bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost-effectiveness of endovascular treatment versus best medical management in basilar artery occlusion stroke: A U.S. healthcare perspective
Authors: Mehrens Dirk , Fabritius Matthias P , Reidler Paul , Liebig Thomas , Afat Saif , Ospel Johanna M , Fröhlich Matthias F , Schwarting Julian , Ricke Jens , Dimitriadis Konstantinos , Goyal Mayank , Kunz Wolfgang G
Published: October 2023

Introduction:

Two recent studies showed clinical benefit for endovascular treatment (EVT) in basilar artery occlusion (BAO) stroke up to 12 h (ATTENTION) and between 6 and 24 h from onset (BAOCHE). Our aim was to investigate the cost-effectiveness of EVT from a U.S. healthcare perspective.

Materials and Methods:

Clinical input data were available for both trials, which were analyzed separately. A decision model was built consisting of a short-run model to analyze costs and functional outcomes within 90 days after the index stroke and a long-run Markov state transition model (cycle length of 12 months) to estimate expected lifetime costs and outcomes from a healthcare and a societal perspective. Incremental cost-effectiveness ratios (ICER) were calculated, deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed.

Results:

EVT in addition to best medical management (BMM) resulted in additional lifetime costs of $32,063 in the ATTENTION trial and lifetime cost savings of $7690 in the BAOCHE trial (societal perspective). From a healthcare perspective, EVT led to incremental costs and effectiveness of $37,389 and 2.0 QALYs (ATTENTION) as well as $3516 and 1.9 QALYs (BAOCHE), compared to BMM alone. The ICER values were $−4052/QALY (BAOCHE) and $15,867/QALY (ATTENTION) from a societal perspective. In each trial, PSA showed EVT to be cost-effective in most calculations (99.9%) for a willingness-to-pay threshold of $100,000/QALY. Cost of EVT and age at stroke represented the greatest impact on the ICER.

Discussion:

From an economic standpoint with a lifetime horizon, EVT in addition to BMM is estimated to be highly effective and cost-effective in BAO stroke.
Expanding the politics of measurement in sustainable finance: Reconceptualizing environmental, social and governance information as infrastructure
Authors: Dimmelmeier Andreas
Published: October 2023

The integration of environmental, social, and governance (ESG) considerations into investment processes, often termed “sustainable finance,” has gained significant traction in the global financial system. Yet, despite its growing significance there remains widespread ambiguity about what sustainable finance refers to. Macro-political oriented studies from different disciplines have traced the evolution of sustainable finance and related it to broader financial and political dynamics like financialization or the rise of private environmental governance. By foregrounding these elements, they have, however, tended to paint a too monolithic picture of sustainable finance and related it to abstract discussions such as whether it is controlled by public or private actors. Micro-political accounts, inspired by Science and Technology Studies, have, by contrast, focused on the nuances and contingencies of amongst other metrics, accounting standards or green bond classification frameworks that make the connection of finance and sustainability possible. While these treatments have provided rich accounts of these technical devices, they de-emphasize the connections and evolutionary dynamics of their objects of study. This article aims to bridge macro- and micro-political treatments of sustainable finance by (re-)conceptualizing the evolution of the field in terms of an emerging and expanding infrastructure of Environmental, Social and Governance (ESG) information. Drawing from secondary literature, interviews, and participant observation data, it provides a three-staged history of sustainable finance from the perspective of the technical devices making up ESG information. It, thereby, offers a comprehensive view that goes beyond attributing sustainable finance to macro-level trends or isolated micro-level occurrences.
A model for partially dependent component damage fragilities in seismic risk analysis
Authors: Baker Jack W , Almeter Ed , Cook Dustin , Liel Abbie B , Haselton Curt
Published: October 2023

This article proposes a model to quantify dependencies in component damage in the Federal Emergency Management Agency (FEMA) P-58 seismic performance assessment methodology and to simulate damage realizations with the desired dependencies. The model is compatible with the prior FEMA P-58 procedure and can quantify more realistic dependencies in component damage with only minor changes to the calculation algorithm and model parameters. This article introduces the proposed model and compares it with the prior procedure. Example calculations are then used to illustrate the quantitative impacts of component damage dependencies on building-level performance metrics. The model is relatively simple to conceptualize and parameterize, so that the degree of dependency can be easily estimated and documented. Given the improved conceptual framing of the problem, and the significant changes it sometimes produces in building-level performance predictions, this model represents an improvement to the general FEMA P-58 seismic performance assessment methodology.
Patterns of CMV infection after letermovir withdrawal in recipients of posttransplant cyclophosphamide–based transplant
Authors: Lin Andrew , Brown Samantha , Chinapen Stephanie , Lee Yeon Joo , Seo Susan K. , Ponce Doris M. , Shahid Zainab , Giralt Sergio , Papanicolaou Genovefa A. , Perales Miguel-Angel , Shaffer Brian C.
Published: October 2023

