bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the relationship between nursing students’ knowledge and attitudes towards climate change and their psychological distress: a cross-national investigation
Authors: Abousoliman Ali D. , Ibrahim Ateya Megahed , Abualruz Hasan , Magdi Hussein M. , Zaghamir Donia Elsaid Fathi , Alhowimel Ahmed , El-Monshed Ahmed Hashem , El-Gazar Heba E. , Zoromba Mohamed A.
Published: April 2024

Background

Climate change poses a worldwide challenge with anticipated exacerbation in the future, resulting in irreversible consequences. Nursing students may be vulnerable to experiencing psychological effects associated with climate change.

Aim

The current study aimed to investigate the relationship between nursing students’ knowledge and attitudes toward climate change and their psychological distress.

Method

This descriptive cross-sectional study recruited 377 nursing students from three universities located in Saudi Arabia, Jordan, and Egypt in the Middle East. Data collection was conducted using scales for assessing nursing students’ knowledge and attitudes towards climate change and their psychological distress. Correlations were assessed and multiple regression analysis was conducted to explore the predictors of students’ psychological distress.

Results

The current study showed that knowledge regarding climate change significantly and positively correlated to the attitude toward climate change (r = 0.213), then again, the score of psychological distress significantly and negatively correlated to the score of students’ knowledge and attitude regarding climate change (r = − 0.182 and − 0.110 respectively). Regression analyses showed that academic achievement had the strongest positive impact on students’ psychological distress, while knowledge regarding climate change and attitude toward climate change had negative impacts (β = 0.381, β=-0.205, and β=-0.045 respectively). Moreover, knowledge and attitude regarding climate change were found to be significant predictors of students’ psychological distress, collectively accounting for 18.2% of the observed variance.

Conclusions/Implication for future practice

The findings highlight the importance of incorporating climate change into nursing education programs. By enhancing nursing students’ knowledge and attitudes towards climate change, there is potential to reduce their psychological distress. This study underscores the need for curriculum reforms that integrate climate change topics, aiming to foster a well-informed and resilient future nursing workforce.
Subregion preference in the long-range connectome of pyramidal neurons in the medial prefrontal cortex
Authors: Tudi Ayizuohere , Yao Mei , Tang Feifang , Zhou Jiandong , Li Anan , Gong Hui , Jiang Tao , Li Xiangning
Published: April 2024

Background

The medial prefrontal cortex (mPFC) is involved in complex functions containing multiple types of neurons in distinct subregions with preferential roles. The pyramidal neurons had wide-range projections to cortical and subcortical regions with subregional preferences. Using a combination of viral tracing and fluorescence micro-optical sectioning tomography (fMOST) in transgenic mice, we systematically dissected the whole-brain connectomes of intratelencephalic (IT) and pyramidal tract (PT) neurons in four mPFC subregions.

Results

IT and PT neurons of the same subregion projected to different target areas while receiving inputs from similar upstream regions with quantitative differences. IT and PT neurons all project to the amygdala and basal forebrain, but their axons target different subregions. Compared to subregions in the prelimbic area (PL) which have more connections with sensorimotor-related regions, the infralimbic area (ILA) has stronger connections with limbic regions. The connection pattern of the mPFC subregions along the anterior–posterior axis showed a corresponding topological pattern with the isocortex and amygdala but an opposite orientation correspondence with the thalamus.

Conclusions

By using transgenic mice and fMOST imaging, we obtained the subregional preference whole-brain connectomes of IT and pyramidal tract PT neurons in the mPFC four subregions. These results provide a comprehensive resource for directing research into the complex functions of the mPFC by offering anatomical dissections of the different subregions.
Unprecedented variation pattern of plastid genomes and the potential role in adaptive evolution in Poales
Authors: Wu Hong , Li De-Zhu , Ma Peng-Fei
Published: April 2024

Background

The plastid is the photosynthetic organelle in plant cell, and the plastid genomes (plastomes) are generally conserved in evolution. As one of the most economically and ecologically important order of angiosperms, Poales was previously documented to exhibit great plastomic variation as an order of photoautotrophic plants.

