bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between triglyceride glucose index and arterial stiffness and coronary artery calcification: a systematic review and exposure-effect meta-analysis
Authors: Liu Fuwei , Ling Qin , Xie Shaofeng , Xu Yi , Liu Menglu , Hu Qingwen , Ma Jianyong , Yan Zhiwei , Gao Yan , Zhao Yujie , Zhu Wengen , Yu Peng , Luo Jun , Liu Xiao
Published: May 2023

Background

The triglyceride and glucose (TyG) index has been linked to various cardiovascular diseases. However, it's still unclear whether the TyG index is associated with arterial stiffness and coronary artery calcification (CAC).

Methods

We conducted a systematic review and meta-analysis of relevant studies until September 2022 in the PubMed, Cochrane Library, and Embase databases. We used a random-effects model to calculate the pooled effect estimate and the robust error meta-regression method to summarize the exposure-effect relationship.

Results

Twenty-six observational studies involving 87,307 participants were included. In the category analysis, the TyG index was associated with the risk of arterial stiffness (odds ratio [OR]: 1.83; 95% CI 1.55–2.17, I2 = 68%) and CAC (OR: 1.66; 95% CI 1.51–1.82, I2 = 0). The per 1-unit increment in the TyG index was also associated with an increased risk of arterial stiffness (OR: 1.51, 95% CI 1.35–1.69, I2 = 82%) and CAC (OR: 1.73, 95% CI 1.36–2.20, I2 = 51%). Moreover, a higher TyG index was shown to be a risk factor for the progression of CAC (OR = 1.66, 95% CI 1.21–2.27, I2 = 0, in category analysis, OR = 1.47, 95% CI 1.29–1.68, I2 = 41% in continuity analysis). There was a positive nonlinear association between the TyG index and the risk of arterial stiffness (Pnonlinearity < 0.001).

Conclusion

An elevated TyG index is associated with an increased risk of arterial stiffness and CAC. Prospective studies are needed to assess causality.

Graphical Abstract
Effects of sumac supplementation on metabolic markers in adults with metabolic syndrome: a triple-blinded randomized placebo-controlled cross-over clinical trial
Authors: Mirenayat Fateme Sadat , Hajhashemy Zahra , Siavash Mansour , Saneei Parvane
Published: May 2023

Background

Despite the prior evidence of the impacts of sumac on glycemic indices, lipid profile and visceral fat, there is a lack of evidence regarding the efficacy of sumac in cases with metabolic syndrome (MetS). Therefore, we aimed to assess the effect of sumac supplementation on MetS markers among adults with this syndrome.

Methods

In this triple-blinded randomized placebo-controlled cross-over clinical trial 47 adults with MetS were randomly assigned to receive 500 mg sumac or placebo (lactose) capsule, twice a day. Each phase took 6 weeks and there was a 2-week washout between phases. All clinical evaluations and laboratory tests were conducted before and after each phase.

Results

At the baseline of the study, mean (± SD) age, weight, and waist circumference of participants were respectively 58.7 (± 5.8) yr, 79.9 (± 14.3) kg, and 107.6 (± 10.8) cm. Intention to treat analysis (ITT) analyses revealed that sumac supplementation decreased systolic blood pressure by 5 mmHg (128.8 ± 21.4 at the baseline vs. 123.2 ± 17.6 after 6 weeks intervention, P = 0.001). The comparison of changes in two trial arms showed that sumac supplementation significantly reduced systolic blood pressure (sumac group -5.59 ± 10.6 vs. control group 0.76 ± 10.5, P = 0.004), but did not change anthropometric indices or diastolic blood pressure. Similar results were also found in the per-protocol analyses.

Conclusions

This cross-over trial revealed that sumac supplementation could reduce systolic blood pressure in men and women with MetS. Daily intake of 1000 mg sumac, as an adjuvant therapy, may be beneficial in management of MetS in adults.
Clinical trial assessing the safety of edoxaban with concomitant chemotherapy in patients with gynecological cancer-associated thrombosis (EGCAT study)
Authors: Oride Tadashi , Sawada Kenjiro , Shimizu Aasa , Kinose Yasuto , Takiuchi Tsuyoshi , Kodama Michiko , Hashimoto Kae , Kobayashi Eiji , Nakatani Eiji , Kimura Tadashi
Published: May 2023

Background

Gynecological cancer is one of the highest risk factors for cancer-associated thrombosis (CAT). Although low-molecular-weight heparin (LMWH) is recommended as an anticoagulant for treating CAT, recent studies have shown that direct oral anticoagulants (DOACs) are an acceptable alternative. Patients with cancer require a series of chemotherapies concomitantly with DOAC administration; however, the extent to which these drugs influence DOAC blood concentrations is unknown. In this study, we measured the plasma concentration of edoxaban during chemotherapy for gynecological cancers to determine its safety.

