bluuebunny/crossref_metadata_2025 huggingface dataset:
Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study
Authors: Qin Shukui , Wang Yusheng , Yao Jun , Liu Yanyan , Yi Tienan , Pan Yueyin , Chen Zhendong , Zhang Xizhi , Lu Jin , Yu Junyan , Zhang Yanjun , Cheng Peng , Mao Yong , Zhang Jian , Fang Meiyu , Zhang Yanming , Lv Jing , Li Runzi , Dou Ning , Tang Qian , Ma Jun
Published: June 2024

Background:

Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis.

Objectives:

This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors.

Design:

A multicenter, randomized, double-blind, placebo-controlled, phase II study.

Methods:

Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles.

Results:

Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0–69.3); odds ratio = 10.44 (95% CI: 2.82–38.65); p value (nominal) based on the Cochran–Mantel–Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo.

Conclusion:

Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors.

Trial registration:

ClinicalTrials.gov identifier: NCT03976882.
Causal Relationships of Ligamentous Injuries in the Knee on Corticospinal Tract Structure: A Mendelian Randomization Analysis
Authors: Yu Le , Tao Weichu , Jin Zhengbiao , Li Yi , Xue Xiao’ao , Wang Ru , Hua Yinghui
Published: June 2024

Background:

The association between ligamentous knee injuries and corticospinal tract (CST) structure has attracted attention; however, any causal relationship remains uncertain. We performed Mendelian randomization (MR) analysis to identify the causal effects of ligamentous knee injuries on the CST.

Hypothesis:

Ligamentous knee injuries impair CST microstructure (ie, by reducing fractional anisotropy [FA] and increasing mean diffusivity [MD]).

Study Design:

MR analysis.

Level of Evidence:

Level 2.

Methods:

MR uses genetic variants as instrumental variables to infer causal relationships between exposures and outcomes. Summary data for ligamentous injuries in knee and CST structure were obtained from genome-wide association study datasets. Significant and independent (5 × 10−6; r2 < 0.001; 10,000 kb) single-nucleotide polymorphisms were extracted for MR analysis. Three methods for MR analysis were used (hypothesis-driven 1-tailed inverse variance weighted, MR-Egger, and weighted median), and sensitivity analyses were conducted to test reliability and stability.

Results:

Results from 3 MR methods consistently demonstrated that ligamentous knee injuries increased MD of the right CST (β, 0.063; 90% CI, 0.003-0.123; P = 0.04), and weak statistical significance suggested increased MD of the left CST (β, 0.060; 90% CI, -0.002 to -0.121; P = 0.05). However, no significant causal relationships were observed in CST FA, and no significant pleiotropy or heterogeneity was observed. Sensitivity analysis utilizing 2-tailed tests had no significant associations between ligamentous knee injuries and changes in CST structure.

Conclusion:

There is statistically weak genetic evidence that corticospinal pathway abnormalities may evolve after ligamentous knee injuries, which manifests as abnormally organized neurites.

Clinical Relevance:

Ligamentous knee injuries require attention not only to damage to the structure of the knee joint itself but also to the process of maladaptive neuroplasticity that leads to structural and functional changes of the CST; novel interventions that target the corticospinal pathway may provide subsequent treatment of ligamentous knee injuries.
Integrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine
Authors: Zeidan Amer M. , Bewersdorf Jan Philipp , Hasle Vanessa , Shallis Rory M. , Thompson Ethan , de Menezes Daniel Lopes , Rose Shelonidta , Boss Isaac , Halene Stephanie , Haferlach Torsten , Fox Brian A.
Published: June 2024

Background:

TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53-mutated AML/HR-MDS is not well defined.

Objectives:

To define the genetic, epigenetic, and immunologic landscape of TP53-mutant and TP53 wild-type AML and HR-MDS patients.

Design:

Post hoc analysis of TP53-mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab.

Methods:

We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53-mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial.

Results:

Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53-mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53-mutant samples suggesting a novel therapeutic target.

Conclusion:

This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53-mutant AML/HR-MDS with mono- or multihit TP53 mutation status.

Trial registration:

FUSION trial (NCT02775903).
Enhancing student experience in remote computer programming course practice: A case of the Java language
Authors: Kaur Harpreet , Kaur Kuljit , Kaur Kamaljit
Published: June 2024

The increasing availability of remote education opportunities enables students to access different types of study programs limited by the dimensions of a classroom. Remote learning has been accredited as an effective technique for delivering education to students and teachers globally. However, some academic disciplines such as Computer Science are abounding with many challenges in practicing programming tasks in remote settings. This research aims to understand the students’ existing setup for practicing JAVA programming in remote settings and proposes an intervention to help students get appropriate hints to fix compiler errors. The proposed solution has implications for both students and teachers, as it is under the teacher’s direct observation. The teacher can monitor the content according to students’ needs, which may potentially save them from teaching challenges. To formulate our study, we first surveyed to understand the challenges that students face in JAVA programming when trying to fix errors in a remote setting. Then, based on the results of the first survey and prior experience of conducting programming course practicals along with the existing literature, the proposed web portal was created and presented to the students to fix errors. An experiment was conducted to evaluate the proposed setup followed by a student attitude survey. The results show the portal’s leverage in reducing the time required to fix errors and the number of compilation attempts. The survey indicates a positive response.
Three cases of African tick bite fever diagnosed in Quebec City: A case series
Authors: Caudrelier Nicolas , Dionne Marie-Claude
Published: June 2024