Results

We acquired 93 plastomes, representing all the 16 families and 5 major clades of Poales to reveal the extent of their variation and evolutionary pattern. Extensive variation including the largest one in monocots with 225,293 bp in size, heterogeneous GC content, and a wide variety of gene duplication and loss were revealed. Moreover, rare occurrences of three inverted repeat (IR) copies in angiosperms and one IR loss were observed, accompanied by short IR (sIR) and small direct repeat (DR). Widespread structural heteroplasmy, diversified inversions, and unusual genomic rearrangements all appeared in Poales, occasionally within a single species. Extensive repeats in the plastomes were found to be positively correlated with the observed inversions and rearrangements. The variation all showed a “small-large-moderate” trend along the evolution of Poales, as well as for the sequence substitution rate. Finally, we found some positively selected genes, mainly in C4 lineages, while the closely related lineages of those experiencing gene loss tended to have undergone more relaxed purifying selection.

Conclusions

The variation of plastomes in Poales may be related to its successful diversification into diverse habitats and multiple photosynthetic pathway transitions. Our order-scale analyses revealed unusual evolutionary scenarios for plastomes in the photoautotrophic order of Poales and provided new insights into the plastome evolution in angiosperms as a whole.
Suicide mortality following the implementation of tobacco packaging and pricing policies in Korea: an interrupted time-series analysis
Authors: Jin Taiyue , Seo Juhee , Ye Shinhee , Lee Seulbi , Park Eun Young , Oh Jin-Kyoung , Han Changwoo , Kim Byungmi
Published: April 2024

Background

To prevent tobacco use in Korea, the national quitline number was added to tobacco packages in December 2012, tobacco prices were raised by 80% in January 2015, and graphic health warning labels were placed on tobacco packages in December 2016. This study evaluated the association of these tobacco packaging and pricing policies with suicide mortality in Korea.

Methods

Monthly mortality from suicide was obtained from Cause-of-Death Statistics in Korea from December 2007 to December 2019. Interrupted time-series analysis was performed using segmented Poisson regression models. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated adjusted for suicide prevention strategies.

Results

Suicide mortality was 20 per 1,000,000 in December 2007 and showed a downward trend over the study period. After the implementation of tobacco packaging and pricing policies, suicide mortality immediately declined by − 0.09 percent points (95% CI =  − 0.19 to 0.01; P > 0.05) for the national quitline number, − 0.22 percent points (95% CI =  − 0.35 to − 0.09; P < 0.01) for tobacco prices, and − 0.30 percent points (95% CI =  − 0.49 to − 0.11; P < 0.01) for graphic health warning labels. The corresponding RRs for these post-implementation changes compared with the pre-implementation level were 0.91 (95% CI = 0.83 to 1.00), 0.80 (95% CI = 0.70 to 0.91), and 0.74 (95% CI = 0.61 to 0.90), respectively. Significant associations between tobacco control policies and suicide mortality were observed even when stratified by sex and region.

Conclusions

The findings of this study provide new evidence for an association between tobacco control policies and deaths by suicide. An array of effective tobacco control policies should be considered for prevention programs targeting suicide.
Smoking status and clinical outcome in idiopathic pulmonary fibrosis: a nationwide study
Authors: Yoon Hee-Young , Kim Hoseob , Bae Yoonjong , Song Jin Woo
Published: April 2024

Background

Smoking status has been linked to the development of idiopathic pulmonary fibrosis (IPF). However, the effect of smoking on the prognosis of patients with IPF is unclear. We aimed to investigate the association between smoking status and all-cause mortality or hospitalisation by using national health claims data.