Methods

Patients histologically diagnosed with ovarian or uterine corpus cancer and CAT were recruited after primary surgery and before the initiation of postoperative adjuvant chemotherapy, including paclitaxel. Patients were administered edoxaban (30 or 60 mg) orally for CAT. The plasma concentrations of edoxaban and active factor Xa were determined and their percentage change before and after chemotherapy was calculated. Additionally, blood coagulation tests were analyzed.

Results

Sixteen patients with gynecological cancer (12 with ovarian cancer and 4 with uterine corpus cancer) were enrolled. Among these, 15 samples were collected one day after chemotherapy initiation. During chemotherapy, the trough concentration of edoxaban changed from 17.6 ± 10.6 to 20.0 ± 15.6 ng/ml, and the mean percentage change in edoxaban concentration was 14.5%. Therefore, the trough concentrations of edoxaban, which represent excretion capacity, were not significantly increased by chemotherapy with paclitaxel. The area under the plasma edoxaban concentration–time curve and the active factor Xa concentration were also unaffected.

Conclusion

Patients with CAT and ovarian or uterine corpus cancer administered edoxaban orally showed no significant increase in the trough concentration of edoxaban while undergoing chemotherapy. This suggests the safety of edoxaban use during the treatment of gynecological cancers.

Trial registration

EGCAT study; Japan Registry of Clinical Trials, jRCTs051190024.
Attracting adolescents to become doctors and nurses: differential importance of personal and environmental factors in 61 economies
Authors: Guo Luyang , Hau Kit-Tai
Published: May 2023

Background

Doctors and nurses play a fundamental role in maintaining global health systems and achieving universal health care coverage. However, significant shortages persist, and little is known about the popularity of these careers among young people in various economies or the relative impact of personal inputs and contextual factors.

Methods

Using data from the large-scale Programme of International Student Assessment (PISA) 2018, we showed the recent distribution of adolescents' medical (doctor) and nursing career expectations in 61 economies. With multilevel logistic and hierarchical linear regression, we examined the relative importance of economic indicators, health work conditions, and personal background factors in affecting adolescents' health career expectations.

Results

Approximately 11% of adolescents expected to be doctors in each economy, while only 2% expected to be nurses. Adolescents were attracted to health professions mainly by system-level favourable conditions (accounting for 1/3 variance), including (a) government health expenditure beyond that expected gross domestic product (GDP); (b) a safe working environment for doctors in wealthy nations; and (c) high salaries for nurses in less-developed economies. In contrast, adolescents' background (gender, social status, and academic ability) was less influential, explaining only 10% of the differences.

Conclusions

In the technological and digital era, high-ability students are equally competitive for emerging careers other than doctors and nurses. In developing countries, a high salary package and societal respect are enough to attract adolescents to nursing careers. In contrast, for developed countries, extra expenditures beyond regular GDP allocation and a safe work environment are crucial in attracting adolescents to become doctors. Salary may effectively attract international-trained doctors and nurses, but the work environment will likely emerge as an essential factor in retaining migrants in their positions.

Trial registration number: No human participants were involved in this study.
What are economic costs and when should they be used in health economic studies?
Authors: Turner Hugo C. , Sandmann Frank G. , Downey Laura E. , Orangi Stacey , Teerawattananon Yot , Vassall Anna , Jit Mark
Published: May 2023

Economic analyses of healthcare interventions are an important consideration in evidence-based policymaking. A key component of such analyses is the costs of interventions, for which most are familiar with using budgets and expenditures. However, economic theory states that the true value of a good/service is the value of the next best alternative forgone as a result of using the resource and therefore observed prices or charges do not necessarily reflect the true economic value of resources. To address this, economic costs are a fundamental concept within (health) economics. Crucially, they are intended to reflect the resources’ opportunity costs (the forgone opportunity to use those resources for another purpose) and they are based on the value of the resource's next-best alternative use that has been forgone. This is a broader conceptualization of a resource’s value than its financial cost and recognizes that resources can have a value that may not be fully captured by their market price and that by using a resource it makes it unavailable for productive use elsewhere. Importantly, economic costs are preferred over financial costs for any health economic analyses aimed at informing decisions regarding the optimum allocation of the limited/competing resources available for healthcare (such as health economic evaluations), and they are also important when considering the replicability and sustainability of healthcare interventions. However, despite this, economic costs and the reasons why they are used is an area that can be misunderstood by professionals without an economic background. In this paper, we outline to a broader audience the principles behind economic costs and when and why they should be used within health economic analyses. We highlight that the difference between financial and economic costs and what adjustments are needed within cost calculations will be influenced by the context of the study, the perspective, and the objective.
Bacterial extracellular vesicles repress the vascular protective factor RNase1 in human lung endothelial cells
Authors: Laakmann Katrin , Eckersberg Jorina Mona , Hapke Moritz , Wiegand Marie , Bierwagen Jeff , Beinborn Isabell , Preußer Christian , Pogge von Strandmann Elke , Heimerl Thomas , Schmeck Bernd , Jung Anna Lena
Published: May 2023

Background

Sepsis is one of the leading causes of death worldwide and characterized by blood stream infections associated with a dysregulated host response and endothelial cell (EC) dysfunction. Ribonuclease 1 (RNase1) acts as a protective factor of vascular homeostasis and is known to be repressed by massive and persistent inflammation, associated to the development of vascular pathologies. Bacterial extracellular vesicles (bEVs) are released upon infection and may interact with ECs to mediate EC barrier dysfunction. Here, we investigated the impact of bEVs of sepsis-related pathogens on human EC RNase1 regulation.

