing on soybean cyst nematodes with an emphasis on deep learning techniques for detection and management. First: we describe soybean vegetation and reproduction stages, SCN life cycles, and factors influencing this disease. Second: we highlight the impact of SCN on soybean yield loss and the challenges associated with its detection. Third: we describe direct sampling methods in which the soil samples are procured and analyzed to evaluate SCN egg counts. Fourth: we highlight the advantages and limitations of these direct methods, then review computer vision- and remote sensing-based detection methods: data collection using ground, aerial, and satellite approaches followed by a review of machine learning methods for image analysis-based soybean cyst nematode detection. We highlight the evaluation approaches and the advantages of overall detection workflow in high-performance and big data environments. Lastly, we discuss various management approaches, such as crop rotation, fertilization, SCN resistant varieties such as PI 88788, and SCN’s increasing resistance to these strategies. We review machine learning approaches for soybean crop yield forecasting as well as the influence of pesticides, herbicides, and fertilizers on SCN infestation reduction. We provide recommendations for soybean research using deep learning and hyperspectral imaging to accommodate the lack of the ground truth data and training and testing methodologies, such as data augmentation and transfer learning, to achieve a high level of detection accuracy while keeping costs as low as possible.
Predictors of major adverse events and complications after ventricular septal defects surgical closure in children less than 10 kg
Authors: Abdelrehim Ayman R. , Al-Muhaya Mustafa , Alkodami Alassal A. , Baangood Luna S. , Al-Mutairi Mansour , Quadeer Abdul , Alabsi Fath A. , Alashwal M. , Morsy Mohamed Mofeed F. , Alnajjar Abdulhameed A. , Salem Sherif S.
Published: September 2022

Background

Ventricular septal defect (VSD) is the most common congenital cardiac defect for which outcomes are not uniform. There is a lack of consensus on the risk factors for the unfavorable outcomes following surgical VSD closure.

Aim

The aim of this study was to determine the risk factors and the predictors of major adverse events (MAEs) and complications following surgical closure of VSD in children weighing less than 10 kg.

Methods

This retrospective cohort study included children less than 10 kg who underwent surgical closure of congenital VSD of any type with or without associated congenital heart diseases. Patients with associated major cardiac anomalies were excluded. Preoperative, operative and postoperative data were collected from medical records.

Results

This study included 127 patients 52.8% were males, the median age was 8.0 months (IQR = 6.0–11.0 months), and their median weight was 5.7 kg (IQR = 4.8–7.0). Mortality was in one patient (0.8%) Multivariable logistic regression analysis revealed that male sex group (observational data), previous pulmonary artery banding (PAB), and significant intraoperative residual VSD were significant risk factors for the development of MAEs (odds ratios were 3.398, 14.282, and 8.634, respectively). Trisomy 21 syndrome (odds ratio: 5.678) contributed significantly to prolonged ventilation. Pulmonary artery banding (odds ratio: 14.415), significant intraoperative (3 mm) residual VSD (odds ratio: 11.262), and long cross-clamp time (odds ratio: 1.064) were significant predictors of prolonged ICU stay, whereas prolonged hospital stay was observed significantly in male sex group (odds ratio: 12.8281), PAB (odds ratio: 2.669), and significant intraoperative (3 mm) residual VSD (odds ratio: 19.551).

Conclusions

Surgical VSD repair is considered a safe procedure with very low mortality. Trisomy 21 was a significant risk factor for prolonged ventilation. Further, PAB, significant intraoperative residual of 3 mm or more that required a second pulmonary bypass, and a greater cross-clamp time were significant predictors of MAE and associated complications with prolonged ICU and hospital stay.
Spatiotemporal Pavlovian head-fixed reversal learning task for mice
Authors: Yamamoto Kohei , Yamada Kota , Yatagai Saya , Ujihara Yusuke , Toda Koji
Published: September 2022