Methods

IPF cases were defined as people who visited medical institutions between January 2002 and December 2018 with IPF and rare incurable disease exempted calculation codes from the National Health Insurance Database. Total 10,182 patients with available data on smoking status were included in this study. Ever-smoking status was assigned to individuals with a history of smoking ≥ 6 pack-years. The multivariable Cox proportional hazard model was used to evaluate the association between smoking status and prognosis.

Results

In the entire cohort, the mean age was 69.4 years, 73.9% were males, and 45.2% were ever smokers (current smokers: 14.2%; former smokers: 31.0%). Current smokers (hazard ratio [HR]: 0.709; 95% confidence interval [CI]: 0.643–0.782) and former smokers (HR: 0.926; 95% CI: 0.862–0.996) were independently associated with all-cause mortality compared with non-smokers. Current smokers (HR: 0.884; 95% CI: 0.827–0.945) and former smokers (HR: 0.909; 95% CI: 0.862–0.959) were also associated with a reduced risk of all-cause hospitalisation compared with non-smokers. A non-linear association between smoking amount and prognosis was found in a spline HR curve and showed increasing risk below 6 pack-years.

Conclusion

Ever-smoking status may be associated with favourable clinical outcomes in patients with IPF.
Association of the triglyceride-glucose index with early-onset atherosclerotic cardiovascular disease events and all-cause mortality: a prospective cohort study
Authors: Hou Qiqi , Qi Qi , Han Quanle , Yu Jie , Wu Jianmei , Yang Hui , Chen Shuohua , Wu Shouling , Li Kangbo
Published: April 2024

Background

The association between the triglyceride glucose (TyG) index and the risk of early-onset atherosclerotic cardiovascular disease (ASCVD) events or all-cause mortality in young and middle-aged people is not fully elucidated.

Methods

The present study included 64,489 young and middle-aged people who participated in the 2006 Kailuan Study physical examination. Multivariate Cox proportional hazards models and restricted cubic spline curves were used to assess the association of TyG index with early-onset ASCVD events and all-cause mortality.

Results

During a median of 11-year follow-up, 1984 (3.08%) participants experienced at least one ASCVD event and 1,392 (2.16%) participants experienced all-cause death. A higher TyG index was significantly associated with a higher risk of early-onset ASCVD events (HR: 1.61, 95% CI 1.38–1.89) and all-cause mortality (HR: 1.39, 95% CI 1.17–1.65), respectively. For each unit increase in TyG index, the risk of early-onset ASCVD events increased by 20%. In addition, there was a non-linear association between the TyG index and early-onset ASCVD events (P for non-linear < 0.01), and a linear association between TyG index and all-cause mortality (P for non-linear = 0.476).

Conclusions

A higher TyG index is significantly associated with an increased incidence of early-onset ASCVD events and all-cause mortality in a young and middle-aged population from North China.
Therapeutic efficacy of generic artemether–lumefantrine in the treatment of uncomplicated malaria in Ghana: assessing anti-malarial efficacy amidst pharmacogenetic variations
Authors: Thomford Nicholas Ekow , Kellermann Tracy , Biney Robert Peter , Dixon Charné , Nyarko Samuel Badu , Ateko Richmond Owusu , Ekor Martins , Kyei George B.
Published: April 2024

Background

Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether–lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy.

Methods

Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR–RFLP.

Results

A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0–2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors.

Conclusions

The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.
Cholesterol mediates the effects of single and multiple environmental phenols in urine on obesity
Authors: Yu Ting , Zhang Yuqing , Yuan Jiali , Zhang Yue , Li Jing , Huang Zhenyao
Published: April 2024

Background

Overweight and obesity are among the leading chronic diseases worldwide. Environmental phenols have been renowned as endocrine disruptors that contribute to weight changes; however, the effects of exposure to mixed phenols on obesity are not well established.

Methods

Using data from adults in National Health and Nutrition Examination Survey, this study examined the individual and combined effects of four phenols on obesity. A combination of traditional logistic regression and two mixed models (weighted quantile sum (WQS) regression and Bayesian kernel-machine regression (BKMR)) were used together to assess the role of phenols in the development of obesity. The potential mediation of cholesterol on these effects was analyzed through a parallel mediation model.