Methods

bEVs from sepsis-associated bacteria were isolated via ultrafiltration and size exclusion chromatography and used for stimulation of human lung microvascular ECs combined with and without signaling pathway inhibitor treatments.

Results

bEVs from Escherichia coli, Klebsiella pneumoniae and Salmonella enterica serovar Typhimurium significantly reduced RNase1 mRNA and protein expression and activated ECs, while TLR2-inducing bEVs from Streptococcus pneumoniae did not. These effects were mediated via LPS-dependent TLR4 signaling cascades as they could be blocked by Polymyxin B. Additionally, LPS-free ClearColi™ had no impact on RNase1. Further characterization of TLR4 downstream pathways involving NF-кB and p38, as well as JAK1/STAT1 signaling, revealed that RNase1 mRNA regulation is mediated via a p38-dependent mechanism.

Conclusion

Blood stream bEVs from gram-negative, sepsis-associated bacteria reduce the vascular protective factor RNase1, opening new avenues for therapeutical intervention of EC dysfunction via promotion of RNase1 integrity.
A novel Chr1-miR-200 driven whole transcriptome signature shapes tumor immune microenvironment and predicts relapse in early-stage lung adenocarcinoma
Authors: Garinet Simon , Didelot Audrey , Marisa Laetitia , Beinse Guillaume , Sroussi Marine , Le Pimpec-Barthes Françoise , Fabre Elizabeth , Gibault Laure , Laurent-Puig Pierre , Mouillet-Richard Sophie , Legras Antoine , Blons Hélène
Published: May 2023

Background

In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems.

Methods

A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets.

Results

We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets.

Conclusion

This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.
The PI3K-Akt-mTOR pathway mediates renal pericyte-myofibroblast transition by enhancing glycolysis through HKII
Authors: Chen Liangmei , Li Xiaofan , Deng Yiyao , Chen Jianwen , Huang Mengjie , Zhu Fengge , Gao Zhumei , Wu Lingling , Hong Quan , Feng Zhe , Cai Guangyan , Sun Xuefeng , Bai Xueyuan , Chen Xiangmei
Published: May 2023

Background

Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes.

Methods

Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration.

Results

An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition.

Conclusions

The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.
IL-10 production by granulocytes promotes Staphylococcus aureus craniotomy infection
Authors: Kak Gunjan , Van Roy Zachary , Heim Cortney E. , Fallet Rachel W. , Shi Wen , Roers Axel , Duan Bin , Kielian Tammy
Published: May 2023

Background

Treatment of brain tumors, epilepsy, or hemodynamic abnormalities requires a craniotomy to access the brain. Nearly 1 million craniotomies are performed in the US annually, which increase to ~ 14 million worldwide and despite prophylaxis, infectious complications after craniotomy range from 1 to 3%. Approximately half are caused by Staphylococcus aureus (S. aureus), which forms a biofilm on the bone flap that is recalcitrant to antibiotics and immune-mediated clearance. However, the mechanisms responsible for the persistence of craniotomy infection remain largely unknown. The current study examined the role of IL-10 in promoting bacterial survival.

Methods

A mouse model of S. aureus craniotomy infection was used with wild type (WT), IL-10 knockout (KO), and IL-10 conditional KO mice where IL-10 was absent in microglia and monocytes/macrophages (CX3CR1CreIL-10 fl/fl) or neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs; Mrp8CreIL-10 fl/fl), the major immune cell populations in the infected brain vs. subcutaneous galea, respectively. Mice were examined at various intervals post-infection to quantify bacterial burden, leukocyte recruitment, and inflammatory mediator production in the brain and galea to assess the role of IL-10 in craniotomy persistence. In addition, the role of G-MDSC-derived IL-10 on neutrophil activity was examined.

Results

Granulocytes (neutrophils and G-MDSCs) were the major producers of IL-10 during craniotomy infection. Bacterial burden was significantly reduced in IL-10 KO mice in the brain and galea at day 14 post-infection compared to WT animals, concomitant with increased CD4+ and γδ T cell recruitment and cytokine/chemokine production, indicative of a heightened proinflammatory response. S. aureus burden was reduced in Mrp8CreIL-10 fl/fl but not CX3CR1CreIL-10 fl/fl mice that was reversed following treatment with exogenous IL-10, suggesting that granulocyte-derived IL-10 was important for promoting S. aureus craniotomy infection. This was likely due, in part, to IL-10 production by G-MDSCs that inhibited neutrophil bactericidal activity and TNF production.