Our world is full of uncertainty. Animals, including humans, need to behave flexibly to adjust to ever-changing environments. Reversal learning tasks have been used to assess behavioral flexibility in many species. However, there are some limitations in the traditional free-moving methodology, including (1) sessions to train the animals, (2) within-session number of trials associated with reversals, (3) factors of physical movement unrelated to the task in the maze or operant box, and (4) incompatibility with techniques, such as two-photon imaging. Therefore, to address these limitations, we established a novel spatiotemporal Pavlovian head-fixed reversal learning task for mice. Six experimentally naive adult C57BL/6J mice were used in this study. First, we trained head-fixed mice on a fixed-time schedule task. Sucrose solution was delivered every 10 s with a single drinking spout placed within the licking distance of the mice. After the mice showed anticipatory licking toward the timing of sucrose solution delivery, we began training the mice on the fixed-time schedule reversal learning task with two licking spouts. In this task, sucrose solution was delivered through one of the two drinking spouts. The rewarding spout was switched every 10 trials. Mice quickly learned to switch anticipatory licking to the rewarding side of the spouts, suggesting that they learned this head-fixed reversal learning task. Using the head-fixed experimental design, behavioral measures can be simplified by eliminating the complex behavioral sequences observed in free-moving animals. This novel head-fixed reversal learning task is a useful assay for studying the neurobiological mechanism of behavioral flexibility that is impaired in various psychopathological conditions.
The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy
Authors: Shi Congqi , Qin Kaiyu , Lin Anqi , Jiang Aimin , Cheng Quan , Liu Zaoqu , Zhang Jian , Luo Peng
Published: September 2022

As our understanding of the mechanisms of cancer treatment has increased, a growing number of studies demonstrate pathways through which DNA damage repair (DDR) affects the immune system. At the same time, the varied response of patients to immune checkpoint blockade (ICB) therapy has prompted the discovery of various predictive biomarkers and the study of combination therapy. Here, our investigation explores the interactions involved in combination therapy, accompanied by a review that summarizes currently identified and promising predictors of response to immune checkpoint inhibitors (ICIs) that are useful for classifying oncology patients. In addition, this work, which discusses immunogenicity and several components of the tumor immune microenvironment, serves to illustrate the mechanism by which higher response rates and improved efficacy of DDR inhibitors (DDRi) in combination with ICIs are achieved.
Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo
Authors: Passariello Margherita , Yoshioka Asami , Takahashi Kota , Hashimoto Shu-ichi , Inoue Toshikazu , Nakamura Koji , De Lorenzo Claudia
Published: September 2022

Background

Immunotherapy based on Bi-specific T Cell Engagers (TCE) represents one of the most attractive strategy to treat cancers resistant to conventional therapies. TCE are antibody-like proteins that simultaneously bind with one arm to a Tumor Associated Antigen (TAA) on cancer cells and with the other one to CD3 complex on a T-cell to form a TCR-independent immune synapse and circumvent Human Leucocyte Antigen restriction. Among them, the tribodies, such as Tb535H, a bi-specific molecule, made up of a Fab and a scFv domain both targeting 5T4 and another scFv targeting CD3, have demonstrated anti-tumor efficacy in preclinical studies.

Methods

Here, we generated five novel tri-specific and multi-functional tribodies, called 53X tribodies, composed of a 5T4 binding Fab arm and a CD3 binding scFv, but differently from the parental Tb535H, they contain an additional scFv derived from an antibody specific for an immune checkpoint, such as PD-1, PD-L1 or LAG-3.

Results

Compared with the parental Tb535H bi-specific T cell engager targeting 5T4, the novel 53X tribodies retained similar binding properties of Tb535H tribody, but showed enhanced anti-tumor potency due to the incorporation of the checkpoint inhibitory moiety. In particular, one of them, called 53L10, a tri-specific T cell engager targeting 5T4, CD3 and PD-L1, showed the most promising anti-tumor efficacy in vitro and led to complete tumor regression in vivo.

Conclusions

The novel tribodies have the potential to become strong and safe therapeutic drugs, allowing to reduce also the cost of production as one single molecule contains three different specificities including the anti-TAA, anti-CD3 and anti-IC binding arms.
Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin
Authors: Li Yi , Wu Anqi , Chen Lin , Cai Aiting , Hu Yuhao , Zhou Zhou , Qi Qianyi , Wu Yixuan , Xia Donglin , Dong Peixin , Ju Shaoqing , Wang Feng
Published: September 2022

Background

Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments.