Results

The results demonstrated that solitary phenols except triclosan were inversely associated with obesity (P-value < 0.05). The WQS index was also negatively correlated with general obesity (β: 0.770, 95% CI: 0.644–0.919, P-value = 0.004) and abdominal obesity (β: 0.781, 95% CI: 0.658–0.928, P-value = 0.004). Consistently, the BKMR model demonstrated the significant joint negative effects of phenols on obesity. The parallel mediation analysis revealed that high-density lipoprotein mediated the effects of all four single phenols on obesity, whereas low-density lipoprotein only mediated the association between benzophenol-3 and obesity. Moreover, Cholesterol acts as a mediator of the association between mixed phenols and obesity. Exposure to single and mixed phenols significantly and negatively correlated with obesity. Cholesterol mediated the association of single and mixed environmental phenols with obesity.

Conclusions

Assessing the potential public health risks of mixed phenols helps to incorporate this information into practical health advice and guidance.
Adapting the EQ-5D-3L for adults with mild to moderate learning disabilities
Authors: O’Dwyer John L. , Bryant Louise D. , Hulme Claire , Kind Paul , Meads David M.
Published: April 2024

Background

Approximately 1.5 million adults in the UK have a learning disability. The difference between age at death for this group and the general population is 26 years for females and 22 years for males. The NHS Long Term Plan (January 2019) recognises learning disabilities as a clinical priority area. People with a learning disability are often excluded from research by design or lack of reasonable adjustments, and self-reported health status/health-related quality of life questionnaires such as the EQ-5D are often not appropriate for this population. Here, we systematically examine the EQ-5D-3L (its wording, content, and format) using qualitative methods to inform the adaption of the measure for use with adults with mild to moderate learning disabilities.

Methods

Think-aloud interviews with carers/advocates of learning-disabled adults were undertaken to explore the difficulties with completing the EQ-5D-3L. Alternative wording, language, structure, and images were developed using focus groups, stakeholder reference groups, and an expert panel. Data analysis followed a framework method.

Results

The dimensions and levels within the EQ-5D-3L were deemed appropriate for adults with mild to moderate learning disabilities. Consensus on wording, structure, and images was reached through an iterative process, and an adapted version of the EQ-5D-3L was finalised.

Conclusion

The EQ-5D-3L adapted for adults with mild to moderate intellectual/learning disabilities can facilitate measurement of self-reported health status. Research is underway to assess the potential use of the adaptation for economic evaluation.
Early career researchers in health policy and systems research: insights from freelancers in a non-profit organization in the Philippines
Authors: Sales Reneepearl Kim , Navarro Marion Abilene
Published: April 2024

Background

The freelance economy has seen rapid growth worldwide in recent years and the Philippines is not an exception. Freelance workers are becoming increasingly common in healthcare and research. Early career researchers carry out most of scientific research and can play a critical role in advancing public health by bringing new perspectives and diversity to the field. Existing literature has mostly focused on the experiences of early career researchers in an institutional academic setting. This study aimed to understand the experiences of freelance early career researchers in the health policy and systems space in the Philippines.

Methods

This qualitative study collected data from 18 to 22 March 2022 through virtual interview and focus group discussions. Themes and codes were created based on the topic guide developed. New themes and codes were generated as they emerged. Two researchers coded the data using both a priori and emergent codes. Any coding conflicts were resolved through discussions until intercoder agreement was reached. Interpretation and conclusions from the data were developed by 2 researchers with consideration for its context and relationship between themes.

Results

Fifteen current and former freelance researchers participated in the study. Most are female, under 35 years old, and with an undergraduate degree as the highest educational attainment. The findings highlight insights and challenges faced by early career researchers in aspects of: (1) work arrangement, (2) tasks, (3) expectations from senior researchers, (4) development in the health policy and systems field, (5) relationship with peers, and (6) motivations for continuing to work as a freelance health policy and systems researcher.

