bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular markers of artemisinin resistance during falciparum malaria elimination in Eastern Myanmar
Authors: Thu Aung Myint , Phyo Aung Pyae , Pateekhum Chanapat , Rae Jade D. , Landier Jordi , Parker Daniel M. , Delmas Gilles , Watthanaworawit Wanitda , McLean Alistair R. D. , Arya Ann , Reyes Ann , Li Xue , Miotto Olivo , Soe Kyaw , Ashley Elizabeth A. , Dondorp Arjen , White Nicholas J. , Day Nicholas P. , Anderson Tim J. C. , Imwong Mallika , Nosten Francois , Smithuis Frank
Published: May 2024

Background

Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013–2019) was characterized.

Methods

Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13—a molecular marker of artemisinin resistance.

Result

The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p < 0.001). In the MDA villages there was no significant change in the K13 proportions before and after MDA. The distribution of different K13 mutations changed substantially; F446I and P441L mutations increased in both MDA and non-MDA villages, while most other K13 mutations decreased. The proportion of C580Y mutations fell from 9.2% (43/467) before MDA to 2.3% (19/813) after MDA (p < 0.001). Similar changes occurred in the 487 villages where MDA was not conducted.

Conclusion

The malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.
Machine learning-based algorithm identifies key mitochondria-related genes in non-alcoholic steatohepatitis
Authors: Dai Longfei , Jiang Renao , Zhan Zhicheng , Zhang Liangliang , Qian Yuyang , Xu Xinjian , Yang Wenqi , Zhang Zhen
Published: May 2024

Background

Evidence suggests that hepatocyte mitochondrial dysfunction leads to abnormal lipid metabolism, redox imbalance, and programmed cell death, driving the onset and progression of non-alcoholic steatohepatitis (NASH). Identifying hub mitochondrial genes linked to NASH may unveil potential therapeutic targets.

Methods

Mitochondrial hub genes implicated in NASH were identified via analysis using 134 algorithms.

Results

The Random Forest algorithm (RF), the most effective among the 134 algorithms, identified three genes: Aldo–keto reductase family 1 member B10 (AKR1B10), thymidylate synthase (TYMS), and triggering receptor expressed in myeloid cell 2 (TREM2). They were upregulated and positively associated with genes promoting inflammation, genes involved in lipid synthesis, fibrosis, and nonalcoholic steatohepatitis activity scores in patients with NASH. Moreover, using these three genes, patients with NASH were accurately categorized into cluster 1, exhibiting heightened disease severity, and cluster 2, distinguished by milder disease activity.

Conclusion

These three genes are pivotal mitochondrial genes implicated in NASH progression.
NIR-activated electrospun nanodetonator dressing enhances infected diabetic wound healing with combined photothermal and nitric oxide-based gas therapy
Authors: Xie Jiajun , Liu Guihua , Chen Rong , Wang Ding , Mai Huaming , Zhong Qiang , Ning Yanhong , Fu Jinlang , Tang Zinan , Xu Yixin , Li Hao , Lei Mingyuan , Cheng Hao , Huang Yuliang , Zhang Yang
Published: May 2024

Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane’s PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague–Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.

Graphical Abstract
Construction of lymph nodes-targeting tumor vaccines by using the principle of DNA base complementary pairing to enhance anti-tumor cellular immune response
Authors: Zha Yongchao , Fu Li , Liu Zonghua , Lin Jiansheng , Huang Linghong
Published: May 2024

Tumor vaccines, a crucial immunotherapy, have gained growing interest because of their unique capability to initiate precise anti-tumor immune responses and establish enduring immune memory. Injected tumor vaccines passively diffuse to the adjacent draining lymph nodes, where the residing antigen-presenting cells capture and present tumor antigens to T cells. This process represents the initial phase of the immune response to the tumor vaccines and constitutes a pivotal determinant of their effectiveness. Nevertheless, the granularity paradox, arising from the different requirements between the passive targeting delivery of tumor vaccines to lymph nodes and the uptake by antigen-presenting cells, diminishes the efficacy of lymph node-targeting tumor vaccines. This study addressed this challenge by employing a vaccine formulation with a tunable, controlled particle size. Manganese dioxide (MnO2) nanoparticles were synthesized, loaded with ovalbumin (OVA), and modified with A50 or T20 DNA single strands to obtain MnO2/OVA/A50 and MnO2/OVA/T20, respectively. Administering the vaccines sequentially, upon reaching the lymph nodes, the two vaccines converge and simultaneously aggregate into MnO2/OVA/A50-T20 particles through base pairing. This process enhances both vaccine uptake and antigen delivery. In vitro and in vivo studies demonstrated that, the combined vaccine, comprising MnO2/OVA/A50 and MnO2/OVA/T20, exhibited robust immunization effects and remarkable anti-tumor efficacy in the melanoma animal models. The strategy of controlling tumor vaccine size and consequently improving tumor antigen presentation efficiency and vaccine efficacy via the DNA base-pairing principle, provides novel concepts for the development of efficient tumor vaccines.