Methods

A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC.

Results

The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3′-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance.

Conclusions

Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.
Glutathione metabolism in Cryptocaryon irritans involved in defense against oxidative stress induced by zinc ions
Authors: Zhong Zhi-Hong , Li Zhi-Cheng , Li Han , Guo Qing-Kai , Wang Chen-Xi , Cao Ji-Zhen , Li An-Xing
Published: September 2022

Background

Cryptocaryon irritans is a fatal parasite for marine teleosts and causes severe economic loss for aquaculture. Galvanized materials have shown efficacy in controlling this parasite infestation through the release of zinc ions to induce oxidative stress.

Methods

In this study, the resistance mechanism in C. irritans against oxidative stress induced by zinc ions was investigated. Untargeted metabolomics analysis was used to determine metabolic regulation in C. irritans in response to zinc ion treatment by the immersion of protomonts in ZnSO4 solution at a sublethal dose (20 μmol). Eight differential metabolites were selected to assess the efficacy of defense against zinc ion stimulation in protomonts of C. irritans. Furthermore, the mRNA relative levels of glutathione metabolism-associated enzymes were measured in protomonts following treatment with ZnSO4 solution at sublethal dose.

Results

The results showed that zinc ion exposure disrupted amino acid metabolism, carbohydrate metabolism, lipid metabolism, and nucleotide metabolism in C. irritans. Four antioxidants, namely ascorbate, S-hexyl-glutathione, syringic acid, and ubiquinone-1, were significantly increased in the Zn group (P < 0.01), while the glutathione metabolism pathway was enhanced. The encystment rate of C. irritans was significantly higher in the ascorbate and methionine treatment (P < 0.05) groups. Additionally, at 24 h post-zinc ion exposure, the relative mRNA level of glutathione reductase (GR) was increased significantly (P < 0.01). On the contrary, the relative mRNA levels of glutathione S-transferase (GT) and phospholipid-hydroperoxide glutathione peroxidase (GPx) were significantly decreased (P < 0.05), thus indicating that the generation of reduced glutathione was enhanced.

Conclusions

These results revealed that glutathione metabolism in C. irritans contributes to oxidative stress resistance from zinc ions, and could be a potential drug target for controlling C. irritans infection.

Graphical Abstract
Effect of heat inactivation and bulk lysis on real-time reverse transcription PCR detection of the SARS-COV-2: an experimental study
Authors: Leta Dereje , Gutema Gadissa , Hagos Gebremedhin Gebremichael , Diriba Regasa , Bulti Gutema , Sura Tolawak , Ayana Desta , Chala Dawit , Lenjiso Boki , Bulti Jaleta , Abdella Saro , Tola Habteyes Hailu
Published: September 2022

Objective

This study aimed to investigate the effect of heat inactivation and chemical bulklysis on SARS-CoV-2 detection.

Results

About 6.2% (5/80) of samples were changed to negative results in heat inactivation at 60 °C and about 8.7% (7/80) of samples were changed to negative in heat inactivation at 100 °C. The Ct values of heat-inactivated samples (at 60 °C, at 100 °C, and bulk lysis) were significantly different from the temperature at 56 °C. The effect of heat on Ct value should be considered when interpreting diagnostic PCR results from clinical samples which could have an initial low virus concentration. The efficacy of heat-inactivation varies greatly depending on temperature and duration. Local validation of heat-inactivation and its effects is therefore essential for molecular testing.
Comparison and impact of associated anomalies on the anal position index in neonates with anorectal malformation
Authors: Pitaka Ririd Tri , Fauzi Aditya Rifqi , Makhmudi Akhmad , Gunadi
Published: September 2022

Objective

Some prognostic factors have affected the functional outcomes of patients with anorectal malformations (ARM) after definitive surgery, including the associated anomalies. Moreover, the anal position index (API) study in neonates from developing countries is minimal. We aimed to (1) compare the API between neonates with ARM and controls; and (2) determine the impact of associated anomalies on the API in neonates with ARM.

