bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex difference in incidence and risk factors of hospitalization for heart failure, and subsequent mortality: findings from the China PEACE million persons project
Authors: Qiu Weida , Cai Anping , Nie Zhiqiang , Wang Jiabin , Ou Yanqiu , Feng Yingqing
Published: November 2023

Background

Epidemiological study of sex differences in incidence and risk factors of heart failure (HF), and subsequent mortality attributed to HF in the Chinese general population is lacking. This study aims to assess the sex differences in the incidence and risk factors of hospitalization for HF and evaluate the sex differences in population attributable fractions (PAFs) for the subsequent mortality among the general population.

Methods

Data were from a sub-cohort of the Patient-Centered Evaluative Assessment of Cardiac Events Million Persons Project in China. Fine and Gray models were conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) accounting for the competing risk of all-cause mortality. Propensity score matching analysis and subgroup analyses were used to verify the robustness of the results. Adjusted PAFs of HF for all-cause and cardiovascular mortality were evaluated by sex.

Results

Of the 102,278 participants, 60.5% were women, and the mean age was 54.3 years. After a median follow-up of 3.52 years, 1588 cases of hospitalization for HF were identified. After adjusting for the covariates, women had 31% (95% CI: 0.61–0.79) lower risk for HF than men. The results were consistent in the propensity score matching cohort and across all subgroup analyses (all P sex-subgroups interaction > 0.05). Although women were associated with a lower risk of HF, they had a higher PAF (24.2%, 95% CI: 16.0-31.6) for subsequent cardiovascular mortality than men (16.5%, 95% CI: 11.3–21.5). Several significant differences in risk factors for HF were noted between sexes.

Conclusion

In the southern Chinese population, women had a lower risk of HF but had a higher cardiovascular mortality fraction attributed to HF than men. Sex-specific preventative strategies and management for HF should be warranted.
A novel fusion algorithm for benign-malignant lung nodule classification on CT images
Authors: Ma Ling , Wan Chuangye , Hao Kexin , Cai Annan , Liu Lizhi
Published: November 2023

The accurate recognition of malignant lung nodules on CT images is critical in lung cancer screening, which can offer patients the best chance of cure and significant reductions in mortality from lung cancer. Convolutional Neural Network (CNN) has been proven as a powerful method in medical image analysis. Radiomics which is believed to be of interest based on expert opinion can describe high-throughput extraction from CT images. Graph Convolutional Network explores the global context and makes the inference on both graph node features and relational structures. In this paper, we propose a novel fusion algorithm, RGD, for benign-malignant lung nodule classification by incorporating Radiomics study and Graph learning into the multiple Deep CNNs to form a more complete and distinctive feature representation, and ensemble the predictions for robust decision-making. The proposed method was conducted on the publicly available LIDC-IDRI dataset in a 10-fold cross-validation experiment and it obtained an average accuracy of 93.25%, a sensitivity of 89.22%, a specificity of 95.82%, precision of 92.46%, F1 Score of 0.9114 and AUC of 0.9629. Experimental results illustrate that the RGD model achieves superior performance compared with the state-of-the-art methods. Moreover, the effectiveness of the fusion strategy has been confirmed by extensive ablation studies. In the future, the proposed model which performs well on the pulmonary nodule classification on CT images will be applied to increase confidence in the clinical diagnosis of lung cancer.
COVision: convolutional neural network for the differentiation of COVID−19 from common pulmonary conditions using CT scans
Authors: Parikh Kush V. , Mathew Timothy J.
Published: November 2023