Conclusion

Collectively, these findings reveal a novel role for granulocyte-derived IL-10 in suppressing S. aureus clearance during craniotomy infection, which is one mechanism to account for biofilm persistence.
An examination of the association between forced sex history and reproductive coercion experiences among Black women attending STD clinics in Baltimore, MD, USA
Authors: Campbell Danielle M. , Lucea Marguerite B. , Cimino Andrea N. , Campbell Jacquelyn C. , Stockman Jamila K.
Published: May 2023

Background

Reproductive coercion victimization (RCV) is a significant public health issue that negatively affects women’s sexual and reproductive health outcomes. Less is known about reproductive coercion perpetration (RCP). Few studies have examined these phenomena among representative samples of Black women.

Methods

Retrospective data of women (n = 298) attending STD clinics in Baltimore, MD were analyzed. We calculated lifetime and 12-month prevalence reports of reproductive coercion, and reported values stratified by forced sex history. Binomial logistic regression models were used to examine the association between forced sex history and RCV, accounting for other types of violence typologies.

Results

Lifetime and past 12-month RCV and RCP prevalence were higher among women with forced sex experiences than their counterparts (Lifetime RCV: 46.9% versus 17.5%; past 12-month RCV: 19.4% versus 8.5%. Lifetime RCP: 24.5% versus 17%; past 12-month RCP: 13.3% versus 10.5%). Adjusted models, lifetime reproductive coercion: Women reporting forced sex had a 3.58 times higher odds of having had experienced RCV compared to women not reporting forced sex (AOR 3.58; 95% CI 2.00, 6.46). Women reporting forced sex had a 3.66 times higher odds of having ever experienced pregnancy coercion compared to their counterparts (AOR 3.66; 95% CI 1.93, 7.03) and 4.30 times higher odds of having ever experienced condom manipulation (AOR 4.30; 95% CI 2.15, 8.86). Adjusted models, past 12-month reproductive coercion: Women reporting forced sex had a 2.72 times higher odds of having had experienced past 12-month RCV compared to women not reporting forced sex (AOR 2.72; 95% CI 1.27, 5.91). Women reporting forced sex had a 3.25 times higher odds of having experienced past 12-month pregnancy coercion compared to their counterparts (AOR 3.25; 95% CI 1.38, 7.83) and 3.41 times higher odds of having experienced past 12-month condom manipulation (AOR 3.41; 95% CI 1.14, 10.98).

Conclusions

Participants in our study reported high rates of RCV. Our novel exploration revealed significantly high rates of co-occurring forced sex experiences and RCV and initial prevalence report of RCP. Agencies have a unique opportunity to intervene by implementing screening protocols and referrals for supportive services. These findings may inform future intervention research efforts aimed at improving reproductive health outcomes among Black women.
Implementing pharmacist-prescriber collaboration to improve evidence-based anticoagulant use: a randomized trial
Authors: Smith Shawna N. , Lanham Michael , Seagull F. Jacob , Dorsch Michael , Errickson Josh , Barnes Geoffrey D.
Published: May 2023

Background

Direct oral anticoagulant medications are commonly used to treat or prevent thrombotic conditions, such as pulmonary embolism, deep vein thrombosis, and atrial fibrillation. However, up to 10–15% of patients receiving these medications get unsafe doses based on a patient’s kidney or liver function, potential interactions with other medications, and indication for taking the medication. Alert systems may be beneficial for improving evidence-based prescribing, but can be burdensome and are not currently able to provide monitoring after the initial prescription is written.

Methods/design

This study will improve upon existing alert systems by testing novel medication alerts that encourage collaboration between prescribers (e.g., physicians, nurse practitioners, physician assistants) and expert pharmacists working in anticoagulation clinics. The study will also improve upon the existing alert system by incorporating dynamic long-term monitoring of patient needs and encouraging collaboration between prescribers and expert pharmacists working in anticoagulation clinics. Incorporating state-of-the-art user-centered design principles, prescribing healthcare providers will be randomized to different types of electronic health record medication alerts when a patient has an unsafe anticoagulant prescription. We will identify which alerts are most effective at encouraging evidence-based prescribing and will test moderators to tailor alert delivery to when it is most beneficial. The aims of the project are to (1) determine the effect of notifications targeting existing inappropriate DOAC prescriptions; (2) examine the effect of alerts on newly prescribed inappropriate DOACs; and (3) examine changes in the magnitude of effects over time for both the new prescription alerts and existing prescription notifications for inappropriate DOACs over the 18-month study period.

Discussion

Findings from this project will establish a framework for implementing prescriber-pharmacist collaboration for high-risk medications, including anticoagulants. If effectively implemented at the more than 3000 anticoagulation clinics that exist nationally, hundreds of thousands of patients taking direct oral anticoagulants stand to benefit from safer, evidence-based healthcare.