Results

We ascertained 68 subjects: 35 neonates with ARM and 33 controls. The API of neonates with ARM was similar to controls, either male or female neonates (p = 0.51 and 0.90, respectively). Interestingly, the API in ARM males with associated anomalies (0.42 ± 0.07) was significantly lower than in control males (0.48 ± 0.02) (p = 0.005). Moreover, the API of ARM neonates with vertebral anomalies (0.35 ± 0.04) was lower than ARM neonates without vertebral anomalies (0.47 ± 0.07) (p = 0.021). In conclusion, associated anomalies and sex might affect the API in neonates with ARM. These findings should be considered and informed during counseling to the parents regarding the prognosis of functional outcomes in ARM neonates, particularly with associated anomalies.
Information and Communication Technologies (ICTs) enabling integrated primary care for complex patients: a protocol for a scoping review
Authors: Tahsin Farah , Armas Alana , Kirakalaprathapan Apery , Cunningham Heather , Kadu Mudathira , Sritharan Jasvinei , Steele Gray Carolyn
Published: September 2022

Introduction

An increasing number of individuals are living with multiple chronic conditions, often combined with psychosocial complexities. For these patients with complex conditions, an integrated primary care model that provides care coordination and a team-based approach can help manage their multiple needs. Information and communication technologies (ICTs) are recognized as a critical enabler of integrated primary care. A better understanding of the use of ICTs in an integrated care setting and how ICTs are being leveraged would be beneficial to identify knowledge gaps and could lead to successful implementation for ICT-based interventions.

Objective

This study will systematically scope the literature on the topic of ICT-enabled integrated healthcare delivery models for patients with complex care needs to identify which technologies have been used in integrated primary care settings.

Method

This study protocol outlines a scoping review of the peer-reviewed literature, using Arksey and O’Malley’s (enhanced by Levac et al.) scoping review methodology. Peer-reviewed literature will be identified using a multi-database search strategy. The results of the search will be screened, abstracted, and charted in duplicate by six research team members.

Discussion

The key findings of the study will be thematically analyzed to describe the implemented ICTs aimed for complex patients within the integrated primary care model. The finding will highlight what types of ICTs are being put in place to support these models, and how these ICTs are enabling care integration. This review will be the first step to formally identify how ICT is used to support integrated primary health care models. The results will be disseminated through peer-reviewed publications, conference presentations, and special interest groups.
Herd behaviour in foreign exchange market
Authors: Yasir Anam , Safdar Umar , Javaid Yasir
Published: September 2022

This study examines the presence of herding behaviour in the forex market of Pakistan. By analysing the daily returns of the top six traded currencies from January 2015 to December 2019, the current research  explores the behaviour of investors towards investment in currencies. Data is analysed using the model proposed by Chang et al. (2000). Results of estimation techniques provide evidence of herd behaviour among investors. Findings suggest that investors do not rely on their own decision-making; rather they follow the patterns of others. Furthermore, this imitating behaviour in same in up and down market events. Findings of this study provide significant insights for future researchers about decision-making of investors in forex market.
Lessons Learnt From Pilot Cervical Cancer Screening and Treatment Programmes Integrated to Routine Primary Health Care Services in Benin, Cote d'Ivoire, and Senegal
Authors: Selmouni Farida , Sauvaget Catherine , Dangbemey Djima Patrice , Kpebo Djoukou Denise Olga , Dieng Ndeye Mbombe , Lucas Eric , Chami Khazraji Youssef , Bennani Maria , Bekkali Rachid , Basu Partha
Published: September 2022

PURPOSE

The project aimed to implement pilot screening and treatment services for cervical cancer integrated with existing primary health centers (PHCs) in Benin, Cote d'Ivoire, and Senegal and evaluate these services using implementation research outcomes such as reach, effectiveness, adoption, and acceptability.