With the growing amount of COVID-19 cases, especially in developing countries with limited medical resources, it is essential to accurately and efficiently diagnose COVID-19. Due to characteristic ground-glass opacities (GGOs) and other types of lesions being present in both COVID-19 and other acute lung diseases, misdiagnosis occurs often — 26.6% of the time in manual interpretations of CT scans. Current deep-learning models can identify COVID-19 but cannot distinguish it from other common lung diseases like bacterial pneumonia. Concretely, COVision is a deep-learning model that can differentiate COVID-19 from other common lung diseases, with high specificity using CT scans and other clinical factors. COVision was designed to minimize overfitting and complexity by decreasing the number of hidden layers and trainable parameters while still achieving superior performance. Our model consists of two parts: the CNN which analyzes CT scans and the CFNN (clinical factors neural network) which analyzes clinical factors such as age, gender, etc. Using federated averaging, we ensembled our CNN with the CFNN to create a comprehensive diagnostic tool. After training, our CNN achieved an accuracy of 95.8% and our CFNN achieved an accuracy of 88.75% on a validation set. We found a statistical significance that COVision performs better than three independent radiologists with at least 10 years of experience, especially in differentiating COVID-19 from pneumonia. We analyzed our CNN’s activation maps through Grad-CAMs and found that lesions in COVID-19 presented peripherally, closer to the pleura, whereas pneumonia lesions presented centrally.
Residual varus alignment after posterior-stabilized total knee arthroplasty limits medial soft tissue remodeling
Authors: Jia Yanfeng , Zhai Leilei , Qin Shiqi , Xu Juncai , Gao Wei , Zhang Boxuan , Wang Xiaofeng , Zhou Kezhen , Sun Zhiwen , Niu Yingzhen , Bao Hongwei , Sun Ran
Published: November 2023

Background

Proper lower limb alignment and soft tissue balance are significant indicators to measure the success of total knee arthroplasty (TKA). Previous studies have confirmed that soft tissue relaxation around the knee after TKA will change over time; however, the relationship between lower limb alignment and soft tissue balance after TKA remains unclear. We studied (1) whether the change of soft tissue balance around the knee with time after posterior-stabilized (PS) TKA would affect the alignment of the lower limbs; (2) Whether the accuracy of lower limb alignment during PS TKA affects postoperative soft tissue remodeling.

Methods

In this study, 100 patients were recruited after PS TKA. Among them, 50 patients with a hip knee ankle (HKA) angle of ≤  ± 3° were set as the neutral group, and 50 patients with an HKA angle of >  ± 3° were set as the deviation group. The imaging results measured the HKA angle before the operation as well as the HKA, varus, and valgus angles at 1, 3, 6, 12, and 24 months after TKA. Clinical assessment included range of motion (ROM), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Society Score (KSS).

Results

Eight people were excluded from the study. After the exclusion, the study enrolled 47 patients in the neutral group and 45 patients in the deviant group and were followed for up to 2 years. There was no statistical significance in mean varus angles as well as HKA angle changes during the follow-up phase of each groups (P > 0.05). The mean valgus angles of the patients in the neutral group group were 2.47°, 3.45°, 3.63°, 3.60° and 3.63°, and in the deviation group were 2.45° (P = 0.841), 2.88° (P < 0.001), 3.07° (P < 0.001), 3.06° (P < 0.001), and 3.10° (P < 0.001). ROM, WOMAC and KSS of the two groups were significantly improved after operation, with no difference between the two groups.

Conclusion

This study shows that whether the alignment is accurate or not in the early stage after TKA, the relaxation of the medial and lateral soft tissues of the knee joint change; however, this change will not significantly affect the alignment of the lower limbs. Postoperative residual varus deformity limits medial soft tissue remodeling.

Level of evidence

III.
A shared decision-making model in pediatric palliative care: a qualitative study of healthcare providers
Authors: Cai Siyu , Cheng Lei , Wang Ruixin , Zhou Xuan , Peng Xiaoxia
Published: November 2023

Background

Pediatric shared decision-making (SDM) is a fundamental part of family-centered care. Pediatric palliative care (PPC) is one of the more difficult fields for healthcare providers when choosing to utilize SDM. However, to our knowledge, there are still few structured approaches of SDM in PPC. We aimed to build a model of SDM in PPC that achieves better care and outcomes for children and their family members.

Methods

This study is a descriptive phenomenology study. Participants included physicians, nurses, and social workers in the PPC team. Participants were individually interviewed face-to-face or via an online meeting software. Data were collected in semi-structured interviews and analyzed using a thematic framework analysis.

Results

In total, 27 healthcare providers were interviewed. The model of SDM in PPC identified three themes, including the participants, the principle and the process of SDM. Decision participants involved the children, parents, the PPC team and others. The decision principle had three sub-themes including type, standard and precondition. The decision process describes the fundamental process of SDM and provides suggestions for mobilizing patients and parents to engage in decision-making and seeking conflict resolution.