Conclusion

This study reveals the challenges freelance early career researchers face, highlighting the need for enhanced support and recognition amidst rapidly evolving workforce demands and complex health dilemmas. Recommendations include structured mentorship, professional development, innovative funding models, and the establishment of a supportive network. Advocacy for policies ensuring freelancer inclusion in the economy and policy-making is crucial. Future research should investigate their experiences further, including their roles, transitions, and the impacts of funding trends, to foster their development and integration into public health research and policy.
What is context in knowledge translation? Results of a systematic scoping review
Authors: Schmitt Tugce , Czabanowska Katarzyna , Schröder-Bäck Peter
Published: April 2024

Knowledge Translation (KT) aims to convey novel ideas to relevant stakeholders, motivating their response or action to improve people’s health. Initially, the KT literature focused on evidence-based medicine, applying findings from laboratory and clinical research to disease diagnosis and treatment. Since the early 2000s, the scope of KT has expanded to include decision-making with health policy implications.

This systematic scoping review aims to assess the evolving knowledge-to-policy concepts, that is, macro-level KT theories, models and frameworks (KT TMFs). While significant attention has been devoted to transferring knowledge to healthcare settings (i.e. implementing health policies, programmes or measures at the meso-level), the definition of 'context' in the realm of health policymaking at the macro-level remains underexplored in the KT literature. This study aims to close the gap.

A total of 32 macro-level KT TMFs were identified, with only a limited subset of them offering detailed insights into contextual factors that matter in health policymaking. Notably, the majority of these studies prompt policy changes in low- and middle-income countries and received support from international organisations, the European Union, development agencies or philanthropic entities.
Was it a HIIT? A process evaluation of a school-based high-intensity interval training intervention
Authors: Duncombe Stephanie L. , Barker Alan R. , Price Lisa , Walker Jacqueline L. , Koep Jodie L. , Woodforde James , Stylianou Michalis
Published: April 2024

Background

Despite a growing body of research investigating high-intensity interval training (HIIT) in schools, there are limited process evaluations investigating their implementation. This is concerning because process evaluations are important for appropriately interpreting outcome findings and augmenting intervention design. This manuscript presents a process evaluation of Making a HIIT, a school-based HIIT intervention.

Methods

The Making a HIIT intervention spanned 8 weeks and was completed at three schools in Greater Brisbane, Australia. Ten classes (intervention group) completed 10-min teacher-led HIIT workouts at the beginning of health and physical education (HPE) lessons, and five classes (control group) continued with regular HPE lessons. The mixed methods evaluation was guided by the Framework for Effective Implementation by Durlak and DuPre.

Results

Program reach: Ten schools were contacted to successfully recruit three schools, from which 79% of eligible students (n = 308, $$\overline{{\text{x}} }$$

x
¯

age: 13.0 ± 0.6 years, 148 girls) provided consent. Dosage: The average number of HIIT workouts provided was 10 ± 3 and the average number attended by students was 6 ± 2. Fidelity: During HIIT workouts, the percentage of time students spent at ≥ 80% of maximum heart rate (HRmax) was 55% (interquartile range (IQR): 29%—76%). Monitoring of the control group: During lessons, the intervention and control groups spent 32% (IQR: 12%—54%) and 28% (IQR: 13%—46%) of their HPE lesson at ≥ 80% of HRmax, respectively. Responsiveness: On average, students rated their enjoyment of HIIT workouts as 3.3 ± 1.1 (neutral) on a 5-point scale. Quality: Teachers found the HIIT workouts simple to implement but provided insights into the time implications of integrating them into their lessons; elements that helped facilitate their implementation; and their use within the classroom. Differentiation: Making a HIIT involved students and teachers in the co-design of HIIT workouts. Adaption: Workouts were modified due to location and weather, the complexity of exercises, and time constraints.