MATERIALS AND METHODS

The Ministry of Health in each country took the lead in setting up a stakeholder's group that designed a protocol tailored to the local context. The target age was 25-49 years in Benin and Cote d'Ivoire and 30-49 years in Senegal. Visual inspection with acetic acid (VIA) was the screening test, and thermal ablation (TA) was the ablative treatment of choice in all. The Ministry in each country identified 4-5 PHCs to set up screening and ablation services and one higher-level center for colposcopy referral. After a master-trainer led training program, nurses, midwives, or general practitioners screened opportunistically the eligible women attending the clinics. The VIA-positive women eligible for ablation were offered immediate treatment.

RESULTS

Between May 2018 and January 2021, 16,530 women were screened opportunistically. VIA positivity was 8.1% with huge variability within and between countries. Sixty-one percent of all VIA-positive cases were eligible for immediate TA, and 88% of them accepted same-day treatment. Compliance to TA at PHCs was 99%. Majority of women treated with TA complained of minor side effects. Significant dropouts occurred as the women were referred to colposcopy clinics.

CONCLUSION

Opportunistic screening provided as part of routine PHC service can screen many women and treat a significant proportion of screen-positive women with TA with minimal side effects. Primary concerns are the hard-to-reach women who remain out of opportunistic screening coverage and noncompliance of the screen-positive women referred to higher-level centers.
A Phase III Study of Pafolacianine Injection (OTL38) for Intraoperative Imaging of Folate Receptor–Positive Ovarian Cancer (Study 006)
Authors: Tanyi Janos L. , Randall Leslie M. , Chambers Setsuko K. , Butler Kristina A. , Winer Ira S. , Langstraat Carrie L. , Han Ernest S. , Vahrmeijer Alexander L. , Chon Hye Sook , Morgan Mark A. , Powell Matthew A. , Tseng Jill H. , Lopez Alexis S. , Wenham Robert M.
Published: September 2022

PURPOSE

The adjunctive use of intraoperative molecular imaging (IMI) is gaining acceptance as a potential means to improve outcomes for surgical resection of targetable tumors. This confirmatory study examined the use of pafolacianine for real-time detection of folate receptor–positive ovarian cancer.

METHODS

This phase III, open-label, 11-center study included subjects with known or suspected ovarian cancer, scheduled to undergo cytoreductive surgery. The objectives were to confirm safety and efficacy of pafolacianine (0.025 mg/kg IV), given ≥ 1 hour before intraoperative near-infrared imaging to detect macroscopic lesions not detected by palpation and normal white light.

RESULTS

From March 2018 through April 2020, 150 patients received a single infusion of pafolacianine (safety analysis set); 109 patients with folate receptor–positive ovarian cancer comprised the full analysis set for efficacy. In 33.0% of patients (95% CI, 24.3 to 42.7; P < .001), pafolacianine with near-infrared imaging identified additional cancer on tissue not planned for resection and not detected by white light assessment and palpation, exceeding the prespecified threshold of 10%. Among patients who underwent interval debulking surgery, the rate was 39.7% (95% CI, 27.0 to 53.4; P < .001). The sensitivity to detect ovarian cancer was 83%, and the patient false-positive rate was 24.8%. Investigators reported achieving complete R0 resection in 62.4% (68 of 109) of patients. Drug-related adverse events were reported by 30% of patients (45 of 150) and most commonly included nausea, vomiting, and abdominal pain. No drug-related serious adverse events or deaths were reported.

CONCLUSION

This phase III study of pafolacianine met its primary efficacy end point, identifying additional cancers not otherwise identified or planned for resection. Pafolacianine may offer an important real-time adjunct to current surgical approaches for ovarian cancer.
Effects of a 6-wk Sprint Interval Training Protocol at Different Altitudes on Circulating Extracellular Vesicles
Authors: WARNIER GEOFFREY , DE GROOTE ESTELLE , DELCORTE OPHÉLIE , NICOLAS MARTINEZ DANIEL , NEDERVEEN JOSHUA P. , NILSSON MATS I. , FRANCAUX MARC , PIERREUX CHRISTOPHE E. , DELDICQUE LOUISE
Published: September 2022

Purpose

This study aimed to investigate the modulation of circulating exosome-like extracellular vesicles (ELVs) after 6 wk of sprint interval training (SIT) at sea level and at 2000, 3000, and 4000 m.