Graphical Abstract
Dual-ROS-scavenging and dual-lingering nanozyme-based eye drops alleviate dry eye disease
Authors: Zhang Wei , Zhao Mengyang , Chu Dandan , Chen Huiying , Cui Bingbing , Ning Qingyun , Wang Xing , Li Zhanrong , Cao Shaokui , Li Jingguo
Published: May 2024

Efficiently removing excess reactive oxygen species (ROS) generated by various factors on the ocular surface is a promising strategy for preventing the development of dry eye disease (DED). The currently available eye drops for DED treatment are palliative, short-lived and frequently administered due to the short precorneal residence time. Here, we developed nanozyme-based eye drops for DED by exploiting borate-mediated dynamic covalent complexation between n-FeZIF-8 nanozymes (n-Z(Fe)) and poly(vinyl alcohol) (PVA) to overcome these problems. The resultant formulation (PBnZ), which has dual-ROS scavenging abilities and prolonged corneal retention can effectively reduce oxidative stress, thereby providing an excellent preventive effect to alleviate DED. In vitro and in vivo experiments revealed that PBnZ could eliminate excess ROS through both its multienzyme-like activity and the ROS-scavenging activity of borate bonds. The positively charged nanozyme-based eye drops displayed a longer precorneal residence time due to physical adhesion and the dynamic borate bonds between phenyboronic acid and PVA or o-diol with mucin. The in vivo results showed that eye drops could effectively alleviate DED. These dual-function PBnZ nanozyme-based eye drops can provide insights into the development of novel treatment strategies for DED and other ROS-mediated inflammatory diseases and a rationale for the application of nanomaterials in clinical settings.

Graphical Abstract
Deep learning imaging phenotype can classify metabolic syndrome and is predictive of cardiometabolic disorders
Authors: Leiby Jacob S. , Lee Matthew E. , Shivakumar Manu , Choe Eun Kyung , Kim Dokyoon
Published: May 2024

Background

Cardiometabolic disorders pose significant health risks globally. Metabolic syndrome, characterized by a cluster of potentially reversible metabolic abnormalities, is a known risk factor for these disorders. Early detection and intervention for individuals with metabolic abnormalities can help mitigate the risk of developing more serious cardiometabolic conditions. This study aimed to develop an image-derived phenotype (IDP) for metabolic abnormality from unenhanced abdominal computed tomography (CT) scans using deep learning. We used this IDP to classify individuals with metabolic syndrome and predict future occurrence of cardiometabolic disorders.

Methods

A multi-stage deep learning approach was used to extract the IDP from the liver region of unenhanced abdominal CT scans. In a cohort of over 2,000 individuals the IDP was used to classify individuals with metabolic syndrome. In a subset of over 1,300 individuals, the IDP was used to predict future occurrence of hypertension, type II diabetes, and fatty liver disease.

Results

For metabolic syndrome (MetS) classification, we compared the performance of the proposed IDP to liver attenuation and visceral adipose tissue area (VAT). The proposed IDP showed the strongest performance (AUC 0.82) compared to attenuation (AUC 0.70) and VAT (AUC 0.80). For disease prediction, we compared the performance of the IDP to baseline MetS diagnosis. The models including the IDP outperformed MetS for type II diabetes (AUCs 0.91 and 0.90) and fatty liver disease (AUCs 0.67 and 0.62) prediction and performed comparably for hypertension prediction (AUCs of 0.77).

Conclusions

This study demonstrated the superior performance of a deep learning IDP compared to traditional radiomic features to classify individuals with metabolic syndrome. Additionally, the IDP outperformed the clinical definition of metabolic syndrome in predicting future morbidities. Our findings underscore the utility of data-driven imaging phenotypes as valuable tools in the assessment and management of metabolic syndrome and cardiometabolic disorders.
Advances and challenges of the cell-based therapies among diabetic patients
Authors: Raoufinia Ramin , Rahimi Hamid Reza , Saburi Ehsan , Moghbeli Meysam
Published: May 2024

Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet and stem cell transplantation technologies used in clinical settings, highlighting their strengths and limitations. We also discussed immunomodulatory strategies employed in cell therapies. Therefore, this review highlights key progresses that pave the way to design transformative treatments to improve the life quality among diabetic patients.
IL-2RG as a possible immunotherapeutic target in CRC predicting poor prognosis and regulated by miR-7-5p and miR-26b-5p
Authors: Gharib Ehsan , Rejali Leili , Piroozkhah Moein , Zonoobi Elham , Nasrabadi Parinaz Nasri , Arabsorkhi Zahra , Baghdar Kaveh , Shams Elahe , Sadeghi Amir , Kuppen Peter J. K. , Salehi Zahra , Nazemalhosseini-Mojarad Ehsan
Published: May 2024