Trials registration

NCT05351749.
Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation
Authors: Peng Qiuwei , Wang Jian , Han Man , Zhao Minghong , Li Kesong , Lu Tianming , Guo Qiuyan , Jiang Quan
Published: May 2023

Rheumatoid arthritis (RA) is characterized by bone destruction in the afflicted joints, and during the process of bone destruction, osteoclasts play a crucial role. Tanshinone IIA (Tan IIA) has shown anti-inflammatory effects in RA. However, the exact molecular mechanisms by which it delays bone destruction remain largely unexplained. Here, we found that Tan IIA decreased the severity of and ameliorated bone loss in an AIA rat model. In vitro, Tan IIA inhibited RANKL-induced osteoclast differentiation. By activity-based protein analysis (ABPP) combined with LC‒MS/MS, we discovered that Tan IIA covalently binds to the lactate dehydrogenase subunit LDHC and inhibits its enzymatic activity. Moreover, we found that Tan IIA inhibits the generation of osteoclast-specific markers by reducing the accumulation of reactive oxygen species (ROS), thus reducing osteoclast differentiation. Finally, our results reveal that Tan IIA suppresses osteoclast differentiation via LDHC-mediated ROS generation in osteoclasts. Tan IIA can thus be regarded as an effective drug for the treatment of bone damage in RA.
The value of 18F-FDG PET/CT in the systemic evaluation of patients with Rosai–Dorfman disease: a retrospective study and literature review
Authors: Lu Xinyu , Wang Rongxi , Zhu Zhaohui
Published: May 2023

Background

Rosai–Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytic disease. The aim of this study was to review the characteristics of RDD using 18F-FDG PET/CT and determine its efficacy in the disease management.

Results

A total of 28 RDD patients underwent 33 18F-FDG PET/CT scans for systematic assessment and follow-up. The common involved sites included the lymph nodes (17, 60.7%), upper respiratory tract (11, 39.3%), and skin (9, 32.1%). Five patients had more lesions detected in PET/CT images than in CT and/or MRI, including inapparent nodules (n = 5) and bone destruction (n = 3). After thorough treatment evaluation using PET/CT, the treatment strategies of 14 patients (14/16, 87.5%) were changed. Five patients underwent PET/CT twice during follow-up and the SUVs were significantly decreased (15.3 ± 3.4 vs. 4.4 ± 1.0, p = 0.02), which demonstrated disease improvement.

Conclusions

18F-FDG PET/CT contributed to displaying the holistic characteristics of RDD, in particular during initial assessment, treatment strategy adjustment, or efficacy evaluation, and could compensate for some disadvantages of CT and MRI images.
Human exposure to pesticides and thyroid cancer: a worldwide systematic review of the literatures
Authors: Norouzi Fatemeh , Alizadeh Ismaeil , Faraji Maryam
Published: May 2023

Thyroid cancer is considered as one of the most prevalent cancers in the world. Some pesticides can play a role as a potentially important risk factor in thyroid cancer by affecting thyroid morphology and thyroid hormone homeostasis. The aim of present study was to systematically review the available epidemiological evidence for human exposure to pesticides and thyroid cancer. Articles were searched in PubMed, Scopus and Web of Science by suitable keywords from January 2000 to May 2021. Standard techniques for systematic reviews were followed in the current study and results reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Based on the inclusion and exclusion criteria, finally seven studies including four cohort studies and three case-control studies were reviewed. Organochlorines (OCPs) in more cases, Organophosphates (OPs) and Carbamates insecticides, herbicides and fungicides were the studied pesticides. Inconsistent results were reported in the surveyed articles on the OCPs. Two articles on the Carbamates (Carbaryl and Mancozeb) showed consistently an inverse association between exposure and thyroid cancer. Increased risk of thyroid cancer due to the exposure to the Malathion was reported in one article on the OPs. Due to the limited current knowledge about the effect of pesticides on thyroid cancer in humans, human health policies must be implemented to control individual’s exposure to chemicals through using of botanical pesticides in agricultural. Also, more studies must be done to fill this gap of knowledge.
Size matters in telomere biology disorders ‒ expanding phenotypic spectrum in patients with long or short telomeres
Authors: Byrjalsen Anna , Brainin Anna Engell , Lund Thomas Kromann , Andersen Mette Klarskov , Jelsig Anne Marie
Published: May 2023

The end of each chromosome consists of a DNA region termed the telomeres. The telomeres serve as a protective shield against degradation of the coding DNA sequence, as the DNA strand inevitably ‒ with each cell division ‒ is shortened. Inherited genetic variants cause telomere biology disorders when located in genes (e.g. DKC1, RTEL1, TERC, TERT) playing a role in the function and maintenance of the telomeres. Subsequently patients with telomere biology disorders associated with both too short or too long telomeres have been recognized. Patients with telomere biology disorders associated with short telomeres are at increased risk of dyskeratosis congenita (nail dystrophy, oral leukoplakia, and hyper- or hypo-pigmentation of the skin), pulmonary fibrosis, hematologic disease (ranging from cytopenia to leukemia) and in rare cases very severe multiorgan manifestations and early death. Patients with telomere biology disorders associated with too long telomeres have in recent years been found to confer an increased risk of melanoma and chronic lymphocytic leukemia. Despite this, many patients have an apparently isolated manifestation rendering telomere biology disorders most likely underdiagnosed. The complexity of telomere biology disorders and many causative genes makes it difficult to design a surveillance program which will ensure identification of early onset disease manifestation without overtreatment.
Short-chain fatty acid-butyric acid ameliorates granulosa cells inflammation through regulating METTL3-mediated N6-methyladenosine modification of FOSL2 in polycystic ovarian syndrome
Authors: Liu Kailu , He Xi , Huang Jingyu , Yu Simin , Cui Meiting , Gao Mengya , Liu Li , Qian Yu , Xie Ying , Hui Miao , Hong Yanli , Nie Xiaowei
Published: May 2023