African tick bite fever is a rickettsiosis of the spotted fever group that is endemic to sub-Saharan Africa and the Caribbean. It is characterized by eschars at the inoculation sites and a maculopapular rash which may be purpuric. We describe three cases that were diagnosed in Quebec City.
Rocky Mountain spotted fever contracted along a Canadian road trip: A case report
Authors: King Aliyah , Spurr Alison , Bose Reetesh
Published: June 2024

Rocky Mountain spotted fever, a potentially fatal tick-borne disease thought to be confined to specific climates and geographic locations, is expanding its reach due to climate change. This is demonstrated by a 73-year-old woman who contracted Rocky Mountain spotted fever outside endemic areas during travel in Canada. Presenting with fevers, arthralgia, weakness, non-bloody diarrhea, conjunctivitis, mild cough, and a rash, this patient was initially started on moxifloxacin (400 mg PO/day) for suspected pneumonia. Treatment was changed to doxycycline (100 mg PO twice daily for 7 days) after dermatology was consulted, and Rocky Mountain spotted fever was thought to be higher on the differential. Rocky Mountain spotted fever was confirmed, and the patient responded well to antibiotics, improving by discharge. The disease’s expansion into previously thought nonendemic areas is thought to be linked to milder winters and more extreme dry summers, facilitating pathogen development and tick lineage expansion.
Acute myocardial infarction following “dry scooping” of a pre-workout supplement in a healthy young man of African origin: A case report
Authors: Pallangyo Pedro , Bhalia Smita V , Komba Makrina , Mkojera Zabella S , Manji Eva S , Millinga Jalack , Gandye Yona , Kisenge Peter R
Published: June 2024

Dry scooping, a rather risky act of consuming undiluted pre-workout protein powder hoping for a more pronounced energy surge, is increasingly becoming a fitness trend worldwide. A previously healthy 25-year-old man of African origin presented with acute onset of crushing mid-sternal chest pain for 4 h. His symptoms began about an hour following completion of his 2-h exercise regimen at the gym. He had an unremarkable past medical history except for an 8-month consumption of a pre-workout supplement as part of his gym routine. He claimed to have adhered to the manufacturer’s recommended method of using the supplement, except for 3 days prior to presentation when he started “dry scooping” following the viewing of a video advocating such practice from his fitness WhatsApp group. Cardiac evaluation revealed features in keeping with diagnosis of anterolateral ST-elevation myocardial infarction. Emergency coronary angiography revealed a thrombotic lesion completely occluding the proximal left anterior descending coronary artery with TIMI 0 flow distally. After successful balloon angioplasty, a drug-eluting stent was implanted successfully, restoring TIMI 3 flow to the proximal left anterior descending coronary artery. This case report aims to raise awareness among both clinicians and the general public regarding the pervasiveness of pre-workout supplements, improper methods of consumption, and the potential life-threatening repercussions of misuse.
Nocardia brasiliensis Pyomyositis in an Immunocompetent Patient Following Gardening Activity
Authors: Rehman Aliya , Olayiwola Ayoola , Vu Christine A. , Bhatt Parjanya , Joseph Joelle-Ann , Ayoade Folusakin
Published: June 2024

Nocardia pyomyositis in immunocompetent patients is a rare occurrence. The diagnosis may be missed or delayed with the risk of progressive infection and suboptimal or inappropriate treatment. We present the case of a 48-year-old immunocompetent firefighter diagnosed with pyomyositis caused by Nocardia brasiliensis acquired by direct skin inoculation from gardening activity. The patient developed a painful swelling on his right forearm that rapidly progressed proximally and deeper into the underlying muscle layer. Ultrasound imaging of his right forearm showed a 7-mm subcutaneous fluid collection with surrounding edema. Microbiologic analysis of the draining pus was confirmed to be N brasiliensis by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) Mass Spectrometry. After incision and drainage deep to the muscle layer to evacuate the abscess and a few ineffective antibiotic options, the patient was treated with intravenous ceftriaxone and oral linezolid for 6 weeks. He was then de-escalated to oral moxifloxacin for an additional 4 months to complete a total antibiotic treatment duration of 6 months. The wound healed satisfactorily and was completely closed by the fourth month of antibiotic therapy. Six months after discontinuation of antibiotics, the patient continued to do well with complete resolution of the infection. In this article, we discussed the risk factors for Nocardia in immunocompetent settings, the occupational risks for Nocardia in our index patient, and the challenges encountered with diagnosis and treatment. Nocardia should be included in the differential diagnosis of cutaneous infections, particularly if there is no improvement of “cellulitis” with traditional antimicrobial regimens and the infection extends into the deeper muscle tissues.
Slide Structure of Pitch Decks From an Accelerator Program
Authors: Cabezas Paula , Bateman John
Published: June 2024

