bluuebunny/crossref_metadata_2025 huggingface dataset:
Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions
Authors: Kuo Grace , Kumbhar Ramhari , Blair William , Dawson Valina L. , Dawson Ted M. , Mao Xiaobo
Published: January 2025

α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies.

Graphical Abstract
Neutrophil-to-lymphocyte ratio as a predictor of short- and long-term complications in pediatric burns
Authors: Delgado-Miguel Carlos , Fuentes Gómez Lara , García Morán Ada , Miguel-Ferrero Miriam , Díaz Mercedes , López-Gutiérrez Juan Carlos
Published: January 2025

Background

Neutrophil-to-Lymphocyte Ratio (NLR) has been postulated as a useful inflammatory biomarker in the prediction of complications in different pediatric diseases. Our aim is to analyze the predictive value of NLR in the development of complications in burned children, both in the short-term (need for grafting) and in the long-term (need for surgery of the sequelae).

Methods

A retrospective study was performed on burned patients under 18-years admitted to our Burn Unit between 2015 and 2021. Demographic, clinical and laboratory data at admission were evaluated. Predictive factors for the development of complications after burns (time of evolution, burned total body surface area, and acute phase reactants) were analyzed using sensitivity and specificity analysis (ROC curves).

Results

A total of 342 patients (198 males, 144 females) were included, with a median age of 27 months (interquartile range 15–83 months). In 97.4% of the cases, burns were primarily caused by thermal injuries (78.4% scald burns). Acute escharectomy and grafting were performed in 85 patients (24.9%), while long-term sequelae were observed in 112 cases (32.7%). NLR was the most sensitive and specific predictor for the need for escharectomy and grafting (Sensitivity 90%, Specificity 88.4%; AUC 0.920), for the development of long-term sequelae (Sensitivity 80.4%, Specificity 83.5%; AUC 0.849) and for the need for surgery of the sequelae (Sensitivity 83.5%, Specificity 80.9%; AUC 0.833).

Conclusion

NLR may be considered a useful predictor for the development of short- and long-term complications in childhood burns. It may help in the identification of high-risk patients to prevent sequelae.
Clinical manifestations in Egyptian Pompe disease patients: Molecular variability and enzyme replacement therapy (ERT) outcomes
Authors: Hussein Mohamed Abdelghafar , ElTaher Heba , Mahmoud Ranim , Sobh Donia , Al-Haggar Mohammad
Published: January 2025

Background

Pompe disease is a rare genetic disorder caused by a deficiency of the enzyme acid alpha-glucosidase. This condition leads to muscle weakness, respiratory problems, and heart abnormalities in affected individuals.

Methods

The aim of the study is to share our experience through cross sectional study of patients with infantile-onset Pompe disease (IOPD) with different genetic variations, resulting in diverse clinical presentations. We evaluated their phenotype, genotype, radiological and laboratory findings including their cross-reactive immunologic material (CRIM) status. Infantile Pompe disease was diagnosed by measurement of the activity of the enzyme alpha-glucosidase. The diagnosis was confirmed by molecular genetic testing using PCR amplification and sequencing of the acid alpha-glucosidase (GAA) gene. Routine two-D echocardiography, and multi-parametric ECG-gated cardiac magnetic resonance imaging (CMR) were done to patients six months after starting enzyme replacement therapy (ERT).

Results

The results of our study revealed different genetic mutations among our patients, different CRIM status and also CMR abnormalities. CMR imaging revealed abnormalities in all cases that underwent the procedure, including myocardial and vascular changes, with feature tracking indicating issues across all parameters and LGE suggesting fibrosis. The patient with a positive immune response had the most severe cardiac abnormalities, despite improvements in muscle weakness and motor skills from ERT. This underscores that delayed diagnosis and ERT can lead to irreversible heart damage from autophagy buildup.

Conclusion

Pompe disease has various clinical presentations and results in significant CMR findings, which can be attributed to different genetic mutations. Early initiation of enzyme replacement therapy in infantile-onset Pompe disease is important to maximize its benefits.
Differential diagnostic value of P wave dispersion and QT interval dispersion between psychogenic pseudosyncope and vasovagal syncope in children and adolescents
Authors: Huang Zifeng , Xu Yi , Wang Shuo , Liu Ping , Zen Xingfang , Wang Yuwen , Li Fang , Zou Runmei , Wang Cheng
Published: January 2025

Background

Both psychogenic pseudosyncope (PPS) and vasovagal syncope (VVS) in children and adolescents are diseases of transient loss of consciousness. It is difficult to distinguish them clinically. This paper will study the differential diagnostic value of P wave dispersion (Pd) and QT interval dispersion (QTd) between PPS and VVS.

Methods

The 31 children with PPS and 40 children with VVS from July 2014 to November 2023 were enrolled as the study group. Meanwhile, 30 healthy children who underwent a physical examination at the same hospital were matched to the control group. P wave duration and QT interval in the 12-lead electrocardiogram were measured at the baseline.