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by chronic low-grade inflammation. Previous studies have demonstrated that the gut microbiome can affect the host tissue cells’ mRNA N6-methyladenosine (m6A) modifications. This study aimed to understand the role of intestinal flora in ovarian cells inflammation by regulating mRNA m6A modification particularly the inflammatory state in PCOS. The gut microbiome composition of PCOS and Control groups was analyzed by 16S rRNA sequencing, and the short chain fatty acids were detected in patients’ serum by mass spectrometry methods. The level of butyric acid was found to be decreased in the serum of the obese PCOS group (FAT) compared to other groups, and this was correlated with increased Streptococcaceae and decreased Rikenellaceae based on the Spearman’s rank test. Additionally, we identified FOSL2 as a potential METTL3 target using RNA-seq and MeRIP-seq methodologies. Cellular experiments demonstrated that the addition of butyric acid led to a decrease in FOSL2 m6A methylation levels and mRNA expression by suppressing the expression of METTL3, an m6A methyltransferase. Additionally, NLRP3 protein expression and the expression of inflammatory cytokines (IL-6 and TNF-α) were downregulated in KGN cells. Butyric acid supplementation in obese PCOS mice improved ovarian function and decreased the expression of local inflammatory factors in the ovary. Taken together, the correlation between the gut microbiome and PCOS may unveil crucial mechanisms for the role of specific gut microbiota in the pathogenesis of PCOS. Furthermore, butyric acid may present new prospects for future PCOS treatments.
Epithelium-derived SCUBE3 promotes polarized odontoblastic differentiation of dental mesenchymal stem cells and pulp regeneration
Authors: Wang Zijie , Chen Chuying , Zhang Jiayi , He Jiangdie , Zhang Lin , Wu Jiayuan , Tian Zhihui
Published: May 2023

Background

Signal peptide-CUB-EGF domain-containing protein 3 (SCUBE3), a secreted multifunctional glycoprotein whose transcript expression is restricted to the tooth germ epithelium during the development of embryonic mouse teeth, has been demonstrated to play a crucial role in the regulation of tooth development. Based on this, we hypothesized that epithelium-derived SCUBE3 contributes to bio-function in dental mesenchymal cells (Mes) via epithelium–mesenchyme interactions.

Methods

Immunohistochemical staining and a co-culture system were used to reveal the temporospatial expression of the SCUBE3 protein during mouse tooth germ development. In addition, human dental pulp stem cells (hDPSCs) were used as a Mes model to study the proliferation, migration, odontoblastic differentiation capacity, and mechanism of rhSCUBE3. Novel pulp–dentin-like organoid models were constructed to further confirm the odontoblast induction function of SCUBE3. Finally, semi-orthotopic animal experiments were performed to explore the clinical application of rhSCUBE3. Data were analysed using one-way analysis of variance and t-tests.

Results

The epithelium-derived SCUBE3 translocated to the mesenchyme via a paracrine pathway during mouse embryonic development, and the differentiating odontoblasts in postnatal tooth germ subsequently secreted the SCUBE3 protein via an autocrine mechanism. In hDPSCs, exogenous SCUBE3 promoted cell proliferation and migration via TGF-β signalling and accelerated odontoblastic differentiation via BMP2 signalling. In the semi-orthotopic animal experiments, we found that SCUBE3 pre-treatment-induced polarized odontoblast-like cells attached to the dental walls and had better angiogenesis performance.

Conclusion

SCUBE3 protein expression is transferred from the epithelium to mesenchyme during embryonic development. The function of epithelium-derived SCUBE3 in Mes, including proliferation, migration, and polarized odontoblastic differentiation, and their mechanisms are elaborated for the first time. These findings shed light on exogenous SCUBE3 application in clinic dental pulp regeneration.
Evaluating the efficacy of human dental pulp stem cells and scaffold combination for bone regeneration in animal models: a systematic review and meta-analysis
Authors: Namjoynik Amin , Islam Md Asiful , Islam Mohammad
Published: May 2023

Introduction

Human adult dental pulp stem cells (hDPSC) and stem cells from human exfoliated deciduous teeth (SHED) hold promise in bone regeneration for their easy accessibility, high proliferation rate, self-renewal and osteogenic differentiation capacity. Various organic and inorganic scaffold materials were pre-seeded with human dental pulp stem cells in animals, with promising outcomes in new bone formation. Nevertheless, the clinical trial for bone regeneration using dental pulp stem cells is still in its infancy. Thus, the aim of this systematic review and meta-analysis is to synthesise the evidence of the efficacy of human dental pulp stem cells and the scaffold combination for bone regeneration in animal bone defect models.