The pitch is a central part of accelerator programs commonly presented with a slide presentation, called pitch deck. This study seeks to understand the ways in which pitch decks are structured. A slide-based approach was taken to describe the structure of 96 pitch decks created at the Start-up Chile accelerator program. Results showed that 7 topics were used in more than half of the pitch decks analyzed (company, team, product, problem, achievements, business model, market) and that certain topics formed sequences that were commonly used across the slide presentations.
Ethical Authorship and Moral Motivation: The Key to Ethical AI Use
Authors: Lentz Paula
Published: June 2024

This article argues that ethical authorship is essential for the ethical use of artificial intelligence (AI). It examines tensions that historical understandings of authorship have created as instructors and students alike navigate AI technologies. Given these tensions, this article proposes a definition of “ethical authorship” and uses de Colle and Werhane’s moral motivation framework to outline how instructors can use ethical authorship and moral motivation to encourage students’ ethical AI use.
The Revenue Implications of Community Colleges’ Reliance on Local Funding
Authors: Ortagus Justin C. , Baker Dominique , Rosinger Kelly Ochs , Kelchen Robert , Morales Olivia , Peters Anna , Lingo Mitchell
Published: June 2024

In this study, we leverage national data sources to examine the relationship between community colleges’ level of reliance on local funding and their total institutional revenue, focusing specifically on community colleges educating the largest shares of low-income and racially minoritized students. We show that local funding is positively related to total institutional revenue for the pooled sample including all public community colleges, suggesting that local appropriations can supplement state appropriations in ways that benefit a historically underfunded sector of higher education. However, we also show that community colleges’ level of reliance on local funding is negatively related to their total institutional revenue for rural community colleges and community colleges serving an above-average share of low-income students. Our findings align with scholarship in K–12 finance, indicating that local appropriations, such as property taxes, may exacerbate inequities facing the institutions serving larger shares of economically disadvantaged students.
Enhancing Intraoral Fluoride Retention in Older Adults: A Randomized Crossover Study
Authors: Baez-Polan J. , Danciu T.E. , Sweier D. , González-Cabezas C. , Fontana M. , Tenuta L.M.A.
Published: June 2024

Introduction:

Previous studies have shown that a calcium prerinse can increase intraoral fluoride retention from a fluoride rinse. To explore the potential of this approach to control root caries, we assessed intraoral fluoride bioavailability after a calcium prerinse in older adults with normal to low salivary flow rates.

Methods:

In a 2-period crossover trial (NCT04239872), 20 participants (65–80 y old), with low or normal salivary flow rate, rinsed for 1 min with a 0.05% NaF mouth rinse (226 ppm F, F only) or with this rinse immediately after a 1-min rinse with 150 mM calcium lactate (Ca→F). Dental biofilm and saliva samples were collected before and up to 2 h after the rinse(s). Fluoride concentrations in saliva (whole and clarified) and dental biofilm (fluid and solid phases) were blindly determined. Data were statistically analyzed by a mixed-effects model for the effect of treatment, time, and their interaction ( α = 5%).

Results:

The Ca→F group resulted in significantly higher fluoride concentrations in all variables analyzed, for almost all of the collection time points. The effect was greater in the biofilm solids and whole saliva (compatible with the formation of calcium fluoride deposits) and still significant ( P < 0.001) after 2 h in the biofilm fluid and clarified saliva, suggesting that fluoride stored in insoluble particles was released, increasing free fluoride.

Conclusion:

The use of a calcium prerinse before a fluoride rinse was able to prolong intraoral fluoride bioavailability in older adults.

Knowledge Transfer Statement:

A calcium prerinse increased intraoral fluoride bioavailability in older individuals. This approach could be used to improve root caries control without the need to increase the fluoride concentration in dental products.
Triple Jeopardy in Oral Health: Additive Effects of Immigrant Status, Education, and Neighborhood
Authors: Soares G.H. , Haag D. , Bastos J.L. , Mejia G. , Jamieson L.
Published: June 2024

Purpose:

To estimate the additive effects of parent’s nativity status/language spoken at country of birth, education, and area-level socioeconomic status (SES) on untreated dental caries among children aged 5 to 9 y in Australia.

Methods:

Cross-sectional population-based data were obtained from the 2014 National Child Oral Health Study (N = 12,140). Indicators of social position used to explore additive effects on dental caries included nativity status, language, university degree, and neighborhood socioeconomic level. Multiple-way interactions were examined, and departure from additivity resulting from 2- and 3-way interactions were estimated as relative excess risk due to interaction (RERI).