Conclusion

The comprehensive evaluation of Making a HIIT provides important insights into the implementation of school-based HIIT, including encouragings findings for student enjoyment and fidelity and recommendations for improving dosage that should be considered when developing future interventions.

Trial Registration

ACTRN, ACTRN12622000534785, Registered 5 April 2022 – Retrospectively registered.
Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases
Authors: Wen Jie , Zhang Jingwei , Zhang Hao , Zhang Nan , Lei Ruoyan , Deng Yujia , Cheng Quan , Li He , Luo Peng
Published: April 2024

Background

Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown.

Methods

Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796–456,380) in 15 autoimmune diseases (N = 14,890–314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases.

Results

In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10–4] and NOX [OR: 1.34, p = 2.86 × 10–3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10–2] and PM2.5 [OR: 2.60, p = 5.96 × 10–3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10–2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10–3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10–4] and PM2.5 [OR: 0.17, p = 3.18 × 10–3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases.

Conclusion

This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases.

Graphical abstract (Built by the Biorender)
Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients
Authors: Thonusin Chanisa , Osataphan Nichanan , Leemasawat Krit , Nawara Wichwara , Sriwichaiin Sirawit , Supakham Siriporn , Gunaparn Siriluck , Apaijai Nattayaporn , Somwangprasert Areewan , Phrommintikul Arintaya , Chattipakorn Siriporn C. , Chattipakorn Nipon
Published: April 2024

Background

We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined.

Methods

HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels.

Results

Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment.

Conclusions

The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity.

Trial registration: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.
Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas
Authors: Chen Junxiao , Liu Ziyuan , Fang Haiting , Su Qing , Fan Yiqi , Song Luyao , He Shuai
Published: April 2024

Background

Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5’-C; antisense strand, 3’-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy.

Methods

IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5’-C; antisense strand, 3’-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-β and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection.

Results

IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-β and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors.

Conclusions

This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5’-C; antisense strand, 3’-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.
Comprehensive analysis of bulk and single-cell transcriptomic data reveals a novel signature associated with endoplasmic reticulum stress, lipid metabolism, and liver metastasis in pancreatic cancer
Authors: Liu Xiaohong , Ren Bo , Fang Yuan , Ren Jie , Wang Xing , Gu Minzhi , Zhou Feihan , Xiao Ruiling , Luo Xiyuan , You Lei , Zhao Yupei
Published: April 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy.

Methods

Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored.

Results

A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group.

Conclusions

We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell–cell communication in the tumor microenvironment.
Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first
Authors: Storwick John A. , Tam Herman , Rosenbaum Daniel G. , Houghton Kristin
Published: April 2024

Background

Immune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature.

Case Presentation

A 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy.

Conclusions

To our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.
Interaction of high-fat diet and brain trauma alters adipose tissue macrophages and brain microglia associated with exacerbated cognitive dysfunction
Authors: Henry Rebecca J. , Barrett James P. , Vaida Maria , Khan Niaz Z. , Makarevich Oleg , Ritzel Rodney M. , Faden Alan I. , Stoica Bogdan A.
Published: April 2024