Methodology

This study was registered in PROSPERO (CRD2021274976), and PRISMA guideline was followed to include the relevant full-text papers using exclusion and inclusion criteria. Data were extracted for the systematic review. Quality assessment and the risk of bias were also carried out using the CAMARADES tool. Quantitative bone regeneration data of the experimental (scaffold + hDPSC/SHED) and the control (scaffold-only) groups were also extracted for meta-analysis.

Results

Forty-nine papers were included for systematic review and only 27 of them were qualified for meta-analysis. 90% of the included papers were assessed as medium to low risk. In the meta-analysis, qualified studies were grouped by the unit of bone regeneration measurement. Overall, bone regeneration was significantly higher (p < 0.0001) in experimental group (scaffold + hDPSC/SHED) compared to the control group (scaffold-only) (SMD: 1.863, 95% CI 1.121–2.605). However, the effect is almost entirely driven by the % new bone formation group (SMD: 3.929, 95% CI 2.612–5.246) while % BV/TV (SMD: 2.693, 95% CI − 0.001–5.388) shows a marginal effect. Dogs and hydroxyapatite-containing scaffolds have the highest capacity in % new bone formation in response to human DPSC/SHED. The funnel plot exhibits no apparent asymmetry representing a lack of remarkable publication bias. Sensitivity analysis also indicated that the results generated in this meta-analysis are robust and reliable.

Conclusion

This is the first synthesised evidence showing that human DPSCs/SHED and scaffold combination enhanced bone regeneration highly significantly compared to the cell-free scaffold irrespective of scaffold type and animal species used. So, dental pulp stem cells could be a promising tool for treating various bone diseases, and more clinical trials need to be conducted to evaluate the effectiveness of dental pulp stem cell-based therapies.
Mesenchymal stem cells transplantation combined with IronQ attenuates ICH-induced inflammation response via Mincle/syk signaling pathway
Authors: Yang Guoqiang , Kantapan Jiraporn , Mazhar Maryam , Bai Xue , Zou Yuanxia , Wang Honglian , Huang Bingfeng , Yang Sijing , Dechsupa Nathupakorn , Wang Li
Published: May 2023

Background

Intracerebral hemorrhage (ICH) is a severe brain-injured disease accompanied by cerebral edema, inflammation, and subsequent neurological deficits. Mesenchymal stem cells (MSCs) transplantation has been used as a neuroprotective therapy in nervous system diseases because of its anti-inflammatory effect. Nevertheless, the biological characteristics of transplanted MSCs, including the survival rate, viability, and effectiveness, are restricted because of the severe inflammatory response after ICH. Therefore, improving the survival and viability of MSCs will provide a hopeful therapeutic efficacy for ICH. Notably, the biomedical applications of coordination chemistry-mediated metal-quercetin complex have been verified positively and studied extensively, including growth-promoting and imaging probes. Previous studies have shown that the iron-quercetin complex (IronQ) possesses extraordinary dual capabilities with a stimulating agent for cell growth and an imaging probe by magnetic resonance imaging (MRI). Therefore, we hypothesized that IronQ could improve the survival and viability of MSCs, displaying the anti-inflammation function in the treatment of ICH while also labeling MSCs for their tracking by MRI. This study aimed to explore the effects of MSCs with IronQ in regulating inflammation and further clarify their potential mechanisms.

Methods

C57BL/6 male mice were utilized in this research. A collagenase I-induced ICH mice model was established and randomly separated into the model group (Model), quercetin gavage group (Quercetin), MSCs transplantation group (MSCs), and MSCs transplantation combined with IronQ group (MSCs + IronQ) after 24 h. Then, the neurological deficits score, brain water content (BWC), and protein expression, such as TNF-α, IL-6, NeuN, MBP, as well as GFAP, were investigated. We further measured the protein expression of Mincle and its downstream targets. Furthermore, the lipopolysaccharide (LPS)-induced BV2 cells were utilized to investigate the neuroprotection of conditioned medium of MSCs co-cultured with IronQ in vitro.

Results

We found that the combined treatment of MSCs with IronQ improved the inflammation-induced neurological deficits and BWC in vivo by inhibiting the Mincle/syk signaling pathway. Conditioned medium derived from MSCs co-cultured with IronQ decreased inflammation, Mincle, and its downstream targets in the LPS-induced BV2 cell line.