Results:

Children marginalized across multiple layers of disadvantage had substantially higher frequencies of dental caries compared with children in the most advantaged category. RERI for the 3-way interaction between immigrant status, education, and neighborhood SES was negative (RERI3: −0.14; 95% confidence interval [CI]: −1.68, 1.40). When operationalizing language, education, and neighborhood SES, the joint effect of the 3 marginalized positions was additive (RERI3: 0.43; 95% CI: −2.08, 2.95).

Conclusion:

Children marginalized across multiple intersecting axes of disadvantage bear the greatest burden of dental caries, with frequencies surpassing the cumulative effect of each social position alone. Findings emphasize the need to account for intersecting inequities and their oral health effects among children with immigrant backgrounds.

Knowledge Transfer Statement:

Our analysis underscores the necessity for policies and public health strategies targeting dental caries–related inequities to comprehensively account for various indicators of social disadvantage, particularly encompassing language proficiency, educational attainment, and neighborhood socioeconomic status. Within the intricate interplay of these factors, we identify a vulnerable subgroup comprising children with the highest prevalence of dental decay. Therefore, prioritizing this specific demographic should be the focal point of policies and public health initiatives aimed at fostering equitable oral health outcomes.
Putting Centrality Central in the Study of Institutional Complexity: On the relative and relational aspects of the centrality of institutional logics
Authors: Stevenson Lars , Honingh Marlies , Brandsen Taco
Published: June 2024

To understand how actors deal with institutional complexity, scholars have focused on the compatibility among different institutional logics, while paying little attention to the centrality of institutional logics: the meaning one logic has to actors relative to other logics. The degree of centrality shapes whether incompatibilities between logics are experienced, whether logics can be compartmentalized or ignored and what logics will be prioritized by powerful actors. Understanding centrality, therefore, is fundamental to the study of institutional complexity. In this article, we argue that the centrality of logics is both relational between a logic and actors and relative between different logics. We discuss the extent to which the assumptions underlying two approaches in institutional theory, the approach of inhabited institutionalism (II) and the institutional logics approach (IL), are conducive to studying the relational and relative aspects of centrality. On the basis of our theoretical analysis, we argue that the assumptions of IL are conducive to studying the relative but not the relational aspect of centrality, whereas the assumptions of II, at first sight, are conducive to studying the relational but not the relative aspect. Finally, we argue that the assumptions of II can be interpreted in such a way that II would be suitable for studying the relative aspect of centrality.
Modulation of anti-cardiac fibrosis immune responses by changing M2 macrophages into M1 macrophages
Authors: Chen Shiqi , Wang Kan , Fan Zhengfeng , Zhou Tingwen , Li Rui , Zhang Bingxia , Chen Jie , Chi Jiangyang , Wei Keke , Liu Jincheng , Liu Zongtao , Ma Jingwei , Dong Nianguo , Liu Junwei
Published: June 2024

Background

Macrophages play a crucial role in the development of cardiac fibrosis (CF). Although our previous studies have shown that glycogen metabolism plays an important role in macrophage inflammatory phenotype, the role and mechanism of modifying macrophage phenotype by regulating glycogen metabolism and thereby improving CF have not been reported.

Methods

Here, we took glycogen synthetase kinase 3β (GSK3β) as the target and used its inhibitor NaW to enhance macrophage glycogen metabolism, transform M2 phenotype into anti-fibrotic M1 phenotype, inhibit fibroblast activation into myofibroblasts, and ultimately achieve the purpose of CF treatment.

Results

NaW increases the pH of macrophage lysosome through transmembrane protein 175 (TMEM175) and caused the release of Ca2+ through the lysosomal Ca2+ channel mucolipin-2 (Mcoln2). At the same time, the released Ca2+ activates TFEB, which promotes glucose uptake by M2 and further enhances glycogen metabolism. NaW transforms the M2 phenotype into the anti-fibrotic M1 phenotype, inhibits fibroblasts from activating myofibroblasts, and ultimately achieves the purpose of treating CF.

Conclusion

Our data indicate the possibility of modifying macrophage phenotype by regulating macrophage glycogen metabolism, suggesting a potential macrophage-based immunotherapy against CF.

Graphical Abstract
Glial fibrillary acidic protein, neurofilament light, matrix metalloprotease 3 and fatty acid binding protein 4 as non-invasive brain tumor biomarkers
Authors: Ghorbani Atefeh , Chatanaka Miyo K. , Avery Lisa M. , Wang Mingyue , Brown Jermaine , Cohen Rachel , Gorham Taron , Misaghian Salvia , Padmanabhan Nikhil , Romero Daniel , Stengelin Martin , Mathew Anu , Sigal George , Wohlstadter Jacob , Horbinski Craig , McCortney Katy , Xu Wei , Zadeh Gelareh , Mansouri Alireza , Yousef George M. , Diamandis Eleftherios P. , Prassas Ioannis
Published: June 2024

Background

Gliomas are aggressive malignant tumors, with poor prognosis. There is an unmet need for the discovery of new, non-invasive biomarkers for differential diagnosis, prognosis, and management of brain tumors. Our objective is to validate four plasma biomarkers – glial fibrillary acidic protein (GFAP), neurofilament light (NEFL), matrix metalloprotease 3 (MMP3) and fatty acid binding protein 4 (FABP4) – and compare them with established brain tumor molecular markers and survival.