Results

(1) Comparison between groups: ① The Pd, corrected P wave dispersion (Pcd), QTd, and corrected QT interval dispersion (QTcd) in PPS group were significantly higher than those in control group (P < 0.05). The minimum P wave duration (Pmin) and corrected P wave duration (Pcmin) in PPS group were significantly lower than those in control group (P < 0.05). There were no significant differences in maximum P wave duration (Pmax), corrected maximum P-wave duration (Pcmax), maximum QT interval (QTmax), minimum QT interval (QTmin), corrected maximum QT interval (QTcmax), and corrected minimum QT interval (QTcmin) between PPS group and control group (P > 0.05). ② The Pd, Pcd, QTd, and QTcd in VVS group were significantly higher than those in control group (P < 0.05). The Pmin, Pcmin, and QTcmin in VVS group were significantly lower than those in control group (P < 0.05). There were no significant differences in Pmax, Pcmax, QTmax, QTmin, and QTcmax between VVS group and control group (P > 0.05). ③ The Pmax, Pd, QTmax, QTd, and QTcd in PPS group were significantly lower than those in VVS group (P < 0.05). There were no significant differences in Pmin, Pcmax, Pcmin, Pcd, QTmin, QTcmax, and QTcmin between PPS group and VVS group (P > 0.05). (2) ROC curve: Pmax, Pd, QTmax, QTd, and QTcd had a certain differential diagnostic value between PPS and VVS in children and adolescents (P < 0.05). QTd had the largest area under curve (0.735), with a sensitivity of 85.00% and a specificity of 53.30% at the cut off value of ≥ 28.11 ms for VVS diagnosis.

Conclusions

In children and adolescents, electrocardiogram parameters such as Pmax, Pd, QTmax, QTd, and QTcd all possess predictive value in differentiating between PPS and VVS. Among them, QTd has the greatest differential diagnostic value.
First report of Haemaphysalis bispinosa, molecular-geographic relationships of Ixodes granulatus and a new Dermacentor species from Vietnam
Authors: Hornok Sándor , Kontschán Jenő , Keve Gergő , Takács Nóra , Van Nguyen Dat , Ho Khanh Ngoc Phuong , Görföl Tamás , Wang Yuanzhi , Farkas Róbert , Dao Thanh Thi Ha
Published: January 2025

Background

Vietnam and its region are regarded as an ixodid tick biodiversity hotspot for at least two genera: Haemaphysalis and Dermacentor. To contribute to our knowledge on the tick fauna of this country, ticks from these two genera as well as an Ixodes species were analyzed morphologically and their molecular-phylogenetic relationships were examined in taxonomic and geographical contexts.

Methods

For this study, seven Haemaphysalis sp. ticks were removed from dogs and collected from the vegetation. These showed morphological differences from congeneric species known to occur in Vietnam. In addition, three Ixodes sp. ticks were collected from pygmy slow lorises (Xanthonycticebus pygmaeus), and a Dermacentor female had been previously collected from the vegetation. After DNA extraction, these were molecularly or phylogenetically analyzed based on the cytochrome c oxidase subunit I (cox1) and 16S rRNA genes.

Results

The three species were morphologically identified as (i) Ixodes granulatus, which had nearly or exactly 100% sequence identities to conspecific ticks reported from large (approximately 2000 km) geographical distances but was more different (having lower, only 94.2% cox1 and 96.7% 16S rRNA sequence identity) from samples collected within 1000 km of Vietnam in Southern China and Malaysia, respectively; (ii) Haemaphysalis bispinosa, which showed 100% sequence identity to samples reported within both narrow and broad geographical ranges; and (iii) a new species, Dermacentor pseudotamokensis Hornok sp. nov., described here morphologically and shown to be phylogenetically a sister species to Dermacentor tamokensis.

Conclusions

Haemaphysalis bispinosa shows genetic homogeneity in the whole of South and Southeast Asia, probably owing to its frequent association with domestic ruminants and dogs (i.e. frequently transported hosts). However, I. granulatus, the Asian rodent tick, has a mixed geographical pattern of haplotypes, probably because it may associate with either synanthropic or wild-living rodents as primary hosts. This tick species is recorded here, for the first time to our knowledge, as parasitizing lorises in Vietnam and its region. Based on phylogenetic analyses, D. pseudotamokensis Hornok sp. nov., recognized and described here for the first time, was almost certainly misidentified previously as Dermacentor steini, drawing attention to the need to barcode all Dermacentor spp. in Southern Asia.

Graphical Abstract
Magnesium ions regulate the Warburg effect to promote the differentiation of enteric neural crest cells into neurons
Authors: Xu Qiongqian , He Xixi , Mou Yaru , Sun Dong , Zhang Xintao , Han Jichang , Liu Xiaoyang , Liu Xingjian , Ren Xue , Wang Dongming , Wang Jian , Ma Chuncan , Zhang Qiangye , Li Aiwu
Published: January 2025

Background

Understanding how enteric neural crest cells (ENCCs) differentiate into neurons is crucial for neurogenesis therapy and gastrointestinal disease research. This study explores how magnesium ions regulate the glycolytic pathway to enhance ENCCs differentiation into neurons.

Materials and methods

We used polymerase chain reaction, western blot, immunofluorescence, and multielectrode array techniques to assess magnesium ions' impact on ENCCs differentiation. Non-targeted metabolomic sequencing, cellular acidification rate, oxygen consumption, and western blot analyzed sugar metabolism changes. D-glucose-13C6 isotope tracing identified key glucose flux changes. Surface plasmon resonance was used to detect the binding affinity of magnesium ions with key glycolysis genes. The elastic modulus of the hydrogel was measured using a universal testing machine, while pore size and porosity were assessed with scanning electron microscopy. Swelling ratios were determined using gravimetric analysis. In vivo, ENCCs in hydrogels were transplanted into renal capsule and subcutaneously, and magnesium ions' effects on ENCCs differentiation were evaluated.