Reactivation of latent cytomegalovirus (CMV) is increased in recipients of allogeneic hematopoietic cell transplantation (allo-HCT) with seropositive CMV using posttransplant cyclophosphamide (PT-Cy)–based graft-versus-host disease (GVHD) prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy–based allo-HCT, including 157 patients with CMV, of whom 80 completed letermovir prophylaxis without csCMVi and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range [IQR], 160-250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (95% confidence interval, 14.3-32.8). There were no episodes of CMV end-organ disease. Hypogammaglobulinemia before letermovir discontinuation was predictive of csCMVi (hazard ratio, 0.33; 95% confidence interval, 0.12-0.93; P = .03), whereas T-cell and B-cell reconstitution before letermovir withdrawal were not predictive of csCMVi. Higher numbers of natural killer cells were found before letermovir withdrawal in patients who experienced csCMVi (median, 202 vs 160; P = .03). In recipients with seropositive CMV, CD3+CD4–CD8+ T-cell reconstitution was faster in patients with CMV regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV-specific adaptive immunity in patients with persistent hypogammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.
Genomic architecture of resistance to latania scale (H. lataniae) in kiwifruit (A. chinensis var. chinensis)
Authors: Flay Casey , Tahir Jibran , Hilario Elena , Fraser Lena , Stannard Kate , Symonds Vaughan , Datson Paul
Published: October 2023

Background

Latania scale (Hemiberlesia lataniae Signoret) is an armoured scale insect known to cause damage to kiwifruit plants and fruit, which ultimately reduces crop values and creates post-harvest export and quarantine issues. Resistance to H. lataniae does exist in some commercial cultivars of kiwifruit. However, some of the commercial cultivars bred in New Zealand have not inherited alleles for resistance to H. lataniae carried by their parents. To elucidate the architecture of resistance in the parents and develop molecular markers to assist breeding, these experiments analysed the inheritance of resistance to H. lataniae from families related to commercial cultivars.

Results

The first experiment identified a 15.97 Mb genomic region of interest for resistance to H. lataniae in rtGBS data of 3.23 to 19.20 Mb on chromosome 10. A larger population was then QTL mapped, which confirmed the region of interest as the sole locus contributing to H. lataniae resistance. inDel markers mapping the region of low recombination under the QTL peak further narrowed the region associated with H. lataniae resistance to a 5.73 Mb region.

Conclusions

The kiwifruit populations and genomic methods used in this study identify the same non-recombinant region of chromosome 10 which confers resistance of A. chinensis var. chinensis to H. lataniae. The markers developed to target the H. lataniae resistance loci will reduce the amount of costly and time-consuming phenotyping required for breeding H. lataniae scale resistance into new kiwifruit cultivars.
Transcriptional and protein structural characterization of homogentisate phytyltransferase genes in barley, wheat, and oat
Authors: Zeng Zhanghui , Jia Yong , Huang Xiaoping , Chen Zhehao , Xiang Taihe , Han Ning , Bian Hongwu , Li Chengdao
Published: October 2023

Background

Homogentisate phytyltransferase (HPT) is the critical enzyme for the biosynthesis of tocopherols (vitamin E), which are the major lipid-soluble antioxidants and help plants adapt to various stress conditions. HPT is generally strictly conserved in various plant genomes; however, a divergent lineage HPT2 was identified recently in some Triticeae species. The molecular function and transcriptional profiles of HPT2 remain to be characterized.

Results

In this study, we performed comprehensive transcriptome data mining of HPT1 and HPT2 in different tissues and stages of barley (Hordeum vulgare), wheat (Triticum aestivum), and oat (Avena sativa), followed by qRT-PCR experiments on HPT1 and HPT2 in different tissues of barley and wheat. We found that the common HPT1 genes (HvHPT1, TaHPT1s, and AsHPT1s) displayed a conserved transcriptional pattern in the three target species and were universally transcribed in various tissues, with a notable preference in leaf. In contrast, HPT2 genes (HvHPT2, TaHPT2, and AsHPT2) were specifically transcribed in spike (developmentally up-regulated) and shoot apex tissues, displaying a divergent tissue-specific pattern. Cis-regulatory elements prediction in the promoter region identified common factors related to light-, plant hormone-, low temperature-, drought- and defense- responses in both HPT1s and HPT2s. We observed the transcriptional up-regulation of HvHPT1 and HvHPT2 under various stress conditions, supporting their conserved function in environmental adaption. We detected a clear, relaxed selection pressure in the HPT2 lineage, consistent with the predicted evolution pattern following gene duplication. Protein structural modelling and substrate docking analyses identified putative catalytic amino acid residues for HvHPT1 and HvHPT2, which are strictly conserved and consistent with their function in vitamin E biosynthesis.

Conclusions

We confirmed the presence of two lineages of HPT in Triticeae and Aveninae, including hexaploid oat, and characterized their transcriptional profiles based on transcriptome and qRT-PCR data. HPT1s were ubiquitously transcribed in various tissues, whilst HPT2s were highly expressed in specific stages and tissue. The active transcription of HPT2s, together with its conserved cis-elements and protein structural features, support HPT2s’ role in tocopherol production in Triticeae. This study is the first protein structural analysis on the membrane-bound plant HPTs and provides valuable insights into its catalytic mechanism.
Metabolic disorders and risk of cardiovascular diseases: a two-sample mendelian randomization study
Authors: Wang Zhe , Chen Jiawei , Zhu Longyang , Jiao Siqi , Chen Yinong , Sun Yihong
Published: October 2023

Background

Metabolic disorders are increasing worldwide and are characterized by various risk factors such as abdominal obesity, insulin resistance, impaired glucose metabolism, and dyslipidemia. Observational studies suggested a bidirectional association between cardiovascular diseases and metabolic disorders and its components. However, the causal associations between them remained unclear. This study aims to investigate the causal relationship between metabolic disorders and cardiovascular disease through Mendelian randomization (MR) analysis.