Methods

Our cohort consisted of patients with benign and malignant brain tumors (GBM = 77, Astrocytomas = 26, Oligodendrogliomas = 23, Secondary tumors = 35, Meningiomas = 70, Schwannomas = 15, Pituitary adenomas = 15, Normal individuals = 30). For measurements, we used ultrasensitive electrochemiluminescence multiplexed immunoassays.

Results

High plasma GFAP concentration was associated with GBM, low GFAP and high FABP4 were associated with meningiomas, and low GFAP and low FABP4 were associated with astrocytomas and oligodendrogliomas. NEFL was associated with progression of disease. Several prognostic genetic alterations were significantly associated with all plasma biomarker levels. We found no independent associations between plasma GFAP, NEFL, FABP4 and MMP3, and overall survival. The candidate biomarkers could not reliably discriminate GBM from primary or secondary CNS lymphomas.

Conclusions

GFAP, NEFL, FABP4 and MMP3 are useful for differential diagnosis and prognosis, and are associated with molecular changes in gliomas.
Explosives leaking from dumped munition contaminate fish from German coastal waters: a reason for chronic effects?
Authors: Kammann Ulrike , Töpker Verena , Schmidt Nicole , Rödiger Marcellus , Aust Marc-Oliver , Gabel Michael , Scharsack Jörn Peter
Published: June 2024

Background

Conventional munition dumped into the North Sea and the Baltic Sea close to the German coastline is corroding. A major concern is that biota, including fish, are negatively affected by toxic explosives leaking into marine environments. With the present study, we investigated fish living in close proximity to munition dumping sites for contamination and for signs of health impairments. The flat fish species common dab (Limanda limanda) was used as a model, since it lives in the vicinity of dumping sites and exhibits minor migratory activity. Since explosives are excreted via the bile, the bile fluids from dab were analysed. Further on we inspected the health status of the fish.

Results

Dab caught in German coastal waters of the Baltic Sea and the North Sea were contaminated with explosives. Probably due to rapid metabolization, concentrations of the explosive 2,4,6-trinitrotoluene (TNT) were always below limit of detection, but its metabolites 2-amino-4,6-dinitrotoluene and 4-amino-2,6-dinitrotoluene were detected in bile fluid up to 26.36 ng/ml and 95.91 ng/ml, respectively. Only few fish from the Baltic Sea were positive for the explosive HMX, octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine with a maximum concentration of 0.89 ng/ml. Highest concentrations of TNT metabolites in bile fluid were detected in dab collected near the dumping site “Kolberger Heide” in the bay of Kiel (Baltic Sea). However, also dab from the North Sea were significantly contaminated with TNT metabolites.

Conclusions

The present study showed for the first time that fish living close to near shore munition dumping sites in the North Sea are contaminated with explosives. Various health indicators (body condition factors, externally visible fish diseases, parasites or liver anomalies) showed differences in health status between fish living in the North Sea and in the Baltic Sea, respectively. However, the health status of fish caught at the most contaminated site in the Baltic Sea was not worse compared to fish living in less contaminated areas. We conclude that fish living in the vicinity of dumping sites in the North Sea and the Baltic Sea can be significantly contaminated with explosives. However, obvious health impairments of the fish were not observed.
Delivery of letrozole-encapsulated niosomes via a 3D bioprinting gelatin–alginate scaffold for potential breast cancer treatment
Authors: Mahdizadeh Neda , Khorshid Shabestari Mahtab , Tafvizi Farzaneh , Khodarahmi Parvin
Published: June 2024

3D printing technology is a powerful tool in scaffold engineering for biomedical applications, especially in anticancer activities and drug delivery. The present study developed a 3D-printed gelatin–alginate scaffold incorporating letrozole-loaded niosomes (Let/Nio@Gel-AL-SC) as a more effective drug delivery system. The findings showed that the fabricated niosomes appeared spherical. 3D-printed scaffolds exhibited biodegradability and sustained drug-release properties. The drug release from the scaffold was less prominent under acidic conditions than physiological ones. Cytotoxicity analysis showed that the engineered Let/Nio@Gel-AL-SC scaffold exhibited significant cytotoxicity against MCF-7 cancer cells. Gene expression analysis demonstrated a significant decrease in the expression of BCL2, CCND1, MMP2, and CDK4 genes and a notable increase in the expression of BAX and P53 genes, as well as the activity of Caspase 3/7 enzyme following treatment with Let/Nio@Gel-AL-SC. In addition, flow cytometry analysis revealed that Let/Nio@Gel-AL-SC significantly reduced necrosis and dramatically increased apoptosis. Also, the Let/Nio@Gel-AL-SC formulation exhibited a significantly greater increase in ROS values. The incorporation of letrozole-loaded niosomes into 3D printing gelatin/alginate scaffold has enhanced the efficacy of anticancer therapy. This is demonstrated by the sustained release of drugs, which indicates a promising potential for effective anticancer activity. Consequently, this combination holds promise as a potential future cancer therapy strategy.