Results

Magnesium ions increased glycolysis levels during ENCCs differentiation into neurons, along with significant upregulation of neuronal markers β-Tubulin and ubiquitin C-terminal hydrolase L1, and enhanced functional neuronal properties. D-glucose-13C6 tracing results showed increased carbon flux in the glycolytic pathway after magnesium supplementation. The binding affinity of magnesium ions with the glycolytic key enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was found to be 1.08 μM. Inhibiting glycolysis suppressed ENCCs differentiation into neurons, emphasizing its crucial role. The double-cross-linked hydrogel gelatin methacryloyl—alginate (gelMA—ALMA), cross-linked with magnesium ions, showed promise in enhancing ENCCs differentiation in vivo without causing systemic hypermagnesemia.

Conclusion

Magnesium ions promote ENCCs differentiation into neurons by activating the Warburg effect. The GelMA-ALMA hydrogel serves as an effective localized magnesium delivery system, supporting neuronal differentiation in vivo.

Graphical abstract

Magnesium ions target PFKFB3, enhancing glucose flux towards G3P and subsequent lactate production, while also promoting ENCCs differentiation into neurons by facilitating NAD+ generation, suppressing ROS, and maintaining mitochondrial homeostasis. Mg: Mg2+, Glu: glucose, LA: lactic acid. Ref to the creation software of the picture.
School principals’ proposals for preventive actions to improve mental health
Authors: Persson Roger , Leo Ulf , Arvidsson Inger , Nilsson Kerstin , Österberg Kai , Håkansson Carita
Published: January 2025

Background

School principals face a demanding work situation that puts them at risk for stress-related poor mental health. Ideally, preventive actions should be based on knowledge about the underlying notions that motivate action. However, knowledge about prevention areas and suitable initiatives for school principals is scarce or lacking, leaving key stakeholders without the overview necessary for effectively engaging in preventive actions.

Objective

To describe school principals’ proposals for suitable target areas and preventive actions that may decrease their workload and improve their mental health.

Methods

An aggregated analysis was conducted using data from a larger project involving two national surveys (N = 2871), nine group interviews (N = 39), and eleven workshops (N = 270). The project was designed a priori to examine multiple questions, including identifying target areas and collecting proposals for preventive actions.

Results

Forty-four proposals for preventive actions spanning various levels and six major themes were identified: Role demands and role conflicts (8 proposals); Organizational support (6 proposals); Resources and resource allocation (3 proposals); Continued professional development and coaching (2 proposals); The principal as a coworker (6 proposals); Personal actions (19 proposals).

Conclusions

The considerable number of proposals and their content reveal that preventive actions are needed at all levels of the educational system and that the school principals’ personal resources matter for improving their work situation and mental health. The pattern of results also underscores the importance of having a deep understanding of what problems to address, and in which context they unfold, before engaging in preventive actions.
Understanding excess mortality during COVID in Belgium: the influence of pre-existing health status and social factors
Authors: Van den Borre Laura , Devleesschauwer Brecht , Gadeyne Sylvie , Vanthomme Katrien , Willaert Didier
Published: January 2025

Background

This study aims to investigate how pre-existing health status and social background contribute to excess mortality during the COVID-19 crisis in Belgium.

Methods

The study population consists of almost 1.4 million adult members of Solidaris, the second largest health insurance fund in Belgium. Pre-existing health status was identified using health care reimbursement data, including medication use. Social characteristics included a proxy for low socio-economic status, nationality of origin, and living arrangement. Excess mortality during the COVID-19 crisis was measured by computing the relative difference between all-cause mortality in 2020 or 2021 and the average yearly mortality in 2015–2019. Directly Standardised Mortality Rates (DSMRs) were calculated to investigate absolute mortality inequalities. Mortality Rate Ratios (MRRs) were computed using Poisson regression analyses to investigate relative mortality inequalities.

Results

DSMRs show that persons with no previous disease experienced significant excess mortality in 2020, like men with one, two or three diseases and women with various numbers of pre-existing diseases. Results by specific disease show heterogenous results. After adjusting for age, sex and social characteristics, persons with cancer experienced a significant mortality deficit of 17% in 2020 and of 9% in 2021. For persons with cancer and asthma or COPD, significant mortality deficits of 10% and  3% were observed in 2020 and 2021, respectively.