Methods

A two-sample MR analysis based on publicly available genome-wide association studies were used to infer the causality. The single-nucleotide polymorphisms with potential pleiotropy were excluded by MR-PRESSO. The effect estimates were constructed using the random-effects inverse-variance-weighted method as the primary estimate. Furthermore, MR-Egger and weighted median were also performed to detect heterogeneity and pleiotropy.

Results

Genetically predicted metabolic disorders increased the risk for coronary heart disease (OR = 1.77, 95% CI: 1.55–2.03, p < 0.001), myocardial infarction (OR = 1.75, 95% CI: 1.52–2.03, p < 0.001), heart failure (OR = 1.26, 95% CI: 1.14–1.39, p < 0.001), hypertension (OR = 1.01, 95% CI: 1.00-1.02, p = 0.002), and stroke (OR = 1.19, 95% CI: 1.08–1.32, p < 0.001). The concordance of the results of various complementary sensitivity MR methods reinforces the causal relationship further.

Conclusion

This study provides evidence of a causal relationship between metabolic disorders and increased risk of coronary heart disease, myocardial infarction, heart failure, hypertension, and stroke. Special attention should be paid to improving metabolic disorders to reduce the development of cardiovascular diseases.
Symmetry of computerised tomography of the brain in traumatic brain injury: a quality improvement audit
Authors: George Ajish Sam , Chitteti Pragnitha , Nair Shalini , Karuppasami Reka , Joseph Mathew
Published: October 2023

Background

Non-contrast Computerised Tomography (NCCT) of brain is the gold standard investigation for diagnosis and management of Traumatic brain injury (TBI). Asymmetrical CT brain images as a result of improper head positioning in the CT gantry will compromise the diagnostic value. Therefore, this audit aimed to assess the degree of asymmetry in CT brain studies carried out in TBI patients.

Methods

This audit was carried out at a level one trauma centre and included CT scans of TBI patients with a Glasgow come scale (GCS) score ≤ 13, admitted to the Neurological intensive care unit (NICU). The first cycle involved a period of three months. The data collected included demographic data and variables such as GCS at the time of the scan and whether the patient was intubated or not. The visualisation of bilateral internal auditory meatuses was used as landmark to determine scan symmetry. If the internal auditory meatus on both sides were visible on the same slice of CT scan, it was considered symmetric. The degree of asymmetry was gauged based on the axial slice difference between bilateral meatuses. The data collected was tabulated and presented to Neurosurgery residents and a checklist was formulated which had to be followed while positioning the patient on CT table prior to imaging.

Results

The first cycle of the audit showed that 83.8% of scans were asymmetric and among them 44.1% revealed gross asymmetry affecting interpretation of the scan. Following, implementation of the checklist the percentage of gross asymmetry dropped to 21.86% in the second and to 22.22% in the third audit.

Conclusion

The use of checklist prior to CT brain studies showed sustainable improvement in reducing gross asymmetry and in acquisition of symmetrical CT brain images.
Epidemiological trends and risk factors related to lower urinary tract symptoms around childbirth: a one-year prospective study
Authors: Wang Xiaojuan , Wang Hongyan , Xu Ping , Mao Minna , Feng Suwen
Published: October 2023

Background

Lower urinary tract symptoms (LUTS) are prevalent and distressing concerns for women worldwide. The prevalence of LUTS reaches the first peak during pregnancy and postnatal period. However, less attention has been paid to LUTS around childbirth and little progress has been made in the prevention of LUTS. Understanding the epidemiological characteristics of LUTS around childbirth would inform decision making for health care providers and perinatal women in the prevention of LUTS. The study aims to investigate the epidemiological trends and associated risk factors related to LUTS around childbirth.

Methods

Pregnant women were consecutively enrolled during pregnancy in the obstetrical wards of a tertiary hospital and followed up at 6–8 weeks and one year postpartum through a prospective design. Urinary incontinence was assessed with the International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence Short Form. Other symptoms were measured with questions based on definitions of the International Incontinence Society. Multiple logistic regression was used to examine the risk factors for LUTS including urinary incontinence, increased daytime frequency, nocturia and urgency. The report followed the STROBE statement.

Results

A total of 1243 pregnant women participated in this study. The prevalence of at least one type of storage symptoms was 94%, 55% and 35% in late pregnancy, at 6–8 weeks and one year postpartum, respectively. The prevalence of urinary incontinence remained at 21% within one year postpartum. The majority of the participants suffered from mild to moderate urinary incontinence. Age, job, BMI before pregnancy, gestational diabetes mellitus, urinary tract infection history, previous history of LUTS, age at first birth and birth mode were predictors of LUTS one year postpartum.