Graphical abstract
SpliceAPP: an interactive web server to predict splicing errors arising from human mutations
Authors: Huang Ang-Chu , Su Jia-Ying , Hung Yu-Jen , Chiang Hung-Lun , Chen Yi-Ting , Huang Yen-Tsung , Yu Chen-Hsin Albert , Lin Hsin-Nan , Lin Chien-Ling
Published: June 2024

Background

Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights.

Results

Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest.

Conclusions

In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://bc.imb.sinica.edu.tw/SpliceAPP. Source code can be downloaded at https://github.com/hsinnan75/SpliceAPP.
Identification of key genes for triacylglycerol biosynthesis and storage in herbaceous peony (Paeonia lactifolra Pall.) seeds based on full-length transcriptome
Authors: Xu Huajie , Li Miao , Ma Di , Gao Jiajun , Tao Jun , Meng Jiasong
Published: June 2024

Background

The herbaceous peony (Paeonia lactiflora Pall.) is extensively cultivated in China due to its root being used as a traditional Chinese medicine known as ‘Radix Paeoniae Alba’. In recent years, it has been discovered that its seeds incorporate abundant unsaturated fatty acids, thereby presenting a potential new oilseed plant. Surprisingly, little is known about the full-length transcriptome sequencing of Paeonia lactiflora, limiting research into its gene function and molecular mechanisms.

Results

A total of 484,931 Reads of Inserts (ROI) sequences and 1,455,771 full-Length non-chimeric reads (FLNC) sequences were obtained for CDS prediction, TF analysis, SSR analysis and lncRNA identification. In addition, gene function annotation and gene structure analysis were performed. A total of 4905 transcripts were related to lipid metabolism biosynthesis pathway, belonging to 28 enzymes. We use these data to identify 10 oleosin (OLE) and 5 diacylglycerol acyltransferase (DGAT) gene members after de-redundancy. The analysis of physicochemical properties and secondary structure showed them similarity in gene family respectively. The phylogenetic analysis showed that the distribution of OLE and DGAT family members was roughly the same as that of Arabidopsis. Quantitative real-time polymerase chain reaction (qRT–PCR) analyses revealed expression changes in different seed development stages, and showed a trend of increasing and then decreasing.

Conclusion

In summary, these results provide new insights into the molecular mechanism of triacylglycerol (TAG) biosynthesis and storage during the seedling stage in Paeonia lactiflora. It provides theoretical references for selecting and breeding oil varieties and understanding the functions of oil storage as well as lipid synthesis related genes in Paeonia lactiflora.
Multi-trait association mapping for phosphorous efficiency reveals flexible root architectures in sorghum
Authors: Hufnagel Barbara , Bernardino Karine C. , Malosetti Marcos , Sousa Sylvia M. , Silva Lidianne A. , Guimaraes Claudia Teixeira , Coelho Antônio Marcos , Santos Thiago Teixeira , Viana Joao H. M. , Schaffert Robert E. , Kochian Leon V. , Eeuwijk Fred A. , Magalhaes Jurandir V.
Published: June 2024

Background

On tropical regions, phosphorus (P) fixation onto aluminum and iron oxides in soil clays restricts P diffusion from the soil to the root surface, limiting crop yields. While increased root surface area favors P uptake under low-P availability, the relationship between the three-dimensional arrangement of the root system and P efficiency remains elusive. Here, we simultaneously assessed allelic effects of loci associated with a variety of root and P efficiency traits, in addition to grain yield under low-P availability, using multi-trait genome-wide association. We also set out to establish the relationship between root architectural traits assessed in hydroponics and in a low-P soil. Our goal was to better understand the influence of root morphology and architecture in sorghum performance under low-P availability.

Result

In general, the same alleles of associated SNPs increased root and P efficiency traits including grain yield in a low-P soil. We found that sorghum P efficiency relies on pleiotropic loci affecting root traits, which enhance grain yield under low-P availability. Root systems with enhanced surface area stemming from lateral root proliferation mostly up to 40 cm soil depth are important for sorghum adaptation to low-P soils, indicating that differences in root morphology leading to enhanced P uptake occur exactly in the soil layer where P is found at the highest concentration.