Obesity increases the morbidity and mortality of traumatic brain injury (TBI). Detailed analyses of transcriptomic changes in the brain and adipose tissue were performed to elucidate the interactive effects between high-fat diet-induced obesity (DIO) and TBI. Adult male mice were fed a high-fat diet (HFD) for 12 weeks prior to experimental TBI and continuing after injury. High-throughput transcriptomic analysis using Nanostring panels of the total visceral adipose tissue (VAT) and cellular components in the brain, followed by unsupervised clustering, principal component analysis, and IPA pathway analysis were used to determine shifts in gene expression patterns and molecular pathway activity. Cellular populations in the cortex and hippocampus, as well as in VAT, during the chronic phase after combined TBI-HFD showed amplification of central and peripheral microglia/macrophage responses, including superadditive changes in selected gene expression signatures and pathways. Furthermore, combined TBI and HFD caused additive dysfunction in Y-Maze, Novel Object Recognition (NOR), and Morris water maze (MWM) cognitive function tests. These novel data suggest that HFD-induced obesity and TBI can independently prime and support the development of altered states in brain microglia and VAT, including the disease-associated microglia/macrophage (DAM) phenotype observed in neurodegenerative disorders. The interaction between HFD and TBI promotes a shift toward chronic reactive microglia/macrophage transcriptomic signatures and associated pro-inflammatory disease-altered states that may, in part, underlie the exacerbation of cognitive deficits. Thus, targeting of HFD-induced reactive cellular phenotypes, including in peripheral adipose tissue immune cell populations, may serve to reduce microglial maladaptive states after TBI, attenuating post-traumatic neurodegeneration and neurological dysfunction.
Clinical accuracy of instrument-based SARS-CoV-2 antigen diagnostic tests: a systematic review and meta-analysis
Authors: Manten Katharina , Katzenschlager Stephan , Brümmer Lukas E. , Schmitz Stephani , Gaeddert Mary , Erdmann Christian , Grilli Maurizio , Pollock Nira R. , Macé Aurélien , Erkosar Berra , Carmona Sergio , Ongarello Stefano , Johnson Cheryl C. , Sacks Jilian A. , Faehling Verena , Bornemann Linus , Weigand Markus A. , Denkinger Claudia M. , Yerlikaya Seda
Published: April 2024

Background

During the COVID-19 pandemic, antigen diagnostic tests were frequently used for screening, triage, and diagnosis. Novel instrument-based antigen tests (iAg tests) hold the promise of outperforming their instrument-free, visually-read counterparts. Here, we provide a systematic review and meta-analysis of the SARS-CoV-2 iAg tests’ clinical accuracy.

Methods

We systematically searched MEDLINE (via PubMed), Web of Science, medRxiv, and bioRxiv for articles published before November 7th, 2022, evaluating the accuracy of iAg tests for SARS-CoV-2 detection. We performed a random effects meta-analysis to estimate sensitivity and specificity and used the QUADAS-2 tool to assess study quality and risk of bias. Sub-group analysis was conducted based on Ct value range, IFU-conformity, age, symptom presence and duration, and the variant of concern.

Results

We screened the titles and abstracts of 20,431 articles and included 114 publications that fulfilled the inclusion criteria. Additionally, we incorporated three articles sourced from the FIND website, totaling 117 studies encompassing 95,181 individuals, which evaluated the clinical accuracy of 24 commercial COVID-19 iAg tests. The studies varied in risk of bias but showed high applicability. Of 24 iAg tests from 99 studies assessed in the meta-analysis, the pooled sensitivity and specificity compared to molecular testing of a paired NP swab sample were 76.7% (95% CI 73.5 to 79.7) and 98.4% (95% CI 98.0 to 98.7), respectively. Higher sensitivity was noted in individuals with high viral load (99.6% [95% CI 96.8 to 100] at Ct-level ≤ 20) and within the first week of symptom onset (84.6% [95% CI 78.2 to 89.3]), but did not differ between tests conducted as per manufacturer’s instructions and those conducted differently, or between point-of-care and lab-based testing.

Conclusion

Overall, iAg tests have a high pooled specificity but a moderate pooled sensitivity, according to our analysis. The pooled sensitivity increases with lower Ct-values (a proxy for viral load), or within the first week of symptom onset, enabling reliable identification of most COVID-19 cases and highlighting the importance of context in test selection. The study underscores the need for careful evaluation considering performance variations and operational features of iAg tests.
Epidemiology of autoimmune liver disease in Korea: evidence from a nationwide real-world database
Authors: Lim Jihye , Kim Hwa Jung
Published: April 2024

Background

Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are all immune-mediated chronic inflammatory liver diseases. Autoimmune liver diseases are rare, making identification and treatment difficult. To improve clinical outcomes and enhance patient quality of life, we performed an epidemiological study of autoimmune liver diseases based on real-world comprehensive data.