Conclusion

LUTS were highly prevalent during pregnancy and postnatal period. The prevalence of urinary incontinence was more stable than that of other LUTS within one year postpartum. Women aged more than 35 years, engaging in manual work, with gestational diabetes mellitus, with a history of urinary tract infection and LUTS, with advanced age at first birth and vaginal delivery were more likely to suffer from LUTS postpartum. The findings provided a novel and deep insight into the epidemiological trends and related risk factors of LUTS around childbirth.
Pharmacotechnical aspects of a stable probiotic formulation toward multidrug-resistance antibacterial activity: design and quality control
Authors: Karimi Farkhonde , Azadi Amir , Omidifar Navid , Najafabady Nima Montazeri , Mohammadi Fatemeh , Kazemi Radmehr , Gholami Ahmad
Published: October 2023

As a well-known group of the probiotic family, the Lactobacillus has increasingly contributed to hindering the growth of pathogens, particularly resistant species, in the last decades. Since antibiotic resistance has become a severe problem in global healthcare systems and considerably increased the mortality and morbidity rate in infectious diseases, we aimed to obtain a new stable formulation of Lactobacillus to overcome resistant infections. For this purpose, we designed various gel formulations containingLactobacillus rhamnosus(L. rhamnosus) as an active pharmaceutical ingredient (API) in a water base and oil base gel, evaluated the probiotic stability in formulation to obtain an optimum formulation, and finally, investigated the antibacterial activities of that against two common hospital-associated multidrug-resistant pathogens, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Furthermore, the pharmaceutical aspects of the optimum formulation, including stability, homogeneity, spreadability, pH value, conductivity, and rheological behavior, were assessed.

The results indicated that the optimum formulation based on glycerol exhibited desirable pharmaceutical properties, including long-term stability, a perfect level of homogeneity, an acceptable range of spreadability with pseudo-plastic thixotropic behavior, and a promising antibacterial potential against MRSA and VRE. Our findings indicate that this novel probiotic formulation could be an excellent candidate to cope with antibiotic-resistant species, representing a hopeful treatment potential for topical applications, particularly in incurable infections. However, further in vivo studies seem warranted to evaluate their bactericidal activity against multi-drug resistant microorganisms.
Two zinc finger proteins, VdZFP1 and VdZFP2, interact with VdCmr1 to promote melanized microsclerotia development and stress tolerance in Verticillium dahliae
Authors: Li Huan , Sheng Ruo-Cheng , Zhang Chen-Ning , Wang Li-Chao , Li Min , Wang Ya-Hong , Qiao Yu-Hang , Klosterman Steven J. , Chen Jie-Yin , Kong Zhi-Qiang , Subbarao Krishna V. , Chen Feng-Mao , Zhang Dan-Dan
Published: October 2023

Background

Melanin plays important roles in morphological development, survival, host–pathogen interactions and in the virulence of phytopathogenic fungi. In Verticillum dahliae, increases in melanin are recognized as markers of maturation of microsclerotia which ensures the long-term survival and stress tolerance, while decreases in melanin are correlated with increased hyphal growth in the host. The conserved upstream components of the VdCmr1-regulated pathway controlling melanin production in V. dahliae have been extensively identified, but the direct activators of this pathway are still unclear.

Results

We identified two genes encoding conserved C2H2-type zinc finger proteins VdZFP1 and VdZFP2 adjacent to VdPKS9, a gene encoding a negative regulator of both melanin biosynthesis and microsclerotia formation in V. dahliae. Both VdZFP1 and VdZFP2 were induced during microsclerotia development and were involved in melanin deposition. Their localization changed from cytoplasmic to nuclear in response to osmotic pressure. VdZFP1 and VdZFP2 act as modulators of microsclerotia melanization in V. dahliae, as confirmed by melanin biosynthesis inhibition and supplementation with the melanin pathway intermediate scytalone in albino strains. The results indicate that VdZFP1 and VdZFP2 participate in melanin biosynthesis by positively regulating VdCmr1. Based on the results obtained with yeast one- and two-hybrid (Y1H and Y2H) and bimolecular fluorescence complementation (BiFC) systems, we determined the melanin biosynthesis relies on the direct interactions among VdZFP1, VdZFP2 and VdCmr1, and these interactions occur on the cell walls of microsclerotia. Additionally, VdZFP1 and/or VdZFP2 mutants displayed increased sensitivity to stress factors rather than alterations in pathogenicity, reflecting the importance of melanin in stress tolerance of V. dahliae.

Conclusions

Our results revealed that VdZFP1 and VdZFP2 positively regulate VdCmr1 to promote melanin deposition during microsclerotia development, providing novel insight into the regulation of melanin biosynthesis in V. dahliae.
Gut mycobiome as a potential non-invasive tool in early detection of lung adenocarcinoma: a cross-sectional study
Authors: Liu Qingyan , Zhang Weidong , Pei Yanbin , Tao Haitao , Ma Junxun , Li Rong , Zhang Fan , Wang Lijie , Shen Leilei , Liu Yang , Jia Xiaodong , Hu Yi
Published: October 2023

Background

The gut mycobiome of patients with lung adenocarcinoma (LUAD) remains unexplored. This study aimed to characterize the gut mycobiome in patients with LUAD and evaluate the potential of gut fungi as non-invasive biomarkers for early diagnosis.

Methods

In total, 299 fecal samples from Beijing, Suzhou, and Hainan were collected prospectively. Using internal transcribed spacer 2 sequencing, we profiled the gut mycobiome. Five supervised machine learning algorithms were trained on fungal signatures to build an optimized prediction model for LUAD in a discovery cohort comprising 105 patients with LUAD and 61 healthy controls (HCs) from Beijing. Validation cohorts from Beijing, Suzhou, and Hainan comprising 44, 17, and 15 patients with LUAD and 26, 19, and 12 HCs, respectively, were used to evaluate efficacy.