Despite advances in treatment strategies, colorectal cancer (CRC) continues to cause significant morbidity and mortality, with mounting evidence a close link between immune system dysfunctions issued. Interleukin-2 receptor gamma (IL-2RG) plays a pivotal role as a common subunit receptor in the IL-2 family cytokines and activates the JAK-STAT pathway. This study delves into the role of Interleukin-2 receptor gamma (IL-2RG) within the tumor microenvironment and investigates potential microRNAs (miRNAs) that directly inhibit IL-2RG, aiming to discern their impact on CRC clinical outcomes. Bioinformatics analysis revealed a significant upregulation of IL-2RG mRNA in TCGA-COAD samples and showed strong correlations with the infiltration of various lymphocytes. Single-cell analysis corroborated these findings, highlighting IL-2RG expression in critical immune cell subsets. To explore miRNA involvement in IL-2RG dysregulation, mRNA was isolated from the tumor tissues and lymphocytes of 258 CRC patients and 30 healthy controls, and IL-2RG was cloned into the pcDNA3.1/CT-GFP-TOPO vector. Human embryonic kidney cell lines (HEK-293T) were transfected with this construct. Our research involved a comprehensive analysis of miRPathDB, miRWalk, and Targetscan databases to identify the miRNAs associated with the 3′ UTR of human IL-2RG. The human microRNA (miRNA) molecules, hsa-miR-7-5p and hsa-miR-26b-5p, have been identified as potent suppressors of IL-2RG expression in CRC patients. Specifically, the downregulation of hsa-miR-7-5p and hsa-miR-26b-5p has been shown to result in the upregulation of IL-2RG mRNA expression in these patients. Prognostic evaluation of IL-2RG, hsa-miR-7-5p, and hsa-miR-26b-5p, using TCGA-COAD data and patient samples, established that higher IL-2RG expression and lower expression of both miRNAs were associated with poorer outcomes. Additionally, this study identified several long non-coding RNAs (LncRNAs), such as ZFAS1, SOX21-AS1, SNHG11, SNHG16, SNHG1, DLX6-AS1, GAS5, SNHG6, and MALAT1, which may act as competing endogenous RNA molecules for IL2RG by sequestering shared hsa-miR-7-5p and hsa-miR-26b-5p. In summary, this investigation underscores the potential utility of IL-2RG, hsa-miR-7-5p, and hsa-miR-26b-5p as serum and tissue biomarkers for predicting CRC patient prognosis while also offering promise as targets for immunotherapy in CRC management.

Graphical Abstract
Rehabilitation of back pain in the pediatric population: a mixed studies systematic review
Authors: Yu Hainan , Southerst Danielle , Wong Jessica J. , Verville Leslie , Connell Gaelan , Ead Lauren , Mior Silvano , Hestbaek Lise , Swain Michael , Brunton Ginny , Shearer Heather M. , Papaconstantinou Efrosini , To Daphne , Germann Darrin , Pohlman Katie , Cedraschi Christine , Cancelliere Carol
Published: May 2024

Background

A significant proportion of children and adolescents experience back pain. However, a comprehensive systematic review on the effectiveness of rehabilitation interventions is lacking.

Objectives

To evaluate benefits and harms of rehabilitation interventions for non-specific low back pain (LBP) or thoracic spine pain in the pediatric population.

Methods

Seven bibliographic electronic databases were searched from inception to June 16, 2023. Moreover, reference lists of relevant studies and systematic reviews, three targeted websites, and the WHO International Clinical Trials Registry Platform were searched. Paired reviewers independently conducted screening, assessed risk of bias, and extracted data related to study characteristics, methodology, subjects, and results. Certainty of evidence was evaluated based on the GRADE approach.

Results

We screened 8461 citations and 307 full-text articles. Ten quantitative studies (i.e., 8 RCTs, 2 non-randomized clinical trials) and one qualitative study were included. With very low to moderate certainty evidence, in adolescents with LBP, spinal manipulation (1–2 sessions/week over 12 weeks, 1 RCT) plus exercise may be associated with a greater likelihood of experiencing clinically important pain reduction versus exercise alone; and group-based exercise over 8 weeks (2 RCTs and 1 non-randomized trial) may reduce pain intensity. The qualitative study found information provided via education/advice and compliance of treatment were related to effective treatment. No economic studies or studies examining thoracic spine pain were identified.

Conclusions

Spinal manipulation and group-based exercise may be beneficial in reducing LBP intensity in adolescents. Education should be provided as part of a care program. The overall evidence is sparse. Methodologically rigorous studies are needed.