Conclusions

This is the first study to develop a SDM model in PPC. This model can provide guidance to PPC teams on SDM practices. In addition, the model contributes to the existing body of knowledge by providing a conceptual model for SDM in the context of PPC.
Equality, diversity, and inclusion in oncology clinical trials: an audit of essential documents and data collection against INCLUDE under-served groups in a UK academic trial setting
Authors: Patel Dhrusti , Kilburn Lucy , Fox Lisa , Hall Emma , Bliss Judith , Lewis Rebecca
Published: November 2023

Background

Clinical trials should be as inclusive as possible to facilitate equitable access to research and better reflect the population towards which any intervention is aimed. Informed by the UK’s National Institute for Health and Care Research (NIHR) Innovations in Clinical Trial Design and Delivery for the Under-served (INCLUDE) guidance, we audited oncology trials conducted by the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London (ICR-CTSU) to identify whether essential documents were overtly excluding any groups and whether sufficient data were collected to assess diversity of trial participants from groups suggested by INCLUDE as under-served by research in the UK.

Methods

Thirty cancer clinical trials managed by ICR-CTSU and approved between 2011–2021 were audited. The first ethics approved version of each trial’s protocol, patient information sheet, and patient completed questionnaire, together with the first case report forms (CRFs) version were reviewed. A range of items aligned with the INCLUDE under-served groups were assessed, including age, sex and gender, socio-economic and health factors. The scope did not cover trial processes in participating hospitals.

Results

Data relating to participants’ age, ethnic group and health status were well collected and no upper age limit was specified in any trials’ eligibility criteria. 23/30 (77%) information sheets used at least one gendered term to address patients. Most CRFs did not specify whether they were collecting sex or gender and only included male or female categories. The median reading age for information sheets was 15–16 years (IQR: 14–15 – 16–17). Socio-economic factors were not routinely collected and not commonly mentioned in trial protocols.

Conclusions

No systemic issues were identified in protocols which would explicitly prevent any under-served group from participating. Areas for improvement include reducing use of gendered words and improving readability of patient information. The challenge of fully assessing adequate inclusion of under-served populations remains, as socio-economic factors are not routinely collected because they fall beyond the data generally required for protocol-specified trial endpoint assessments. This audit has highlighted the need to agree and standardise demographic data collection to permit adequate monitoring of the under-served groups identified by the NIHR.
The mediation of health-promoting lifestyle on self-perceived health status and quality of life among nurses: a cross-sectional study
Authors: Wang Kuei-Ying , Chien Ching-Ming , Lee Huan-Fang , Yobelina Yohana
Published: November 2023

Background

Nurses with busy workloads lack the time to maintain health, leading to a decline in physical and mental health and quality of life. It is widely accepted that self-perception of health triggers health-promoting behaviors and impacts the quality of life; however, the relationship between these factors among nurses is unclear. The purpose of this study was to investigate the ability of a health-promoting lifestyle to mediate the relationship between self-perceived health and quality of life among nurses.

Methods

A cross-sectional survey was conducted in four regional Taiwanese teaching hospitals with over 500 beds. The survey used stratified random sampling of 600 nurses who had worked for more than six months. The Self-Perceived Health Questionnaire, the Health-Promoting Lifestyle Profile, and the World Health Organization Quality of Life Scale were used to measure nurses’ self-perceived health (SPH), health-promoting lifestyle (HPL), and quality of life (QoL). A Hayes PROCESS analysis and bootstrapping method were used for the mediation analysis.

Results

A total of 518 nurses’ data was included in the analysis. Nurses perceived their health status as less favorable than their colleagues, but frequently adopted health promotion behaviors. Nurses reported a moderate QoL. QoL and SPH were correlated (r = .33) and a high correlation between QoL and HPL (r = .64) was found. SPH and HPL both affect QoL (B = 0.077 and 0.070). SPH and HPL explained 42.6% of the variation in QoL. HPL played a partial mediation role.

Conclusions

The study confirmed that HPL has an important role in mediating nurses’ SPH and QoL. Nurse administrators are advised to encourage nurses to monitor their health status and provide health promotion mechanisms to improve their quality of life.
Adherence to the 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations and risk of 14 lifestyle-related cancers in the UK Biobank prospective cohort study
Authors: Malcomson Fiona C. , Parra-Soto Solange , Ho Frederick K. , Lu Liya , Celis-Morales Carlos , Sharp Linda , Mathers John C.
Published: November 2023

Background

The World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations are lifestyle-based recommendations which aim to reduce cancer risk. This study investigated associations between adherence, assessed using a standardised scoring system, and the risk of all cancers combined and of 14 cancers for which there is strong evidence for links with aspects of lifestyle in the UK.