Results

Fungal biodiversity and richness increased in patients with LUAD. At the phylum level, the abundance of Ascomycota decreased, while that of Basidiomycota increased in patients with LUAD. Candida and Saccharomyces were the dominant genera, with a reduction in Candida and an increase in Saccharomyces, Aspergillus, and Apiotrichum in patients with LUAD. Nineteen operational taxonomic unit markers were selected, and excellent performance in predicting LUAD was achieved (area under the curve (AUC) = 0.9350) using a random forest model with outcomes superior to those of four other algorithms. The AUCs of the Beijing, Suzhou, and Hainan validation cohorts were 0.9538, 0.9628, and 0.8833, respectively.

Conclusions

For the first time, the gut fungal profiles of patients with LUAD were shown to represent potential non-invasive biomarkers for early-stage diagnosis.
Hypoxia enhances anti-fibrotic properties of extracellular vesicles derived from hiPSCs via the miR302b-3p/TGFβ/SMAD2 axis
Authors: Paw Milena , Kusiak Agnieszka A. , Nit Kinga , Litewka Jacek J. , Piejko Marcin , Wnuk Dawid , Sarna Michał , Fic Kinga , Stopa Kinga B. , Hammad Ruba , Barczyk-Woznicka Olga , Cathomen Toni , Zuba-Surma Ewa , Madeja Zbigniew , Ferdek Paweł E. , Bobis-Wozowicz Sylwia
Published: October 2023

Background

Cardiac fibrosis is one of the top killers among fibrotic diseases and continues to be a global unaddressed health problem. The lack of effective treatment combined with the considerable socioeconomic burden highlights the urgent need for innovative therapeutic options. Here, we evaluated the anti-fibrotic properties of extracellular vesicles (EVs) derived from human induced pluripotent stem cells (hiPSCs) that were cultured under various oxygen concentrations.

Methods

EVs were isolated from three hiPSC lines cultured under normoxia (21% O2; EV-N) or reduced oxygen concentration (hypoxia): 3% O2 (EV-H3) or 5% O2 (EV-H5). The anti-fibrotic activity of EVs was tested in an in vitro model of cardiac fibrosis, followed by a detailed investigation of the underlying molecular mechanisms. Sequencing of EV miRNAs combined with bioinformatics analysis was conducted and a selected miRNA was validated using a miRNA mimic and inhibitor. Finally, EVs were tested in a mouse model of angiotensin II-induced cardiac fibrosis.

Results

We provide evidence that an oxygen concentration of 5% enhances the anti-fibrotic effects of hiPS-EVs. These EVs were more effective in reducing pro-fibrotic markers in activated human cardiac fibroblasts, when compared to EV-N or EV-H3. We show that EV-H5 act through the canonical TGFβ/SMAD pathway, primarily via miR-302b-3p, which is the most abundant miRNA in EV-H5. Our results show that EV-H5 not only target transcripts of several profibrotic genes, including SMAD2 and TGFBR2, but also reduce the stiffness of activated fibroblasts. In a mouse model of heart fibrosis, EV-H5 outperformed EV-N in suppressing the inflammatory response in the host and by attenuating collagen deposition and reducing pro-fibrotic markers in cardiac tissue.

Conclusions

In this work, we provide evidence of superior anti-fibrotic properties of EV-H5 over EV-N or EV-H3. Our study uncovers that fine regulation of oxygen concentration in the cellular environment may enhance the anti-fibrotic effects of hiPS-EVs, which has great potential to be applied for heart regeneration.

Graphical Abstract
Joint association of sedentary behavior and vitamin D status with mortality among cancer survivors
Authors: Yu Yu , Cheng Sijing , Huang Hao , Deng Yu , Cai Chi , Gu Min , Chen Xuhua , Niu Hongxia , Hua Wei
Published: October 2023

Background

Sedentary behavior and vitamin D deficiency are independent risk factors for mortality in cancer survivors, but their joint association with mortality has not been investigated.

Methods

We analyzed data from 2914 cancer survivors who participated in the National Health and Nutrition Examination Survey (2007–2018) and followed up with them until December 31, 2019. Sedentary behavior was assessed by self-reported daily hours of sitting, and vitamin D status was measured by serum total 25-hydroxyvitamin D (25(OH)D) levels.

Results

Among 2914 cancer survivors, vitamin D deficiency was more prevalent in those with prolonged daily sitting time. During up to 13.2 years (median, 5.6 years) of follow-up, there were 676 deaths (cancer, 226; cardiovascular disease, 142; other causes, 308). The prolonged sitting time was associated with a higher risk of all-cause and noncancer mortality, and vitamin D deficiency was associated with a higher risk of all-cause and cancer mortality. Furthermore, cancer survivors with both prolonged sitting time (≥ 6 h/day) and vitamin D deficiency had a significantly higher risk of all-cause (HR, 2.05; 95% CI: 1.54–2.72), cancer (HR, 2.33; 95% CI, 1.47–3.70), and noncancer mortality (HR, 1.91; 95% CI, 1.33–2.74) than those with neither risk factor after adjustment for potential confounders.

Conclusions

In a nationally representative sample of U.S. cancer survivors, the joint presence of sedentary behavior and vitamin D deficiency was significantly associated with an increased risk of all-cause and cancer-specific mortality.
Do alternative tobacco products induce less adverse respiratory risk than cigarettes?
Authors: Bhat Tariq A. , Kalathil Suresh G. , Leigh Noel , Hutson Alan , Goniewicz Maciej L. , Thanavala Yasmin M.
Published: October 2023

Rationale

Due to the relatively short existence of alternative tobacco products, gaps exist in our current understanding of their long-term respiratory health effects. We therefore undertook the first-ever side-by-side comparison of the impact of chronic inhalation of aerosols emitted from electronic cigarettes (EC) and heated tobacco products (HTP), and combustible cigarettes (CC) smoke.