Methods

Thirty trained endurance male athletes (18–35 yr) participated in a 6-wk SIT program (30-s all-out sprint, 4-min 30-s recovery; 4–9 repetitions, 2 sessions per week) at sea level (n = 8), 2000 m (fraction of inspired oxygen (Fio
2) 0.167, n = 8), 3000 m (Fio
2 0.145, n = 7), or 4000 m (Fio
2 0.13, n = 7). Venous blood samples were taken before and after the training period. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis, and characterized according to international standards. Candidate ELV microRNAs (miRNAs) were quantified by real-time polymerase chain reaction.

Results

When the three hypoxic groups were analyzed separately, only very minor differences could be detected in the levels of circulating particles, ELV markers, or miRNA. However, the levels of circulating particles increased (+262%) after training when the three hypoxic groups were pooled, and tended to increase at sea level (+65%), with no difference between these two groups. A trend to an increase was observed for the two ELV markers, TSG101 (+65%) and HSP60 (+441%), at sea level, but not in hypoxia. Training also seemed to decrease the abundance of miR-23a-3p and to increase the abundance of miR-21-5p in hypoxia but not at sea level.

Conclusions

A 6-wk SIT program tended to increase the basal levels of circulating ELVs when performed at sea level but not in hypoxia. In contrast, ELV miRNA cargo seemed to be modulated in hypoxic conditions only. Further research should explore the potential differences in the origin of ELVs between normoxic and local and systemic hypoxic conditions.
Correlated MR spectroscopic imaging of breast cancer to investigate metabolites and lipids: acceleration and compressed sensing reconstruction
Authors: Joy Ajin , Saucedo Andres , Joines Melissa , Lee-Felker Stephanie , Kumar Sumit , Sarma Manoj K , Sayre James , DiNome Maggie , Thomas M Albert
Published: September 2022

Objectives:

The main objective of this work was to detect novel biomarkers in breast cancer by spreading the MR spectra over two dimensions in multiple spatial locations using an accelerated 5D EP-COSI technology.

Methods:

The 5D EP-COSI data were non-uniformly undersampled with an acceleration factor of 8 and reconstructed using group sparsity-based compressed sensing reconstruction. Different metabolite and lipid ratios were then quantified and statistically analyzed for significance. Linear discriminant models based on the quantified metabolite and lipid ratios were generated. Spectroscopic images of the quantified metabolite and lipid ratios were also reconstructed.

Results:

The 2D COSY spectra generated using the 5D EP-COSI technique showed differences among healthy, benign, and malignant tissues in terms of their mean values of metabolite and lipid ratios, especially the ratios of potential novel biomarkers based on unsaturated fatty acids, myo-inositol, and glycine. It is further shown the potential of choline and unsaturated lipid ratio maps, generated from the quantified COSY signals across multiple locations in the breast, to serve as complementary markers of malignancy that can be added to the multiparametric MR protocol. Discriminant models using metabolite and lipid ratios were found to be statistically significant for classifying benign and malignant tumor from healthy tissues.

Conclusions:

Accelerated 5D EP-COSI technique demonstrates the potential to detect novel biomarkers such as glycine, myo-inositol, and unsaturated fatty acids in addition to commonly reported choline in breast cancer, and facilitates metabolite and lipid ratio maps which have the potential to play a significant role in breast cancer detection.

Advances in knowledge:

This study presents the first evaluation of a multidimensional MR spectroscopic imaging technique for the detection of potentially novel biomarkers based on glycine, myo-inositol, and unsaturated fatty acids, in addition to commonly reported choline. Spatial mapping of choline and unsaturated fatty acid ratios with respect to water in malignant and benign breast masses are also shown. These metabolic characteristics may serve as additional biomarkers for improving the diagnostic and therapeutic evaluation of breast cancer.