Conclusion

The study provides insights into the complex dynamics of mortality during the COVID-19 crisis, emphasising the need to consider individual-level information on pre-existing health and social background jointly.
Community supported agriculture’s perceived positive impacts on mental health and vegetable consumption in Norway and the UK
Authors: Milford Anna-Birgitte , Keech Daniel , Muiruri Sarah Wangui
Published: January 2025

Community supported agriculture (CSA) is a format for provisioning food, usually vegetables, where consumers are involved, to various degrees, in the production process. In this study of survey data, we explore differences between CSAs in Norway and the UK in terms of organisational models and member characteristics, particularly the factors that contribute to increase member contentment with CSAs, and their perceptions of their own mental health and vegetable consumption. Results show that compared to the British, Norwegian CSA members participate far more actively in the cultivation and harvesting of the vegetables, and more often prepay subscriptions for the whole season. In both countries, CSA membership was perceived to have caused improvements in members’ life quality, vegetable intake and physical and mental health. Members who participated more actively in the CSA and who received more of their vegetables through the CSA, were also more satisfied with their CSA and had a stronger perception that their vegetable consumption level and their mental health were positively affected by membership. Members with lower educational attainment levels were more likely to have discovered new vegetables through the CSA. Environmentally friendly production methods were also found to be important for CSA members. Vegetable quality and affordability were associated with higher contentment, and learning how to cook and grow vegetables through the CSA was associated with higher consumption of, and interest in, new vegetables. Overall, the results indicate that CSAs can stimulate contentment due to their members’ perceptions of social and environmental benefits.
Disproportionate, differential and targeted treatment: people who use drugs’ experiences of policing during the COVID-19 pandemic
Authors: Walker Shelley , Rathnayake Kasun , Dietze Paul , Higgs Peter , Ward Bernadette , Hellard Margaret , Doyle Joseph , Stoove Mark , Maher Lisa
Published: January 2025

Background

During the COVID-19 pandemic, governments worldwide introduced law enforcement measures to deter and punish breaches of emergency public health orders. For example, in Victoria, Australia, discretionary fines of A$1,652 were issued for breaching stay-at-home orders, and A$4,957 fines for ‘unlawful gatherings’; to date, approximately 30,000 fines remain outstanding or not paid in full. Studies globally have revealed how the expansion of policing powers produced significant collateral damage for marginalized populations, including people from low-income neighboorhoods, Indigenous Peoples, sex workers, and people from culturally diverse backgrounds. For people who use drugs, interactions with police are commonplace due to the criminalization of drug use, however, little empirical attention has been given to their experiences of pandemic policing; we aimed to address this gap in the literature.

Methods

We conducted a mixed methods study involving participants of two prospective observational cohort studies of people who use drugs (n = 2,156) in Victoria, Australia, to understand impacts of the pandemic on their lives. Between 2020 and 2022 pandemic-related questions were added to survey instruments; during this period, 1,130 participants completed surveys. We descriptively analyzed the data of participants who reported police interactions related to pandemic restrictions (n = 125) and conducted qualitative interviews with 89 participants. Qualitative data were analysed thematically and integrated with quantitative results.

Results

11% (n = 125) of survey respondents reported pandemic-related interactions with police; most (26%) were for breaching curfews and 30% received COVID-19 fines. Qualitative interviewees observed increased policing in street-based drug markets and local neighborhoods; many felt harassed and believed policing practices were targeted and discriminatory. Thirty-eight interviewees received COVID-19 fines; some were fined while homeless or travelling to or from harm reduction services. All lacked the financial means to pay fines, resulting in fear of additional criminalizing effects such as additional financial penalties, court orders, criminal convictions, and incarceration; for some fears became a reality.

Conclusion

Our study demonstrates how public health emergency responses centred around policing and criminalization exacerbated harms for people who use drugs, with detrimental effects enduring beyond the pandemic. Results provide insights for future public health emergencies, including highlighting the need for responses that protect, rather than abrogate the health and safety needs of marginalized and criminalized groups.
Extracellular vesicles-derived miR-21 as a biomarker for early diagnosis and tumor activity in breast cancer subtypes
Authors: Omarini Claudia , Catani Virginia , Mastrolia Ilenia , Toss Angela , Banchelli Federico , Isca Chrystel , Medici Daniele , Ponzoni Ornella , Brucale Marco , Valle Francesco , Baschieri Maria Cristina , D’Amico Roberto , Masciale Valentina , Chiavelli Chiara , Caggia Federica , Bortolotti Carlo Augusto , Piacentini Federico , Dominici Massimo
Published: January 2025

Emerging evidence highlights the key role of microRNA (miR)-21 in cell-to-cell communication and tumorigenesis. However, limited knowledge exists on the levels and clinical meaning of miR-21 in extracellular vesicles (EVs) of patients with breast cancer (BC). We assessed EV-derived miR-21 levels in one hundred women: 30 with early BC (EBC), 30 with metastatic BC on treatment progression (MBC), 30 cancer survivors on follow-up (FU) and 10 healthy donors (HD) as age- and body mass index (BMI)-matched controls. EVs isolated from serum samples were characterized using nanoparticle tracking analysis, scanning electron microscopy and atomic force microscopy to detect their concentration, size, morphology and mechanical properties. The levels of miR-21 in EVs was evaluated using real time PCR and compared between groups (EBC, MBC and FU vs. HD) by calculating the fold change and ΔΔCt statistic. EVs size and concentration did not differ significantly among patient groups. In the EBC group, the clinical stage at diagnosis and tumor subtype did not influence miR-21 levels. The levels of miR-21 were higher in the MBC group than in the HD group (p = 0.029), mainly in those who were human epidermal growth factor receptor 2 (HER2)+ (p = 0.0005) and hormone receptor-positive (p = 0.036). In particular, in the HER2 + subgroup, the miR-21 levels were significantly higher in those with active BC (both EBC and MBC) than in HDs (p = 0.002). Our findings suggest that miR-21 may be a promising biomarker for diagnosis and tumor activity, mainly in HER2 + BC.
Global, regional, and national burden of heart failure and its underlying causes, 1990–2021: results from the global burden of disease study 2021
Authors: Ran Jun , Zhou Ping , Wang Jinxi , Zhao Xuemei , Huang Yan , Zhou Qiong , Zhai Mei , Zhang Yuhui
Published: January 2025

Background

Heart failure (HF) remains a significant public health challenge globally. This study aims to systematically analyze the global HF disease burden from 1990 to 2021 across temporal, spatial, and demographic dimensions to provide evidence for targeted prevention and control strategies.