Objectives

To evaluate the potential differential effects of alternative tobacco products on lung inflammatory responses and efficacy of vaccination in comparison to CC.

Methods

Mice were exposed to emissions from EC, HTP, CC, or air for 8 weeks. BAL and lung tissue were analyzed for markers of inflammation, lung damage, and oxidative stress. Another group was exposed for 12 weeks and vaccinated and challenged with a bacterial respiratory infection. Antibody titers in BAL and sera and pulmonary bacterial clearance were assessed.

Main results

EC- and HTP-aerosols significantly augmented lung immune cell infiltrates equivalent to that achieved following CC-exposure. HTP and CC significantly increased neutrophil numbers compared to EC. All products augmented numbers of B cells, T cells, and pro-inflammatory IL17A+ T cells in the lungs. Decreased lung antioxidant activity and lung epithelial and endothelial damage was induced by all products. EC and HTP differentially augmented inflammatory cytokines/chemokines in the BAL. Generation of immunity following vaccination was impaired by EC and HTP but to a lesser extent than CC, with a CC > HTP > EC hierarchy of suppression of pulmonary bacterial clearance.

Conclusions

HTP and EC-aerosols induced a proinflammatory pulmonary microenvironment, lung damage, and suppressed efficacy of vaccination.
Awareness and acceptability of malaria vaccine among caregivers of under-5 children in Northern Nigeria
Authors: Ajayi Mary Yetunde , Emeto Daniel Chukwuyere
Published: October 2023

Background

Malaria vaccine, RTS, S/AS01, has demonstrated modest efficacy against malaria and holds promises for children living in areas where malaria transmission is high. This study assessed caregivers’ awareness and willingness to accept the vaccine and provided vital information for policymakers, health workers, and social mobilizers on critical areas to focus on promoting the new vaccine uptake before its arrival for use in Nigeria.

Methods

The study was a community-based cross-sectional survey. A multistage sampling technique was used to select four states in Northern Nigeria, where the incidence and prevalence of malaria are highest in the country and 504 caregivers of under-five children were interviewed. A semi-structured interviewer-administered questionnaire was used and data analysis was done with p-value at 0.05.

Results

Two hundred and three (40.3%) respondents were aware of malaria vaccine while four hundred and sixty-three (91.9%) were willing to accept the vaccine when it is introduced for use in the country. Level of education (AOR; 0.42; CI 0.23–0.78), employment status (AOR; 3.03; CI 1.82–5.03), previous experience of other childhood vaccinations (AOR; 4.87; CI 2.89–8.20), and caregivers having suffered malaria within the last one year (AOR; 1.85; CI 1.10 −3.13) significantly predicted malaria vaccine awareness. Awareness of the new malaria vaccine (AOR = 6.88; 95% CI 1.53–30.99), and previous experience of other childhood vaccinations (AOR = 6.16; 95% CI 2.54–14.94) were significant predictors of the vaccine acceptability.

Conclusion

Caregiver’s awareness of the new malaria vaccine was inadequate. There is a need to intensify efforts on social and behavioural communication change activities tailoring messages on the vaccine to address uptake hesitancy. Also, an intense community engagement with focus on providing information on the safety of the vaccine is encouraged.
Dietary pesticide exposure and non-communicable diseases and mortality: a systematic review of prospective studies among adults
Authors: Baudry Julia , Rebouillat Pauline , Samieri Cécilia , Berlivet Justine , Kesse-Guyot Emmanuelle
Published: October 2023

Background

Research on the effect of pesticide exposure on health has been largely focused on occupational settings. Few reviews have synthesized the associations between dietary pesticide exposure and health outcomes in non-occupationally exposed adults.

Objective

We aim to summarize the evidence regarding dietary pesticide exposure and non-communicable diseases (NCD) in adults, using a systematic review of prospective studies.

Methods

Electronic and manual searches were performed until July 2023. The inclusion criteria were the following: 1) adults aged ≥ 18years, 2) (non)-randomized trials, prospective cohort studies, 3) dietary exposure to pesticides. A bias analysis was carried out using the Nutrition Evidence Systematic Review guidelines based on the Cochrane ROBINS-I.

Results

A total of 52 studies were retrieved and 6 studies that met the above criteria were included. Studies were conducted either in France or in the United States. The studies investigated the risk of cancer (n = 3), diabetes (n = 1), cardiovascular diseases (n = 1), and mortality (n = 1). The quality of the studies varied with overall grades derived from the bias analysis ranging from low to moderate bias. The level of evidence was estimated as low for the risk of cancer while the grading was not assignable for other outcomes, as only one study per outcome was available.