Conclusions

These data suggested that the combined treatment exerts a collaborative effect in alleviating ICH-induced inflammatory response through the downregulation of the Mincle/syk signaling pathway following ICH, further improving the neurologic deficits and brain edema.
Paralinguistic and spectral feature extraction for speech emotion classification using machine learning techniques
Authors: Liu Tong , Yuan Xiaochen
Published: May 2023

Emotion plays a dominant role in speech. The same utterance with different emotions can lead to a completely different meaning. The ability to perform various of emotion during speaking is also one of the typical characters of human. In this case, technology trends to develop advanced speech emotion classification algorithms in the demand of enhancing the interaction between computer and human beings. This paper proposes a speech emotion classification approach based on the paralinguistic and spectral features extraction. The Mel-frequency cepstral coefficients (MFCC) are extracted as spectral feature, and openSMILE is employed to extract the paralinguistic feature. The machine learning techniques multi-layer perceptron classifier and support vector machines are respectively applied into the extracted features for the classification of the speech emotions. We have conducted experiments on the Berlin database to evaluate the performance of the proposed approach. Experimental results show that the proposed approach achieves satisfied performances. Comparisons are conducted in clean condition and noisy condition respectively, and the results indicate better performance of the proposed scheme.
Wellposedness and controllability results of stochastic integrodifferential equations with noninstantaneous impulses and Rosenblatt process
Authors: Kasinathan Ravikumar , Kasinathan Ramkumar , Sandrasekaran Varshini , Nieto Juan J.
Published: May 2023

The purpose of this work is to investigate a novel class of noninstantaneous impulsive stochastic integrodifferential equations (SIDEs) driven by Brownian motion and Rosenblatt process. We construct a new set of adequate assumptions for the existence and uniqueness of mild solutions using stochastic analysis, analytic semigroup theory, integral equation theory, and a fixed point methodology. Additionally, we study the asymptotic behavior of mild solutions and provide stochastic system controllability results. Finally, we include an example to illustrate the application of our main findings.
Finite element method-enhanced neural network for forward and inverse problems
Authors: Meethal Rishith E. , Kodakkal Anoop , Khalil Mohamed , Ghantasala Aditya , Obst Birgit , Bletzinger Kai-Uwe , Wüchner Roland
Published: May 2023

We introduce a novel hybrid methodology that combines classical finite element methods (FEM) with neural networks to create a well-performing and generalizable surrogate model for forward and inverse problems. The residual from finite element methods and custom loss functions from neural networks are merged to form the algorithm. The Finite Element Method-enhanced Neural Network hybrid model (FEM-NN hybrid) is data-efficient and physics-conforming. The proposed methodology can be used for surrogate models in real-time simulation, uncertainty quantification, and optimization in the case of forward problems. It can be used to update models for inverse problems. The method is demonstrated with examples and the accuracy of the results and performance is compared to the conventional way of network training and the classical finite element method. An application of the forward-solving algorithm is demonstrated for the uncertainty quantification of wind effects on a high-rise buildings. The inverse algorithm is demonstrated in the speed-dependent bearing coefficient identification of fluid bearings. Hybrid methodology of this kind will serve as a paradigm shift in the simulation methods currently used.
Analysis of the relation between adverse events and overall survival in patients treated with pembrolizumab as a first-line treatment for metastatic NSCLC
Authors: Faoro Lisa , Brusegan Adriana , Russi Alberto , Calderone Vincenzo , Martelli Alma , Marranconi Ettore , Carpanese Debora , Berti Elena , Coppola Marina
Published: May 2023

Background

Many trials supported pembrolizumab as a first-line monotherapy to significantly improve overall survival (OS) in selected patients with previously untreated metastatic Non–Small Cell Lung Cancer (mNSCLC) and a PD-L1 TPS of ≥50% without EGFR/ALK mutations. The aim of this study was to reveal the correlation between OS and adverse events in real-world settings after 42 months.

Methods

This retrospective observational study involved 98 patients with mNSCLC, TPS ≥ 50%, and no EGFR/ALK aberrations. Patients were treated with pembrolizumab (200 mg q3w) as a first-line treatment. Clinical data, including PD-L1 expression, Performance Status (ECOG-PS), treatment duration, toxicity, and outcomes were retrieved from local electronic medical records and from the Italian Regulatory Agency Registry.

Results

The cohort’s main characteristics were as follows: median age 73 [44-89] years, 64.3% were male and 35.7% were female, an ECOG-PS score of 0 (n = 73) and 1 or 2 (n = 25), and a PD-L1 > 90% in 29.6% of patients. The entire cohort had stage IV NSCLC at diagnosis. The median number of cycles was 8.5 at a median follow-up of 13 months. The median OS of 13.6 months (95% CI: 11.7-NA) was not influenced by sex and PD-L1, but was significantly associated with ECOG-PS (p = 0.02). Immune-Related Adverse Events (irAEs) occurred in 77.5% of patients (30.1% cutaneous, 27.5% gastrointestinal, and 20.4% endocrinological), but no grade 4 or 5 irAEs were identified. Patients experiencing any type of toxicity had a significantly longer median OS (20.39 months, 95% CI: 13.08-NA) than those with no toxicities (6.46 months, 95% CI: 1.41-NA, p = 0.006).

Conclusion

The percentage of irAEs detected was comparable to that reported in KEYNOTE-024 and KEYNOTE-042. These real-world findings demonstrated the significant correlation between OS and cutaneous toxicities.