Methods

Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed the global HF burden through prevalent cases, years lived with disability (YLDs), and age-standardized rates per 100,000 population. Temporal trends were evaluated using estimated annual percentage change (EAPC) and joinpoint regression analysis. The relationship between the Socio-demographic Index (SDI) and disease burden was explored through Pearson correlation analysis, while attribution analysis identified the main causes of HF. When appropriate, analyses were stratified by 5 SDI regions, 21 GBD regions, 204 countries and territories, 20 age groups, and both sexes.

Results

Global HF prevalence and YLDs burden showed substantial increases from 1990 to 2021, with age-standardized prevalence increasing from 641.14 to 676.68 per 100,000 population. Notably, high-SDI regions exhibited a declining burden since 2019, indicating a potential global turning point. High-income North America bears the heaviest burden while South Asia shows the fastest growth rate. The correlation between disease burden and SDI level was negligible. The disease burden in males consistently exceeded that in females, with prevalence and YLDs rates rising sharply after age 60. The main causes and their attributable proportions were: ischemic heart disease (34.53%), hypertensive heart disease (22.53%), other cardiomyopathies (7.61%), chronic obstructive pulmonary disease (6.51%), and congenital heart anomalies (5.69%), with their distribution patterns differing across age groups and regions.

Conclusion

Global burden of HF increased significantly over recent decades, with a potential turning point in 2019 and marked regional disparities. It is essential to prioritize regions with heavy burdens or rapid growth rates, strengthen the management of major causes, and monitor HF burden trends in the post-COVID era.
ROR1 CAR-T cells and ferroptosis inducers orchestrate tumor ferroptosis via PC-PUFA2
Authors: Li Dan , Zhang Wenjie , Wang Ruiheng , Xie Shufeng , Wang Yixin , Guo Wanxin , Huang Zixuan , Lu Chaoqun , Shan Liang , Liu Han , Ma Lifang , Hou Xumin , Xu Zhenshu , Wang Jiayi
Published: January 2025

Background

Lung cancer, particularly non-small cell lung cancer (NSCLC), has high recurrence rates and remains a leading cause of cancer-related death, despite recent advances in its treatment. Emerging therapies, such as chimeric antigen receptor (CAR)-T cell therapy, have shown promise but face significant challenges in targeting solid tumors. This study investigated the potential of combining receptor tyrosine kinase-like orphan receptor 1 (ROR1)-targeting CAR-T cells with ferroptosis inducers to promote ferroptosis of tumor cells and enhance anti-tumor efficacy.

Methods

RNA-seq data and immunofluorescence analysis of relapsed NSCLC patient samples were used to explore ROR1 expression. In addition, ROR1-targeting CAR-T cells were developed to assess cytotoxic activity against ROR1+ tumor cells, and the effect of cytokine stimulation on their efficacy was evaluated. Lipidomics, immunofluorescent histochemistry, and western blotting were used to explore the observed effects. Ferroptosis indicators, including levels of reactive oxygen species, were used to detect the combined effect of CAR-T cells and ferroptosis-inducing drugs. Finally, tumor-bearing mice were used to validate the in vivo efficacy of the combination therapy strategy.

Results

Tumor cells treated with ferroptosis inducers showed increased sensitivity to Interferon gamma (IFN-γ) secreted by ROR1 CAR-T cells. Furthermore, ROR1 CAR-T cells enhanced the production of phosphatidylcholine with diacyl-polyunsaturated fatty acid tails (PC-PUFA2) by working in tandem with IFN-γ. This enhancement promoted the expression of acyl-CoA synthetase long chain family member 4 (ACSL4), which in turn strengthened the overall anti-tumor response.

Conclusions

Combining ROR1 CAR-T cells with ferroptosis inducers enhanced anti-tumor efficacy in NSCLC by promoting ferroptosis through increased lipid peroxidation.
Proposal for modifying procedures for declaring significant trends in TIMSS
Authors: Braun Henry Isaiah , von Davier Matthias , Chen Jihang
Published: January 2025