Conclusions

Although further research is warranted to examine more in depth the relationships between low-dose chronic exposure to pesticides through diet and NCD outcomes in non-occupationally-exposed adults, studies suggest a possible role of exposure to dietary pesticide on health. Standardized methodological guidelines should also be proposed to allow for comparison across studies.
Targeting and repolarizing M2-like tumor-associated macrophage-mediated MR imaging and tumor immunotherapy by biomimetic nanoparticles
Authors: Chong Lijuan , Jiang Yao-Wen , Wang Dongxu , Chang Pengzhao , Xu Kai , Li Jingjing
Published: October 2023

Anti-tumor M1-like and pro-tumor M2-like tumor-associated macrophages (TAMs) coexist in tumor microenvironments (TME). The adverse effects of these M1/M2 subsets on tumors directly affect the current strategies to improve anti-tumor immune response. Therefore, it has attracted great attention to change the tumor immunosuppressive microenvironment by reprogramming TAMs. In this paper, we constructed biomimetic nanoparticles (HMMDN-Met@PM) targeting M2-like TAMs for macrophage re-polarization. In detail, the core of the biomimetic nanoparticles is metformin-loaded hollow mesoporous manganese dioxide nanoparticles (HMMDN-Met). Benefited from the hollow and porous structure of HMMDN, metformin, the regulator of M1/M2 adopted in this work, can be easily and widely loaded into HMMDN. Moreover, macrophage membranes were utilized for HMMDN-Met coating (HMMDN-Met@MM) to prevent the premature drug leakage and provide specific molecular recognition/TME targeting. In addition, M2 macrophage targeting peptide (M2pep) was modified on the surface of macrophage membrane to specifically deliver the drug to M2-like TAMs to promote the polarization of M2 to M1 macrophages. Through in vitro and in vivo studies, we found that the expression of surface markers and inflammatory factors CD206, Arg-1 and IL-10 of type M2 macrophages decreased, while the surface markers of type M1 macrophages and the expression of inflammatory factors CD80, TNF-α and iNOS increased, indicating the successful re-polarization of M2 macrophages and finally realizing the inhibition of tumor growth. At the same time, under the acidic and GSH conditions of tumor, HMMDN was decomposed into Mn2+, which is a contrast agent for magnetic resonance imaging, thus realizing the tracking of tumor. This work practices biomimetic nanosystem in targeted imaging and immunotherapy, paving the way for strategy designing for tumor inhibition.
KRASG12C inhibition using MRTX1257: a novel radio-sensitizing partner
Authors: Laurent Pierre-Antoine , Milic Marina , Quevrin Clément , Meziani Lydia , Liu Winchygn , Morel Daphné , Signolle Nicolas , Clémenson Céline , Levy Antonin , Mondini Michele , Deutsch Eric
Published: October 2023

Background

KRAS activating mutations are considered the most frequent oncogenic drivers and are correlated with radio-resistance in multiple cancers including non-small cell lung cancer (NSCLC) and colorectal cancer. Although KRAS was considered undruggable until recently, several KRAS inhibitors have recently reached clinical development. Among them, MRTX849 (Mirati Therapeutics) showed encouraging clinical outcomes for the treatment of selected patients with KRASG12C mutated NSCLC and colorectal cancers. In this work, we explore the ability of MRTX1257, a KRASG12C inhibitor analogous to MRTX849, to radio-sensitize KRASG12C+/+ mutated cell lines and tumors.

Methods

Both in vitro and in vivo models of radiotherapy (RT) in association with MRTX1257 were used, with different RAS mutational profiles. We assessed in vitro the radio-sensitizing effect of MRTX1257 in CT26 KRASG12C+/+, CT26 WT, LL2 WT and LL2 NRAS KO (LL2 NRAS−/−) cell lines. In vivo, we used syngeneic models of subcutaneous CT26 KRASG12C+/+ tumors in BALB/c mice and T cell deficient athymic nu/nu mice to assess both the radio-sensitizing effect of MRTX1257 and its immunological features.

Results

MRTX1257 was able to radio-sensitize CT26 KRASG12C+/+ cells in vitro in a time and dose dependent manner. Moreover, RT in association with MRTX1257 in BALB/c mice bearing CT26 KRASG12C+/+ subcutaneous tumors resulted in an observable cure rate of 20%. However, no durable response was observed with similar treatment in athymic nude mice. The analysis of the immune microenvironment of CT26 KRASG12C+/+ tumors following RT and MRTX1257 showed an increase in the proportion of various cell subtypes including conventional CD4 + T cells, dendritic cells type 2 (cDC2) and inflammatory monocytes. Furthermore, the expression of PD-L1 was dramatically down-regulated within both tumor and myeloid cells, thus illustrating the polarization of the tumor microenvironment towards a pro-inflammatory and anti-tumor phenotype following the combined treatment.

Conclusion

This work is the first to demonstrate in vitro as in vivo the radio-sensitizing effect of MRTX1257, a potent KRASG12C inhibitor compatible with oral administration, in CT26 KRASG12C mutated cell lines and tumors. This is a first step towards the use of new combinatorial strategies using KRAS inhibitors and RT in KRASG12C mutated tumors, which are the most represented in NSCLC with 14% of patients harboring this mutational profile.
National governance and excess mortality due to COVID-19 in 213 countries: a retrospective analysis and perspectives on future pandemics
Authors: da Silva Ricardo Eccard , Novaes Maria Rita Carvalho Garbi , de Oliveira Cesar , Guilhem Dirce Bellezi
Published: October 2023

Background

National governance may have influenced the response of institutions to the Covid-19 pandemic, being a key factor in preparing for the next pandemics. The objective was to analyze the association between excess mortality due to COVID-19 (daily and cumulative per 100 thousand people) and national governance indicators in 213 countries.