Trial registration

CRD42019135009 (PROSPERO)
Systematic investigation of the material basis, effectiveness and safety of Thesium chinense Turcz. and its preparation Bairui Granules against lung inflammation
Authors: Peng Guang-Cheng , Hao Jin-Hua , Guan Yue-Qin , Wang Ying-Yue , Liu Ming-Jie , Li Guo-Hui , Xu Zhen-Peng , Wen Xue-Sen , Shen Tao
Published: May 2024

Background

Thesium chinense Turcz. (Named as Bai Rui Cao in Chinese) and its preparations (e.g., Bairui Granules) have been used to treat inflammatory diseases, such as acute mastitis, lobar pneumonia, tonsillitis, coronavirus disease 2019 (COVID-19), and upper respiratory tract infection. However, the material basis, pharmacological efficiency, and safety have not been illustrated.

Methods

Anti-inflammatory activity-guided isolation of constituents has been performed using multiple column chromatography, and their structures were elucidated by NMR spectroscopy and ECD calculations. The inhibitory effects on lung inflammation and safety of the crude ethanol extract (CE), Bairui Granules (BG), and the purified active constituents were evaluated using lipopolysaccharide (LPS)-stimulated acute lung inflammation (ALI) mice model or normal mice.

Results

Seven new compounds (1–7) and fifty-six known compounds (8–63) were isolated from T. chinense, and fifty-four were reported from this plant for the first time. The new flavonoid glycosides 1–2, new fatty acids 4–5, new alkaloid 7 as well as the known constituents including flavonoid aglycones 8–11, lignans 46–54, alkaloids 34 and 45, coumarins 57, phenylpropionic acids 27, and simple aromatic compounds 39, 44 and 58 exhibited anti-inflammatory activity. Network pharmacology analysis indicated that anti-inflammation of T. chinense was attributed to flavonoids and alkaloids by regulating inflammation-related proteins (e.g., TNF, NF-κB, TGF-β). Furthermore, constituents of T. chinense including kaempferol-3-O-glucorhamnoside (KN, also named as Bairuisu I, 19), astragalin (AG, Bairuisu II, 12), and kaempferol (KF, Bairuisu III, 8), as well as CE and BG could alleviate lung inflammation caused by LPS in mice by preventing neutrophils infiltration and the expression of the genes for pro-inflammatory cytokines NLRP3, caspase-1, IL-1β, and COX-2. After a 28-day subacute toxicity test, BG at doses of 4.875 g/kg and 9.750 g/kg (equivalent to onefold and twofold the clinically recommended dose) and CE at a dose of 11.138 g/kg (equivalent to fourfold the clinical dose of BG) were found to be safe and non-toxic.

Conclusions

The discovery of sixty-three constituents comprehensively illustrated the material basis of T. chinense. T. chinense and Bairui Granules could alleviate lung inflammation by regulating inflammation-related proteins and no toxicity was observed under the twofold of clinically used doses.
Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives
Authors: Lin Hao , Liu Chaxian , Hu Ankang , Zhang Duanwu , Yang Hui , Mao Ying
Published: May 2024

Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite the established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, and the exploration of emerging modalities such as immunotherapy and integration of medicine and engineering technology therapy, the efficacy of these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny of the inhibitory and immunosuppressive milieu within GBM has underscored the significance of cellular constituents of the GBM microenvironment and their interactions with malignant cells and neurons. Novel immune and targeted therapy strategies have emerged, offering promising avenues for advancing GBM treatment. One pivotal mechanism orchestrating immunosuppression in GBM involves the aggregation of myeloid-derived suppressor cells (MDSCs), glioma-associated macrophage/microglia (GAM), and regulatory T cells (Tregs). Among these, MDSCs, though constituting a minority (4–8%) of CD45+ cells in GBM, play a central component in fostering immune evasion and propelling tumor progression, angiogenesis, invasion, and metastasis. MDSCs deploy intricate immunosuppressive mechanisms that adapt to the dynamic tumor microenvironment (TME). Understanding the interplay between GBM and MDSCs provides a compelling basis for therapeutic interventions. This review seeks to elucidate the immune regulatory mechanisms inherent in the GBM microenvironment, explore existing therapeutic targets, and consolidate recent insights into MDSC induction and their contribution to GBM immunosuppression. Additionally, the review comprehensively surveys ongoing clinical trials and potential treatment strategies, envisioning a future where targeting MDSCs could reshape the immune landscape of GBM. Through the synergistic integration of immunotherapy with other therapeutic modalities, this approach can establish a multidisciplinary, multi-target paradigm, ultimately improving the prognosis and quality of life in patients with GBM.
Fertility-sparing surgery in children and adolescents with borderline ovarian tumors: a retrospective study
Authors: Zhao Jiayuan , Wang Dan , Wang Ruojiao , He Yonglan , Jia Congwei , Pan Lingya , Ma Shuiqing , Wu Ming , Wang Weidi , Cheng Xinghan , Yang Junjun , Xiang Yang
Published: May 2024

Objective

To describe the characteristics of children and adolescents with borderline ovarian tumors (BOTs) and evaluate the efficacy and safety of fertility-sparing surgery (FSS) in these patients.