Conclusion

Integrated QTLs detected in different mapping populations now provide a comprehensive molecular genetic framework for P efficiency studies in sorghum. This indicated extensive conservation of P efficiency QTL across populations and emphasized the terminal portion of chromosome 3 as an important region for P efficiency in sorghum. Increases in root surface area via enhancement of lateral root development is a relevant trait for sorghum low-P soil adaptation, impacting the overall architecture of the sorghum root system. In turn, particularly concerning the critical trait for water and nutrient uptake, root surface area, root system development in deeper soil layers does not occur at the expense of shallow rooting, which may be a key reason leading to the distinctive sorghum adaptation to tropical soils with multiple abiotic stresses including low P availability and drought.
Genome-wide analysis of AP2/ERF transcription factors that regulate fruit development of Chinese prickly ash
Authors: Ma Lei , Shi Qianqian , Ma Qin , Wang Xiaona , Chen Xin , Han Peilin , Luo Yingli , Hu Haichao , Fei Xitong , Wei Anzhi
Published: June 2024

Background

AP2/ERF is a large family of plant transcription factor proteins that play essential roles in signal transduction, plant growth and development, and responses to various stresses. The AP2/ERF family has been identified and verified by functional analysis in various plants, but so far there has been no comprehensive study of these factors in Chinese prickly ash. Phylogenetic, motif, and functional analyses combined with transcriptome analysis of Chinese prickly ash fruits at different developmental stages (30, 60, and 90 days after anthesis) were conducted in this study.

Results

The analysis identified 146 ZbAP2/ERF genes that could be classified into 15 subgroups. The motif analysis revealed the presence of different motifs or elements in each group that may explain the functional differences between the groups. ZbERF13.2, ZbRAP2-12, and ZbERF2.1 showed high levels of expression in the early stages of fruit development. ZbRAP2-4, and ZbERF3.1 were significantly expressed at the fruit coloring stage (R2 and G2). ZbERF16 were significantly expressed at fruit ripening and expression level increased as the fruit continued to develop. Relative gene expression levels of 6 representative ZbAP2/ERFs assessed by RT-qPCR agreed with transcriptome analysis results.

Conclusions

These genes identified by screening can be used as candidate genes that affect fruit development. The results of the analysis can help guide future genetic improvement of Chinese prickly ash and enrich our understanding of AP2/ERF transcription factors and their regulatory functions in plants.
Integrated analysis of transcriptomics and metabolomics of garden asparagus (Asparagus officinalis L.) under drought stress
Authors: Zhang Xuhong , Han Changzhi , Wang Yubo , Liu Tao , Liang Yuqin , Cao Yanpo
Published: June 2024

Background

Drought is a leading environmental factor affecting plant growth. To explore the drought tolerance mechanism of asparagus, this study analyzed the responses of two asparagus varieties, namely, ‘Jilv3’ (drought tolerant) and ‘Pacific Early’ (drought sensitive), to drought stress using metabolomics and transcriptomics.

Results

In total, 2,567 and 7,187 differentially expressed genes (DEGs) were identified in ‘Pacific Early’ and ‘Jilv3’, respectively, by comparing the transcriptome expression patterns between the normal watering treatment and the drought stress treatment. These DEGs were significantly enriched in the amino acid biosynthesis, carbon metabolism, phenylpropanoid biosynthesis, and plant hormone signal transduction pathways. In ‘Jilv3’, DEGs were also enriched in the following energy metabolism-related pathways: citrate cycle (TCA cycle), glycolysis/gluconeogenesis, and pyruvate metabolism. This study also identified 112 and 254 differentially accumulated metabolites (DAMs) in ‘Pacific Early’ and ‘Jilv3’ under drought stress compared with normal watering, respectively. The amino acid, flavonoid, organic acid, and soluble sugar contents were more significantly enhanced in ‘Jilv3’ than in ‘Pacific Early’. According to the metabolome and transcriptome analysis, in ‘Jilv3’, the energy supply of the TCA cycle was improved, and flavonoid biosynthesis increased. As a result, its adaptability to drought stress improved.

Conclusions

These findings help to better reveal the molecular mechanism underlying how asparagus responds to drought stress and improve researchers’ ability to screen drought-tolerant asparagus varieties as well as breed new varieties.
Sampling weighting strategies in causal mediation analysis
Authors: Coffman Donna L. , Zhou Haoyu , Castellano Katherine E. , Schuler Megan S. , McCaffrey Daniel F.
Published: June 2024

Background

Causal mediation analysis plays a crucial role in examining causal effects and causal mechanisms. Yet, limited work has taken into consideration the use of sampling weights in causal mediation analysis. In this study, we compared different strategies of incorporating sampling weights into causal mediation analysis.