Results

We used National Health Insurance Service claims data in Korea from 2005 to 2019. Patients were identified using the International Classification of Disease 10th Revision code, and rare intractable disease codes assigned according to the strict diagnostic criteria. In the AIH cohort, 8,572 (83.9%) were females and the mean age at diagnosis was 56.3 ± 14.3 years. PBC also showed female dominance (83.3%) and the mean age was 57.8 ± 12.6 years. Patients with PSC showed no sex predominance and had a mean age of 57.8 ± 21.5 years. During the study period, there were 10,212, 6,784, and 888 AIH, PBC, and PSC patients, respectively. The prevalence of AIH, PBC, and PSC in 2019 were 18.4, 11.8, and 1.5 per 100,000 population, while the corresponding incidences were 2.3, 1.4, and 0.3 per 100,000 population, respectively. Analysis of sex-age-standardized data showed that the annual prevalence of these diseases is increasing. The 10-year survival rates were 89.8%, 74.9%, and 73.4% for AIH, PBC, and PSC, respectively.

Conclusions

The number of patients with autoimmune liver disease in South Korea is increasing over time. Further research on autoimmune liver disease is needed to fulfill unmet clinical needs.
Application of tandem mass spectrometry in the screening and diagnosis of mucopolysaccharidoses
Authors: Li Jing-Wen , Mao Shao-Jia , Chao Yun-Qi , Hu Chen-Xi , Qian Yan-Jie , Dai Yang-Li , Huang Ke , Shen Zheng , Zou Chao-Chun
Published: April 2024

Mucopolysaccharidoses (MPSs) are caused by a deficiency in the enzymes needed to degrade glycosaminoglycans (GAGs) in the lysosome. The storage of GAGs leads to the involvement of several systems and even to the death of the patient. In recent years, an increasing number of therapies have increased the treatment options available to patients. Early treatment is beneficial in improving the prognosis, but children with MPSs are often delayed in their diagnosis. Therefore, there is an urgent need to develop a method for early screening and diagnosis of the disease. Tandem mass spectrometry (MS/MS) is an analytical method that can detect multiple substrates or enzymes simultaneously. GAGs are reliable markers of MPSs. MS/MS can be used to screen children at an early stage of the disease, to improve prognosis by treating them before symptoms appear, to evaluate the effectiveness of treatment, and for metabolomic analysis or to find suitable biomarkers. In the future, MS/MS could be used to further identify suitable biomarkers for MPSs for early diagnosis and to detect efficacy.
Germline biallelic BRCA2 pathogenic variants and medulloblastoma: an international cohort study
Authors: Kastellan Svenja , Kalb Reinhard , Sajjad Bia , McReynolds Lisa J. , Giri Neelam , Samuel David , Milde Till , Elbracht Miriam , Holzhauer Susanne , Niewisch Marena R. , Kratz Christian P.
Published: April 2024

Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes. Among patients with FA, the highest cancer risks are observed in patients with biallelic pathogenic variants in BRCA2 or PALB2. These patients develop a range of embryonal tumors and leukemia during the first decade of life, however, little is known about specific clinical, genetic and pathologic features or toxicities. Here, we present genetic, clinical, pathological and treatment characteristics observed in an international cohort of eight patients with FA due to biallelic BRCA2 pathogenic variants and medulloblastoma (MB), an embryonal tumor of the cerebellum. Median age at MB diagnosis was 32.5 months (range 7–58 months). All patients with available data had sonic hedgehog-MB. Six patients received chemotherapy and one patient also received proton radiation treatment. No life-threatening toxicities were documented. Prognosis was poor and all patients died shortly after MB diagnosis (median survival time 4.5 months, range 0–21 months) due to MB or other neoplasms. In conclusion, MB in patients with biallelic BRCA2 pathogenic variants is a lethal disease. Future experimental treatments are necessary to help these patients.