Methods

Patients with BOTs younger than 20 years who underwent FSS were included in this study.

Results

A total of 34 patients were included, with a median patient age of 17 (range, 3–19) years; 97.1% (33/34) of cases occurred after menarche. Of the patients, 82.4% had mucinous borderline tumors (MBOTs), 14.7% had serous borderline tumors (SBOTs), and 2.9% had seromucinous borderline tumor (SMBOT). The median tumor size was 20.4 (range, 8–40)cm. All patients were at International Federation of Gynecology and Obstetrics stage I and all underwent FSS: cystectomy (unilateral ovarian cystectomy, UC, 14/34, 41.2% and bilateral ovarian cystectomy, BC, 1/34, 2.9%), unilateral salpingo-oophorectomy (USO; 18/34; 52.9%), or USO + contralateral ovarian cystectomy (1/34; 2.9%). The median follow-up time was 65 (range, 10–148) months. Recurrence was experienced by 10 of the 34 patients (29.4%). One patient with SBOT experienced progression to low-grade serous carcinoma after the third relapse. Two patients had a total of four pregnancies, resulting in three live births. The recurrence rate of UC was significantly higher in MBOTs than in USO (p = 0.005). The 5-year disease-free survival rate was 67.1%, and the 5-year overall survival rate was 100%.

Conclusions

Fertility-sparing surgery is feasible and safe for children and adolescents with BOTs. For patients with MBOTs, USO is recommended to lower the risk of recurrence.
Approaches and experiences implementing remote, electronic consent at the Leeds Clinical Trials Research Unit
Authors: Cragg William J , Taylor Chris , Moreau Lauren , Collier Howard , Gilberts Rachael , McKigney Niamh , Dennett Joanna , Graca Sandra , Wheeler Ian , Bishop Liam , Barrett Adam , Hartley Suzanne , Greenwood John P , Swoboda Peter P , Farrin Amanda J
Published: May 2024

Background

Use of electronic methods to support informed consent (‘eConsent’) is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK.

Main text

We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system’s generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system.

We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake.

Conclusions

We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach.
Insecticidal activity of fluralaner (Exzolt®) administered to Gallus gallus domesticus against triatomines (Hemiptera, Reduviidae, Triatominae)
Authors: Pereira Luanderson Cardoso , Pereira Nathalie de Sena , Barbosa da Silva Andressa Noronha , Bezerra Clarice de Freitas , Sousa Kivia Millana de , Fagundes Neto João Ciro , Sampaio George Harisson Felinto , Brito Carlos Ramon do Nascimento , Souza Rita de Cássia Moreira , Galvão Lúcia Maria da Cunha , Câmara Antônia Claudia Jácome da , Nascimento Manuela Sales Lima , Guedes Paulo Marcos Matta
Published: May 2024

Background

Triatoma infestans, Triatoma brasiliensis, Triatoma pseudomaculata and Rhodnius prolixus are vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. Chickens serve as an important blood food source for triatomines. This study aimed to assess the insecticidal activity of fluralaner (Exzolt®) administered to chickens against triatomines (R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata).

Methods

Twelve non-breed chickens (Gallus gallus domesticus) were randomized based on weight into three groups: negative control (n = 4); a single dose of 0.5 mg/kg fluralaner (Exzolt®) (n = 4); two doses of 0.5 mg/kg fluralaner (Exzolt®) (n = 4). Nymphs of 3rd, 4th and 5th instars of R. prolixus, T. infestans, T. brasiliensis and T. pseudomaculata (all n = 10) were allowed to feed on chickens before treatment, and at intervals of 1, 7, 14, 21, 28, 35 and 56 days after treatment, with insect mortality determined.

Results

Treatment with two doses of fluralaner showed higher insecticidal efficacy against R. prolixus, T. infestans and T. brasiliensis compared to the single-dose treatment. Similar insecticidal efficacy was observed for T. pseudomaculata for one and two doses of fluralaner. Insecticidal activity of fluralaner (Exzolt®) against triatomine bugs was noted up to 21 and 28 days after treatment with one and two doses of fluralaner, respectively.

Conclusions

The results demonstrate that treatment of chickens with fluralaner (Exzolt®) induces insecticidal activity against triatomines for up to 28 days post-treatment, suggesting its potential use as a control strategy for Chagas disease in endemic areas.