International large-scale assessments (ILSA) are an important source of information for education policymakers across the globe. Despite sponsors’ warnings, when results are published, media attention focuses on country rankings and changes in scores. Score changes are evaluated using a two-sided z-statistic, with statistical significance declared if the statistic exceeds 1.96 in absolute value. Findings of significance occasion much commentary and may also have policy implications. Particularly problematic, however, are cases in which a significant trend in one direction is followed in the next cycle by a significant trend in the opposite direction. Such reporting reversals are often difficult to explain on substantive grounds and, consequently, can undermine the credibility of the ILSA. This article proposes and evaluates a new approach to determining the significance of observed score changes. It employs a two one-sided test (TOST) procedure. A key feature is establishing an equivalence zone around zero. A change is declared only if the test statistic does not fall in the equivalence zone. Thus, the procedure combines consideration of statistical significance and substantive importance. We augment the TOST procedure with the Benjamini–Hochberg procedure (BH-TOST) to control the False Discovery Rate , to address the problem of multiplicity. Using data from TIMSS (2011, 2015, 2019), we explore different parameter choices for BH-TOST and evaluate the operating characteristics of the selected version with respect to three different criteria. Our results indicate that BH-TOST is generally superior to the current procedure, concluding that it merits serious consideration as a basis for reporting TIMSS results.
Filtration flow rate at low convection volume in continuous hemodiafiltration using cytokine adsorbing hemofilter does not affect cytokine clearance in an experimental model
Authors: Kudo Mototsugu , Chihara Shinya , Tatsumi Hiroomi , Masuda Yoshiki
Published: January 2025

Background

In recent years, continuous kidney replacement therapy (CKRT) with a cytokine adsorbing hemofilter (CAH) has been used in clinical practice to treat acute kidney injury associated with hypercytokinemia. Two types of CAH are available, including polymethyl methacrylate (PMMA) and polyethylenimine-coated polyacrylonitrile (AN69ST), each having distinct adsorption mechanisms. PMMA adsorbs substances with hydrophobic bases through hydrophobic interactions, resulting in occlusion of the membrane pores. AN69ST adsorbs positively charged substances through electrostatic bonds because its bulk layer is negatively charged. In both CAH, the adsorption efficiency of cytokines with large molecular weights is likely affected by filtration rather than by diffusion transfer. These adsorbing-type membranes have limitations in terms of filtration flow rate because of their low water permeability. The relationship between the adsorption effect and the filtration flow rate in CAH-CKRT has not been fully investigated.

Purpose

The effect of low-convection volume settings below 600 mL/h on cytokine adsorption characteristics was experimentally investigated in CKRT.

Materials and methods

Test solutions, including albumin (4.5%), creatinine (10 mg/dL), interleukin (IL)-6 (1000 pg/mL), and IL-8 (1000 pg/mL), were prepared. The test solution was circulated through the experimental circuit of continuous hemodiafiltration (CHDF) with a total convection volume ranging from 0 to 600 mL/h. The test solution was circulated through the experimental circuit of hemodiafiltration (CHDF) with various dialysate flow rates (QD; 0, 200, 400, and 600 ml/h) and filtration flow rates (QF; 0, 200, 400, and 600 ml/h). Samples immediately before and after CAH from the sampling port of the circuit were collected seven times at 1-min intervals. Clearances of creatinine, IL-6, and IL-8 were calculated for each setting of the proportions of QD and QF during CKRT using PMMA and AN69ST.

Results

Creatinine clearance increased with increasing QD and QF, regardless of the membrane type. There were no significant differences in the adsorption clearance of IL-6 and IL-8 among the different settings, regardless of the membrane type.

Conclusion

The results of this study indicate that the cytokine clearance at a low convection volume in CAH-CKRT was not affected by the filtration flow rate.
Delay discounting predicts COVID-19 vaccine booster willingness
Authors: Halilova Julia G. , Fynes‑Clinton Samuel , Terao Caitlin M. , Addis Donna Rose , Rosenbaum R. Shayna
Published: January 2025

Developing ways to predict and encourage vaccine booster uptake are necessary for durable immunity responses. In a multi-nation sample, recruited in June–August 2021, we assessed delay discounting (one’s tendency to choose smaller immediate rewards over larger future rewards), COVID-19 vaccination status, demographics, and distress level. Participants who reported being vaccinated were invited back one year later (n = 2547) to report their willingness to receive a booster dose, along with reasons for their decision. After controlling for demographic variables and distress level, a greater tendency to discount future rewards was associated with reduced willingness to receive a booster dose. Thematic coding revealed that the most common reason for booster willingness was protection against COVID-19, and for unwillingness was non-necessity. The results identify delay discounting as a behavioral predictor of booster willingness that may be used to inform tailored approaches to increase booster uptake (e.g., trust in science vs. vaccine mandates).
Comparing physiological and psychological effects of virtual reality vs. traditional high-intensity interval training in healthy individuals: results from a preliminary pilot randomised controlled trial
Authors: Robinson Jonathan , Razak Mohammad Haziq Bin Abdul
Published: January 2025

Background

Physical inactivity is a growing concern, contributing significantly to the development of chronic diseases. Virtual reality and active video games have emerged as potential solutions to promote physical activity by integrating immersive experiences with exercise. High-intensity interval training (HIIT) is a time-efficient method for improving fitness, but its intensity may reduce motivation. Recent studies suggest that virtual reality (VR) could enhance both the psychological experience and motivation to engage in exercise, making it a promising alternative to traditional HIIT training.

Objectives

The study aimed to explore the feasibility, efficacy, and potential effects of VR compared to traditional HIIT in terms of physiological and psychological outcomes in physically active adults.