Method

Multiple linear regression models using secondary data from large international datasets that are in the public domain were performed. Governance indicators corresponded to six dimensions: (i) Voice and Accountability; (ii) Political Stability and Absence of Violence/Terrorism; (iii) Government Effectiveness; (iv) Regulatory Quality; (v) Rule of Law and (vi) Control of Corruption. The statistical analysis consisted of adjusting a multiple linear regression model. Excess mortality due to COVID-19 was adjusted for potential confounding factors (demographic, environmental, health, economic, and ethnic variables).

Results

The indicators Control of Corruption, Government Effectiveness, Regulatory Quality and Rule of Law had a significant inverse association (p < 0.0001) with the estimated excess mortality in 2020, 2021 and 2022. Furthermore, the governance indicators had a direct significant association (p < 0.0001) with the vaccination variables (People_fully_vaccinated; Delivered population; The total number of vaccination doses administered per 100 people at the country level), except for the variables Vaccination policies and Administration of first dose, which were inversely associated. In countries with better governance, COVID-19 vaccination was initiated earlier.

Conclusion

Better national governance indicators were associated with lower excess mortality due to COVID-19 and faster administration of the first dose of the COVID-19 vaccine.
Palliative radiotherapy for tumor bleeding in patients with unresectable pancreatic cancer: a single-center retrospective study
Authors: Shibuki Taro , Sasaki Mitsuhito , Yamaguchi Shota , Inoue Kanae , Taira Tomonao , Satake Tomoyuki , Watanabe Kazuo , Imaoka Hiroshi , Mitsunaga Shuichi , Fujisawa Takeshi , Tomizawa Kento , Oyoshi Hidekazu , Nakamura Masaki , Hojo Hidehiro , Ikeda Masafumi
Published: October 2023

Background

Patients with unresectable pancreatic cancer (PC) sometimes experience gastrointestinal bleeding (GIB) due to tumor invasion of the gastrointestinal tract (tumor bleeding); no standard treatment has been established yet for this complication. Palliative radiotherapy (PRT) could be promising, however, there are few reports of PRT for tumor bleeding in patients with unresectable PC. Therefore, we evaluated the outcomes of PRT for tumor bleeding in patients with unresectable PC.

Methods

We reviewed the medical records of patients with unresectable PC diagnosed at our institution between May 2013 and January 2022, and identified patients with endoscopically confirmed tumor bleeding who had received PRT. PRT was administered at a total dose of 30 Grays (Gy) in 10 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction, and the dose selection was left to the discretion of the attending radiation oncologists.

Results

During the study period, 2562 patients were diagnosed as having unresectable PC at our hospital, of which 225 (8.8%) developed GIB. Among the 225 patients, 63 (2.5%) were diagnosed as having tumor bleeding and 20 (0.8%) received PRT. Hemostasis was achieved in 14 of the 20 patients (70%) who received PRT, and none of these patients developed grade 3 or more adverse events related to the PRT. The median time to hemostasis was 8.5 days (range 7–14 days). The rebleeding rate was 21.4% (3/14). The median hemoglobin level increased significantly (p < 0.001) from 5.9 to 9.1 g/dL, and the median volume of red blood cell transfusion tended (p = 0.052) to decrease, from 1120 mL (range 280–3360 mL) to 280 mL (range 0–5560 mL) following the PRT. The median overall survival (OS) was 52 days (95% confidence interval [CI] 39–317). Of the 14 patients in whom hemostasis was achieved following PRT, chemotherapy could be started/resumed in seven patients (50%), and the median OS in these patients was 260 days (95% CI 76–not evaluable [NE]). Three patients experienced rebleeding (21.4%), on days 16, 22, and 25, after the start of PRT.

Conclusion

This study showed that PRT is an effective and safe treatment modality for tumor bleeding in patients with unresectable PC.
Novel screw-cable integrated system(SCIS) for minimally invasive treatment of patella transverse fractures: a finite element analysis
Authors: Liu Songyang , Liu Shen , Gu Feng , Wei Xing , Liang Yonghui
Published: October 2023

Background

The most recommended method for treating transverse patella fractures is modified tension band wiring (MTBW). However, the optimal instrument for use with MTBW is still undetermined. Hence, we aimed to design a novel screw-cable integrated system (SCIS) and compare its biomechanical characteristics with Kirschner-wire, SCIS, and Cable-Pin systems in treating transverse patellar fracture.

Methods

A finite-element (FE) model of transverse patella fracture was created. The fracture model was fixed with either K-wire, SCIS, or Cable-pin. Different tension force loading (400 N and 800 N), direction(0° and 45°), and screw or K-wire depth(5 mm and 10 mm) were set. The maximum displacement of the fragment and maximum gap opening were measured by using FE analysis.

Results

Compared with the K-wire and Cable-pin system, SCIS increased the stability of the fractured patella by reducing fragment displacement and gap opening. Under 400 N loading in the direction 45°, SCIS with screw placing at 5-mm depth reduced the maximum fragment displacement (0.43 mm) by 49.62% and 26%, respectively, compared with the K-wire (0.22 mm) and Cable-pin (0. 22 mm) group. Meanwhile, the gap opening in SCIS (0.05 mm) was reduced by 83% and 59.8% (0.05 to 0.18) compared with the K-wire (0.30 mm) and Cable-pin (0.18 mm) group.

Conclusion

SCIS demonstrated improved biomechanical stability for treating transverse patellar fractures compared to MTBW with Kirschner wire and the Cable-Pin system. Finite element analysis showed SCIS substantially reduced fracture fragment displacement and gap opening under various loading conditions.