Graphical Abstract
miR-449a disturbs atherosclerotic plaque stability in streptozotocin and high-fat diet-induced diabetic mice by targeting CEACAM1
Authors: Yu Jie , Liu Han , Chen Yu , Wang Ling , Chen Peng , Zhao Yue , Ou Chunxia , Chen Wei , Hu Jie , Wang Yu , Wang Yan
Published: May 2024

Background

Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS.

Methods

We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE−/−) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay.

Results

miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs.

Conclusion

These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1.
Stenting for subclavian steal phenomenon to restore cerebral perfusion due to acute carotid occlusion following carotid endarterectomy: a case report
Authors: Hirota Shin , Yoshimura Masataka , Cho Junshi , Hayashi Toshihiko , Kaneoka Azumi , Ito Kei , Kiyokawa Juri , Yamamoto Shinji
Published: May 2024

Background

Perioperative symptomatic carotid artery occlusion after carotid endarterectomy is a rare complication. In this study, we present a case of symptomatic acute carotid artery occlusion that occurred after carotid endarterectomy in a patient with coexistent subclavian artery steal phenomenon, which was successfully treated with subclavian artery stenting.

Case presentation

A 57-year-old East Asian female presented with stenosis in the left common carotid artery and left subclavian artery along with subclavian steal. The proximal segment of the left anterior cerebral artery was hypoplastic, and the posterior communicating arteries on both sides were well-developed. Left internal carotid artery stenosis progressed during the follow-up examination; therefore, left carotid endarterectomy was performed. On the following day, symptoms of cerebral perfusion deficiency appeared due to occlusion of the left carotid artery. The stenotic origin of the left common carotid artery and the suspected massive thrombus in the left carotid artery posed challenges to carotid revascularization. Therefore, left subclavian artery stenting for the subclavian steal phenomenon was determined to be the best option for restoring cerebral blood flow to the whole brain. Her symptoms improved after the procedure, and the postprocedural workup revealed improved cerebral blood flow.

Conclusion

Subclavian artery stenting is safe and may be helpful in patients with cerebral perfusion deficiency caused by intractable acute carotid occlusion coexisting with the subclavian steal phenomenon. Revascularization of asymptomatic subclavian artery stenosis is generally not recommended. However, cerebral circulatory insufficiency as a comorbidity may be worth considering.
The role of validation in optimization models for forest management
Authors: Janová Jitka , Bödeker Kai , Bingham Logan , Kindu Mengistie , Knoke Thomas
Published: May 2024

Key message

A validation convention can be established for forest management optimization models. It consists of (1) the delivery of face validation, (2) performing at least one other validation technique, and (3) an explicit discussion of how the optimization model fulfills the stated purpose. Validation by potential users or external experts is of high importance.

Context

Optimization modeling has long assisted the management of forest ecosystems, but the credibility of these models has always been debated with criticisms concerning data quality, failures to include relevant processes in the scope of models, and the inclusion of unrealistic assumptions. Validation is widely considered to be crucial to establishing the credibility of models in general, but how to validate optimization models in particular represents a permanent question generally in operations research.

Aims

We aim to synthesize practical recommendations for the development of validation frameworks in the optimization modeling for forest management.

Methods

We selected a sample of 46 studies devoted to optimization models to be applied in practice, analysed the contents with respect to validation, and provided a critical review.

Results

We (1) clarified the meaning and usage of different validation-related terms that are commonly encountered in the literature, (2) identified and categorised the various methods and frameworks that are used to demonstrate model credibility, and (3) derived organizing principles that helped to suggest improvements in validation frameworks.

Conclusions

A practical validation convention can be established and we suggest the convention to consist of three stages. By providing structured and consistent information about validation processes, researchers in forest management optimization can better demonstrate the credibility of their work to readers and potential users.
Dual-polarized IRS-assisted wireless network: relative phase modulation
Authors: Munawar Muteen , Lee Kyungchun
Published: May 2024

The metasurface is a promising technology that can help next-generation wireless communication systems not only improve the signal-to-noise ratio (SNR), but also increase security and mitigate interference. Further, introducing dual polarization (DP) in a metasurface can enhance its capabilities with polarization diversity, polarization multiplexing, and polarization-switched modulation. In this paper, we study a DP-metasurface-assisted single-user wireless communication system and propose a novel scheme that can improve the spectral efficiency (SE) and bit-error-rate (BER) performance compared to those of conventional schemes by exploiting the orthogonal property of dual-polarized waves. We employ the DP metasurface to increase the SNR at the receiver and create a specific phase difference between the polarized signals by controlling the transmit precoder and the phases of the metasurface reflecting elements representing some modulated bits. At the receiver, we use the recovered phase information to realign the modulated symbols in both polarizations, which are then added coherently. The simulation results demonstrate that the proposed scheme achieves significantly higher SE and BER performance than those of some closely related works.
Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis
Authors: Zeng Longjin , Zhang Longyao , Yin Chenrui , Chen Xu , Chen Xiewan , Sun Lingyou , Sun Jianguo
Published: May 2024

Background

Previous studies suggested that zinc finger protein 536 (ZNF536) was abundant in the central brain and regulated neuronal differentiation. However, the role of ZNF536 in cancer has remained unclear.