Methods

We used data from 94,778 participants (53% female, mean age 56 years) from the UK Biobank. Total adherence scores (range 0–7 points) were derived from dietary, physical activity, and anthropometric data. Associations between total score and cancer risk (all cancers combined; and prostate, breast, colorectal, lung, uterine, liver, pancreatic, stomach, oesophageal, head and neck, ovarian, kidney, bladder, and gallbladder cancer) were investigated using Cox proportional hazard models, adjusting for age, sex, deprivation index, ethnicity, and smoking status.

Results

Mean total score was 3.8 (SD 1.0) points. During a median follow-up of 8 years, 7296 individuals developed cancer. Total score was inversely associated with risk of all cancers combined (HR: 0.93; 95%CI: 0.90–0.95 per 1-point increment), as well as breast (HR: 0.90; 95%CI: 0.86–0.95), colorectal (HR: 0.90; 95%CI: 0.84–0.97), kidney (HR: 0.82; 95%CI: 0.72–0.94), oesophageal (HR: 0.84; 95%CI: 0.71–0.98), ovarian (HR: 0.76; 95%CI: 0.65–0.90), liver (HR: 0.78; 95%CI: 0.63–0.97), and gallbladder (HR: 0.70; 95%CI: 0.53–0.93) cancers.

Conclusions

Greater adherence to lifestyle-based recommendations was associated with reduced risk of all cancers combined and of breast, colorectal, kidney, oesophageal, ovarian, liver, and gallbladder cancers. Our findings support compliance with the Cancer Prevention Recommendations for cancer prevention in the UK.
Butterflies in the gut: the interplay between intestinal microbiota and stress
Authors: Lai Tzu-Ting , Liou Chia-Wei , Tsai Yu-Hsuan , Lin Yuan-Yuan , Wu Wei-Li
Published: November 2023

Psychological stress is a global issue that affects at least one-third of the population worldwide and increases the risk of numerous psychiatric disorders. Accumulating evidence suggests that the gut and its inhabiting microbes may regulate stress and stress-associated behavioral abnormalities. Hence, the objective of this review is to explore the causal relationships between the gut microbiota, stress, and behavior. Dysbiosis of the microbiome after stress exposure indicated microbial adaption to stressors. Strikingly, the hyperactivated stress signaling found in microbiota-deficient rodents can be normalized by microbiota-based treatments, suggesting that gut microbiota can actively modify the stress response. Microbiota can regulate stress response via intestinal glucocorticoids or autonomic nervous system. Several studies suggest that gut bacteria are involved in the direct modulation of steroid synthesis and metabolism. This review provides recent discoveries on the pathways by which gut microbes affect stress signaling and brain circuits and ultimately impact the host’s complex behavior.
METTL3-mediated m6A RNA methylation induces the differentiation of lung resident mesenchymal stem cells into myofibroblasts via the miR-21/PTEN pathway
Authors: Lu Yi , Liu Zeyu , Zhang Yunjiao , Wu Xiuhua , Bian Wei , Shan Shan , Yang Danrong , Ren Tao
Published: November 2023

Background

The accumulation of myofibroblasts is the key pathological feature of pulmonary fibrosis (PF). Aberrant differentiation of lung-resident mesenchymal stem cells (LR-MSCs) has been identified as a critical source of myofibroblasts, but the molecular mechanisms underlying this process remain largely unknown. In recent years, N6-methyladenosine (m6A) RNA modification has been implicated in fibrosis development across diverse organs; however, its specific role in promoting the differentiation of LR-MSCs into myofibroblasts in PF is not well defined.

Methods

In this study, we examined the levels of m6A RNA methylation and the expression of its regulatory enzymes in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. The downstream target genes of m6A and their related pathways were identified according to a literature review, bioinformatic analysis and experimental verification. We also assessed the expression levels of myofibroblast markers in treated LR-MSCs and confirmed the involvement of the above-described pathway in the aberrant differentiation direction of LR-MSCs under TGF-β1 stimulation by overexpressing or knocking down key genes within the pathway.

Results

Our results revealed that METTL3-mediated m6A RNA methylation was significantly upregulated in both TGF-β1-treated LR-MSCs and fibrotic mouse lung tissues. This process directly led to the aberrant differentiation of LR-MSCs into myofibroblasts by targeting the miR-21/PTEN pathway. Moreover, inhibition of METTL3 or miR-21 and overexpression of PTEN could rescue this abnormal differentiation.