Methods

Using a parallel-design pilot randomised controlled trial, 10 participants completed the study and were randomly allocated to either the VR group (n = 5) or non-VR group (n = 5). The VR group participated in a single session of HIIT using the Facebook Oculus Quest 2 VR headset, while the non-VR group underwent a single session of traditional HIIT training. Physiological outcomes, including heart rate parameters (measured using a Polar HR monitor) and rating of perceived exertion (RPE, assessed using the Borg scale), as well as psychological outcomes of the flow experience (measured using the Flow State Scale questionnaire) were assessed.

Results

Statistical analysis showed no significant difference in heart rate parameters between the VR and non-VR groups, indicating that both interventions achieved comparable exercise intensity and meeting the recommended levels for health benefits. However, the VR group demonstrated a lower RPE score (p < 0.001, d = − 3.7; BF
10 = 58.7), suggesting a reduced perception of effort during the exercise session compared to the non-VR group. Additionally, the VR group reported a significantly higher post-intervention flow state score — a state of deep focus and immersion — in the subscale of unambiguous feedback (p = 0.04, d = 1.6; BF
10 = 2.2), reflecting clear, immediate feedback and a more engaging, intrinsically motivating exercise experience.

Conclusions

This pilot study suggests that fully immersive VR can be an effective alternative to traditional HIIT, providing a high-flow experience and potentially enhancing motivation among physically active users.

Trial registration

ClinicalTrials.gov, NCT06420414. Registered 20 May 2024 — retrospectively registered, https://clinicaltrials.gov/study/NCT06420414
A Natural Hydrogen Carbonate Play: Sandino Forearc Basin, Pacific Offshore Nicaragua
Authors: Powney Mike , Jackson Owain , Lawrenc Steve , Barnicoat Andy , Hutchinson Ian
Published: January 2025

The Sandino Forearc Basin of Pacific offshore Nicaragua forms part of the Central American convergent margin where the Cocos plate is subducting beneath the crust of Central America. In subduction zones aqueous fluids are released by dehydration processes in the subducting slab and sediments. These fluids have the potential to cause serpentinization and generate hydrogen in ultramafic rocks of both the crust and mantle above the subduction zone (the upper plate). Geophysical data are used to investigate the hydrogen system formed in this forearc setting. Gravity-seismic modelling along the margin has shown that dense ophiolitic rocks form the crust of the upper plate whilst mantle rocks of the mantle wedge come to within 10km of the bottom of the forearc basin. Both rock-types constitute potential protoliths for serpentinization by aqueous fluids driven off from the hydrous down-going Cocos slab. The configuration and thermal structure of the convergent margin offshore Nicaragua is such that serpentinization of ultramafic protoliths and hydrogen generation is predicted to be occurring below the basin and Outer High of the forearc. The hydrogen generated will move upwards by buoyancy and access the sediments of the basin via faults and fracture networks formed by accretionary tectonics. Late Cretaceous-early Tertiary shallow-water carbonates are known from outcrop and are interpreted from 2D and 3D seismic data in the forearc basin. These carbonates have reservoir potential and form part of the basal section of the basin along the flanks of the Outer High. Thus, they are ideally-placed to be charged by hydrogen emanating from the basement. The shallow-water carbonates form a natural hydrogen exploration play in the Sandino Basin with a fairway definable from seismic interpretation.#xD;
The Association Between Pregnancy Complications and Long-term Maternal Cardiometabolic Health in the MIREC Cohort Study
Authors: Fisher Mandy , Smith Graeme , Potter Beth K , Arbuckle Tye E , Little Julian , Weiler Hope , Morisset Anne-Sophie , Lanphear Bruce , Braun Joseph M , Kumarathasan Premkumari , Walker Mark , Borghese Michael M , Ashley-Martin Jillian , Shutt Robin , Dodds Linda , Bruin Jennifer E , Palaniyandi Jana , Helewa Michael , Taback Shayne , Massarelli Isabelle , Palmert Mark R , Krzeczkowski John , Fraser William D
Published: January 2025

Context

During pregnancy, women who experience certain pregnancy complications show elevations in biomarkers of inflammation and insulin resistance; however, few studies have examined these cardiometabolic biomarkers in the decade following pregnancy.

Objective

To examine the association between pregnancy complications and cardiometabolic biomarkers 9 years postpartum including blood pressure, blood lipids, body fat percentage, insulin resistance [glucose, insulin, proinsulin, C-peptide, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), glycated hemoglobin (HbA1c), leptin, adiponectin], and inflammation (high-sensitivity-C-reactive protein).

Methods

Using data from the Maternal-Infant Research on Environmental Chemicals cohort study (2008-2021), we determined 3 groups of pregnancy complications: (1) hypertensive disorders of pregnancy (HDP) (n = 35); (2) any pregnancy complication in the index pregnancy, defined as preterm birth, HDP, impaired glucose tolerance or gestational diabetes mellitus (n = 55); and (3) self-reported recurrence of 1 of these pregnancy complications (n = 19). Our comparison group included 186 women with uncomplicated pregnancies.

Results

In our adjusted linear regression results, all pregnancy complication groups showed significantly higher systolic and diastolic blood pressure 9 years later. HOMA-IR was 23% [95% confidence interval (CI): −4.4%, 57%], 26% (95% CI: 2.0%, 55%), and 51% (95% CI: 12%, 104%) higher at follow-up in participants who had experienced a prior HDP, an index pregnancy complication, or a recurrent pregnancy complication, respectively. Elevations were also seen with HbA1c, insulin, C-peptide, and leptin, especially among those with recurrent complications.