Methods

ZNF536 mutation, copy number alteration, DNA methylation, and RNA expression were explored using public portals. Data from The Cancer Genome Atlas (TCGA) were utilized to analyze pathways and tumor microenvironment (TME), with a focus on prognosis in both TCGA and immunotherapy pan-cancer cohorts. Methylated ZNF536 from small cell lung cancer (SCLC) cell lines were utilized to train with probes for conducting enrichment analysis. Single-cell RNA profile demonstrated the sublocalization and co-expression of ZNF536, and validated its targets by qPCR.

Results

Genetic alterations in ZNF536 were found to be high-frequency and a single sample could harbor different variations. ZNF536 at chromosome 19q12 exerted a bypass effect on CCNE1, supported by CRISPR data. For lung cancer, ZNF536 mutation was associated with longer survival in primary lung adenocarcinoma (LUAD), but its prognosis was poor in metastatic LUAD and SCLC. Importantly, ZNF536 mutation and amplification had opposite prognoses in Stand Up To Cancer-Mark Foundation (SU2C-MARK) LUAD cohort. ZNF536 mutation altered the patterns of genomic alterations in tumors, and had distinct impacts on the signaling pathways and TME compared to ZNF536 amplification. Additionally, ZNF536 expression was predominantly in endocrine tumors and brain tissues. High-dimensional analysis supported this finding and further revealed regulators of ZNF536. Considering that the methylation of ZNF536 was involved in the synaptic pathway associated with neuroendocrine neoplasms, demonstrating both diagnostic and prognostic value. Moreover, we experimentally verified ZNF536 upregulated neuroendocrine markers.

Conclusions

Our results showed that ZNF536 alterations in cancer, including variations in copy number, mutation, and methylation. We proved the involvement of ZNF536 in neuroendocrine regulation, and identified highly altered ZNF536 as a potential biomarker for immunotherapy.
Human pan-cancer analysis of the predictive biomarker for the CDKN3
Authors: Chen Yingjun , Li Dai , Sha Kaihui , Zhang Xuezhong , Liu Tonggang
Published: May 2024

Background

Cell cycle protein-dependent kinase inhibitor protein 3 (CDKN3), as a member of the protein kinase family, has been demonstrated to exhibit oncogenic properties in several tumors. However, there are no pan-carcinogenic analyses for CDKN3.

Methods

Using bioinformatics tools such as The Cancer Genome Atlas (TCGA) and the UCSC Xena database, a comprehensive pan-cancer analysis of CDKN3 was conducted. The inverstigation encompassed the examination of CDKN3 function actoss 33 different kinds of tumors, as well as the exploration of gene expressions, survival prognosis status, clinical significance, DNA methylation, immune infiltration, and associated signal pathways.

Results

CDKN3 was significantly upregulated in most of tumors and correlated with overall survival (OS) of patients. Methylation levels of CDKN3 differed significantly between tumors and normal tissues. In addition, infiltration of CD4 + T cells, cancer-associated fibroblasts, macrophages, and endothelial cells were associated with CDKN3 expression in various tumors. Mechanistically, CDKN3 was associated with P53, PI3K-AKT, cell cycle checkpoints, mitotic spindle checkpoint, and chromosome maintenance.

Conclusion

Our pan-cancer analysis conducted in the study provides a comprehensive understanding of the involvement of CDKN3 gene in tumorigenesis. The findings suggest that targeting CDKN3 may potentially lead to novel therapeutic strategies for the treatment of tumors.
Evaluating German PISA stratification designs: a simulation study
Authors: Mang Julia , Küchenhoff Helmut , Meinck Sabine
Published: May 2024