Methods

We conducted a simulation study to assess 4 different sampling weighting strategies-1) not using sampling weights, 2) incorporating sampling weights into mediation “cross-world” weights, 3) using sampling weights when estimating the outcome model, and 4) using sampling weights in both stages. We generated 8 simulated population scenarios comprising an exposure (A), an outcome (Y), a mediator (M), and six covariates (C), all of which were binary. The data were generated so that the true model of A given C and the true model of A given M and C were both logit models. We crossed these 8 population scenarios with 4 different sampling methods to obtain 32 total simulation conditions. For each simulation condition, we assessed the performance of 4 sampling weighting strategies when calculating sample-based estimates of the total, direct, and indirect effects. We also applied the four sampling weighting strategies to a case study using data from the National Survey on Drug Use and Health (NSDUH).

Results

Using sampling weights in both stages (mediation weight estimation and outcome models) had the lowest bias under most simulation conditions examined. Using sampling weights in only one stage led to greater bias for multiple simulation conditions.

Discussion

Using sampling weights in both stages is an effective approach to reduce bias in causal mediation analyses under a variety of conditions regarding the structure of the population data and sampling methods.
Clinicians’ experiences implementing an advance care planning pathway in two Canadian provinces: a qualitative study
Authors: Stevens Julie , Elston Dawn , Tan Amy , Barwich Doris , Carter Rachel Zoe , Cochrane Diana , Frenette Nicole , Howard Michelle
Published: June 2024

Background

Advance care planning (ACP) is a process which enables patients to communicate wishes, values, fears, and preferences for future medical care. Despite patient interest in ACP, the frequency of discussions remains low. Barriers to ACP may be mitigated by involving non-physician clinic staff, preparing patients ahead of visits, and using tools to structure visits. An ACP care pathway incorporating these principles was implemented in longitudinal generalist outpatient care, including primary care/family medicine and general internal medicine, in two Canadian provinces. This study aims to understand clinician experiences implementing the pathway.

Methods

The pathway was implemented in one family practice in Alberta, two family practices in British Columbia (BC), and one BC internal medicine outpatient clinic. Physicians and allied health professionals delivered structured pathway visits based on the Serious Illness Conversation Guide. Twelve physicians and one social worker participated in interviews or focus groups at the end of the study period. Qualitative data were coded inductively using an iterative approach, with regular meetings between coders.

Results

Clinicians described experiences with the ACP care pathway, impact at the clinician level, and impact at the patient level. Within each domain, clinicians described barriers and facilitators experienced during implementation. Clinicians also reflected candidly about potential for future implementation and the sustainability of the pathway.

Conclusions

While the pathway was implemented slightly differently between provinces, core experiences were that implementation of the pathway, and integration with current practice, were feasible. Across settings, similar themes recurred regarding usefulness of the pathway structure and its tools, impact on clinician confidence and interactions with patients, teamwork and task delegation, compatibility with existing workflow, and patient preparation and readiness. Clinicians were supportive of ACP and of the pathway.

Trial registration

The study was prospectively registered with clinicaltrials.gov (NCT03508557). Registered April 25, 2018. https://classic.clinicaltrials.gov/ct2/show/NCT03508557.
Real-world performance of HIV low viral load values in diagnosing acute HIV infection in a tertiary care hospital in Beijing, China
Authors: Li Li , Feng Xia , Zhao Fei , Yuan Defu , An Xizhao , Tian Xiaoxue , Wu Hao , Su Bin , Zhang Tong , Liu Lifeng
Published: June 2024

Background

Early diagnosis of HIV infection decreases the time from HIV diagnosis to viral suppression and reduces further HIV transmission. The Chinese Guidelines for the Diagnosis and Treatment of HIV/AIDS (2021 edition) state that an HIV RNA level > 5,000 copies/mL is the threshold for diagnosing HIV infection. The impact of low viral load values on HIV diagnosis needs to be investigated.

Methods

There were 3455 human immunodeficiency virus (HIV1 + 2) antibody results (immunoblotting method) and 65,129 HIV viral load values at Beijing Youan Hospital from 2019 to 2022. A total of 2434 patients had both antibody confirmatory results and viral load results. The confirmatory antibody results and HIV viral load results of 2434 patients were analyzed to investigate the impact of low viral load values on HIV diagnosis.

Results

Of the 2434 patients who had both confirmatory antibody results and viral load results, the viral load values of 140 patients (5.8%) had viral loads ranging from 40 copies/mL to 5,000 copies/mL before positive confirmatory antibody result, and of these 140 patients, the sample receipt time for the viral load tests of 96 (66.7%) individuals was 1 to 6 days earlier than the corresponding sample receipt time for the confirmatory antibody test. In addition, 34 patients (1.4%) had low viral loads ranging from 40 copies/mL to 1,000 copies/mL before positive confirmatory antibody result.

Conclusion

This study revealed that there is a risk of missed diagnosis if a threshold of 5000 copies/mL is used for the diagnosis of HIV infection. These data provide valuable information for the early diagnosis of HIV infection, and our findings have potential benefits for decreasing HIV transmission.