Conclusion

This study contributes to the body of evidence that women with a history of certain pregnancy complications merit special attention in the prevention of cardiovascular disease. We recommend further exploration into these associations in larger cohorts.
Acquired Generalized Lipodystrophy as an Adverse Event of Combined Immune Checkpoint Inhibitor Therapy
Authors: Kennedy Randol , Macrohon Calvin Rei L , David Mary Lourdes Grace V , Lee Meg , Salama April K S , Shariff Afreen
Published: January 2025

Acquired generalized lipodystrophy (AGL) is rarely associated with immune checkpoint inhibitors (ICIs). A few cases report associations with inhibitors to programmed cell death protein 1 (PD-1 inhibitors); however, association with combined immunotherapies has not been reported. We present a 48-year-old female with recurrent malignant melanoma who underwent 23 cycles of nivolumab, a PD-1 inhibitor, and 11 cycles of combined cytotoxic T lymphocyte associated antigen 4 (CTLA-4) inhibitor and PD-1 inhibitor ipilimumab-nivolumab. During the latter course of combination therapy, she experienced progressive weight loss and a dramatic change in body habitus over 3 to 6 months. Physical examination showed generalized loss of subcutaneous fat with protruding veins and muscular definition. Metabolic workup showed new-onset diabetes mellitus, a very low high-density lipoprotein, severe hypertriglyceridemia, and undetectable leptin/adiponectin levels. Whole-body fluorodeoxyglucose positron emission tomography performed for restaging and response assessment revealed generalized soft tissue edema and diffuse hepatic steatosis. An excisional skin biopsy identified changes consistent with involutional lipoatrophy/lipodystrophy. Treatment included insulin (average total daily dose 0.13-0.26 Units/kg/day) and a combination of lipid-lowering therapy (statins, fenofibrate, icosapent ethyl), which led to marked improvement in triglycerides and symptoms. This case further underscores the emerging challenges with endocrinopathies associated with checkpoint inhibitors.
Lust Room
Authors: Goldberg Greg
Published: January 2025

Over the past decade, liberals have rallied around the cause of gender-inclusive public restrooms, putatively as a way to provide trans and gender-nonconforming people with access to safe facilities, while also building a social movement for gender freedom. At the same time, liberals have remained largely silent on the ongoing surveillance, harassment, assault, arrest, and public shaming of men who cruise public restrooms. How might we make sense of this discrepancy? This essay offers a hypothesis for this relative silence: cruising is intolerable to liberals insofar as it evokes the pleasure of antisocial and self-shattering relations, thereby threatening social commitments. This hypothesis helps explain why liberals, in defending trans and gender-nonconforming peoples’ restroom access, have characterized and reinforced restrooms as nonsexual spaces, effectively insulating gender non-normativity from the stain of sexual perversion. The issues of restroom access and cruising are thus more closely related than they may initially appear to be, as are the liberal silence surrounding cruising and conservative transphobia and transmisogyny.
“Jai Hijra, Jai Jai Hijra”
Authors: Das Rajorshi
Published: January 2025

This article focuses on the 2015 Telangana Queer Swabhimana Walk to explore the relationality of trans activism to questions of culture and region. Documented by Moses Tulasi's film, Walking the Walk (2015), this pride march can be read as a site of decolonial theory-making that reorients the gaze of the mainstream public to hijra and other trans people's historic attachment to land and their fight for justice. The article employs podcast interviews with Tulasi and one of the organizers of the walk, Rachana Mudraboyina, to unpack the distinctiveness of swabhimana (roughly translates to “self-respect”) from globalized notions of pride and caste-based understanding of dignity and respect. In the process, it highlights how working-class trans activists “disidentify” with the Hindu caste system as well as Dalit and anti-caste critiques of sex work to rally for the dignity of their labor and everyday living.
Se ele está em trabalho remoto, por que eu não posso? O dilema da escolha dos servidores para o home office em um tribunal de contas municipal
Authors: Pimentel Rosiane Graziele Rodrigues , Texeira Germano
Published: January 2025

Esse caso aborda as dificuldades de um gestor público na implantação do trabalho remoto no contexto da pandemia de Covid-19. Com o anúncio das medidas de controle sanitário pelos órgãos de saúde, o chefe de um departamento que atende vários agentes teve que reorganizar o funcionamento do setor. Quando a situação sanitária melhorou, veio a necessidade de realizar novos ajustes, e definir quais tarefas e/ou servidores permaneceriam em trabalho remoto ou presencial. Nesse contexto, em um cenário de disputa, alimentado por conflitos antigos, o gestor se vê no seguinte dilema: Autorizar que toda equipe realize seu trabalho de forma remota, agradando a todos, mas podendo prejudicar a produtividade do setor, ou limita esta a modalidade de trabalho para apenas algumas funções e pessoas, e assume os eventuais prejuízos no relacionamento, motivação e engajamento da equipe. O caso tem como objetivo desenvolver em alunos graduandos em Administração (em disciplinas que abordem Gestão de Pessoas, Recursos Humanos e Administração Pública) as reflexões experienciais a partir de uma situação real de implantação de trabalho remoto em um órgão da administração pública.