Stratification is an important design feature of many studies using complex sampling designs and it is often used in large-scale assessment (LSA) studies, such as the Programme for International Student Assessment (PISA), for two main reasons. First, stratification variables that achieve a high between and low within strata variance can improve the efficiency of a survey design. Second, stratification allows one to, explicitly or implicitly, control for sample sizes across subpopulations. It ensures that some parts of a population are in the sample in predetermined proportions. In this study, we determine through simulation which stratification scheme is best for PISA in Germany. For this, we consider the constraints imposed by the international sampling design, the available information about schools, and specific national characteristics of the German educational system. We examine seven different stratification designs selected based on scenarios used in past LSAs in Germany and theoretical considerations for future implementations. The chosen scenarios were compared with two reference scenarios: (1) an unstratified design and (2) a synthetic optimal stratification design. The simulation study reveals that the stratification design currently applied in PISA produces satisfactory results regarding sampling precision. The present stratification design is based on Germany's federal states and school types. However, this approach leads to small strata, which has been problematic for estimating sampling variance in previous cycles. Therefore, alternative stratification scenarios were considered and, in addition to overcoming the small-strata problem, also led to smaller standard errors for estimates of student mean performance in mathematics, science, and reading. As a result of this study, we recommend considering three different stratification designs for Germany in future cycles of PISA. These recommendations aim to: (1) improve the sampling efficiency while keeping the sample size constant, (2) follow a sound methodological approach, and (3) make conservative and cautious changes while maintaining a reflection of the structure of the German federal school system with different school types. These suggestions include a reinvented stratification of grouped German federal states and designs with school types as explicit stratifiers and federal states as implicit stratifiers.
Activated clotting time-guided heparinization during open AAA surgery: a pilot study
Authors: Roosendaal Liliane C. , Hoebink Max , Wiersema Arno M. , Blankensteijn Jan D. , Jongkind Vincent
Published: May 2024

Background

Arterial thrombo-embolic complications (TEC) are still common during and after non-cardiac arterial procedures (NCAP). While unfractionated heparin has been used during NCAP for more than 70 years to prevent TEC, there is no consensus regarding the optimal dosing strategy. The aim of this pilot study was to test the effectiveness and feasibility of an activated clotting time (ACT)-guided heparinization protocol during open abdominal aortic aneurysm (AAA) surgery, in anticipation of a randomized controlled trial (RCT) investigating if ACT-guided heparinization leads to better clinical outcomes compared to a single bolus of 5000 IU of heparin.

Methods

A prospective multicentre pilot study was performed. All patients undergoing elective open repair for an AAA (distal of the superior mesenteric artery) between March 2017 and January 2020 were included. Two heparin dosage protocols were compared: ACT-guided heparinization with an initial dose of 100 IU/kg versus a bolus of 5000 IU. The primary outcome was the effectiveness and feasibility of an ACT-guided heparinization protocol with an initial heparin dose of 100 IU/kg during open AAA surgery. Bleeding complications, TEC, and mortality were investigated for safety purposes.

Results

A total of 50 patients were included in the current study. Eighteen patients received a single dose of 5000 IU of heparin and 32 patients received 100 IU/kg of heparin with additional doses based on the ACT. All patients who received the 100 IU/kg dosing protocol reached the target ACT of > 200 s. In the 5000 IU group, TEC occurred in three patients (17%), versus three patients (9.4%) in the 100 IU/kg group. Bleeding complications were found in six patients (33%) in the 5000 IU group and in 9 patients (28%) in the 100 IU/kg group. No mortality occurred in either group.

Conclusions

This pilot study demonstrated that ACT-guided heparinization with an initial dose of 100 IU/kg appears to be feasible and leads to adequate anticoagulation levels. Further randomized studies seem feasible and warranted to determine whether ACT-guided heparinization results in better outcomes after open AAA repair.
Connectedness of cryptocurrency markets to crude oil and gold: an analysis of the effect of COVID-19 pandemic
Authors: Foroutan Parisa , Lahmiri Salim
Published: May 2024

The notion that investors shift to gold during economic market crises remains unverified for many cryptocurrency markets. This paper investigates the connectedness between the 10 most traded cryptocurrencies and gold as well as crude oil markets pre-COVID-19 and during COVID-19. Through the application of various statistical techniques, including cointegration tests, vector autoregressive models, vector error correction models, autoregressive distributed lag models, and Granger causality analyses, we explore the relationship between these markets and assess the safe-haven properties of gold and crude oil for cryptocurrencies. Our findings reveal that during the COVID-19 pandemic, gold is a strong safe-haven for Bitcoin, Litecoin, and Monero while demonstrating a weaker safe-haven potential for Bitcoin Cash, EOS, Chainlink, and Cardano. In contrast, gold only exhibits a strong safe-haven characteristic before the pandemic for Litecoin and Monero. Additionally, Brent crude oil emerges as a strong safe-haven for Bitcoin during COVID-19, while West Texas Intermediate and Brent crude oils demonstrate weaker safe-haven properties for Ether, Bitcoin Cash, EOS, and Monero. Furthermore, the Granger causality analysis indicates that before the COVID-19 pandemic, the causal relationship predominantly flowed from gold and crude oil toward the cryptocurrency markets; however, during the COVID-19 period, the direction of causality shifted, with cryptocurrencies exerting influence on the gold and crude oil markets. These findings provide subtle implications for policymakers, hedge fund managers, and individual or institutional cryptocurrency investors. Our results highlight the need to adapt risk exposure strategies during financial turmoil, such as the crisis precipitated by the COVID-19 pandemic.