Conclusion

Our study demonstrated that m6A RNA methylation induced aberrant LR-MSC differentiation into myofibroblasts via the METTL3/miR-21/PTEN signaling pathway. We indicated a novel mechanism to promote PF progression. Targeting METTL3-mediated m6A RNA methylation and its downstream targets may present innovative therapeutic approaches for the prevention and treatment of PF.
SIRT1 mediates the inhibitory effect of Dapagliflozin on EndMT by inhibiting the acetylation of endothelium Notch1
Authors: Wang Weijie , Li Yilan , Zhang Yanxiu , Ye Tao , Wang Kui , Li Shuijie , Zhang Yao
Published: November 2023

Background

Endothelial–mesenchymal transition (EndMT) plays a crucial role in promoting myocardial fibrosis and exacerbating cardiac dysfunction. Dapagliflozin (DAPA) is a sodium–glucose-linked transporter 2 (SGLT-2) inhibitor that has been shown to improve cardiac function in non-diabetic patients with heart failure (HF). However, the precise mechanisms by which DAPA exerts its beneficial effects are yet to be fully elucidated.

Methods

Isoproterenol (ISO) was used to generate a HF model in mice. For in vitro experiments, we used TGF-β1-stimulated human umbilical vein endothelial cells (HUVECs) and mouse aortic endothelial cells (MAECs).

Results

Both our in vivo and in vitro results showed that EndMT occurred with decreased SIRT1 (NAD+-dependent deacetylase) protein expression, which could be reversed by DAPA therapy. We found that the protective effect of DAPA was significantly impaired upon SIRT1 inhibition. Mechanistically, we observed that SIRT1 phosphorylation, a required modification for its ubiquitination and degradation, was reduced by DAPA treatment, which induces the nucleus translocation of SIRT1 and promotes its binding to the active intracellular domain of Notch1 (NICD). This interaction led to the deacetylation and degradation of NICD, and the subsequent inactivation of the Notch1 signaling pathway which contributes to ameliorating EndMT.

Conclusions

Our study revealed that DAPA can attenuate EndMT induced by ISO in non-diabetic HF mice. This beneficial effect is achieved through SIRT1-mediated deacetylation and degradation of NICD. Our findings provide greater insight into the underlying mechanisms of the therapeutic effects of DAPA in non-diabetic HF.

Graphical Abstract
Cost-effectiveness of finerenone in chronic kidney disease associated with type 2 diabetes in The Netherlands
Authors: Quist Sara W. , van Schoonhoven Alexander V. , Bakker Stephan J. L. , Pochopień Michał , Postma Maarten J. , van Loon Jeanni M. T. , Paulissen Jeroen H. J.
Published: November 2023

Background

In the Netherlands, more than one million patients have type 2 diabetes (T2D), and approximately 36% of these patients have chronic kidney disease (CKD). Yearly medical costs related to T2D and CKD account for approximately €1.3 billion and €805 million, respectively. The FIDELIO-DKD trial showed that the addition of finerenone to the standard of care (SoC) lowers the risk of CKD progression and cardiovascular (CV) events in patients with CKD stages 2–4 associated with T2D. This study investigates the cost-effectiveness of adding finerenone to the SoC of patients with advanced CKD and T2D compared to SoC monotherapy.

Methods

The validated FINE-CKD model is a Markov cohort model which simulates the disease pathway of patients over a lifetime time horizon. The model was adapted to reflect the Dutch societal perspective. The model estimated the incremental costs, utilities, and incremental cost-effectiveness ratio (ICER). Sensitivity and scenario analyses were performed to assess the effect of parameter uncertainty on model robustness.

Results

When used in conjunction with SoC, finerenone extended time free of CV events and renal replacement therapy by respectively 0.30 and 0.31 life years compared to SoC alone, resulting in an extension of 0.20 quality-adjusted life years (QALYs). The reduction in renal and CV events led to a €6136 decrease in total lifetime costs per patient compared to SoC alone, establishing finerenone as a dominant treatment option. Finerenone in addition to SoC had a 83% probability of being dominant and a 93% probability of being cost-effective at a willingness-to-pay threshold of €20,000.

Conclusion

By reducing the risk of CKD progression and CV events, finerenone saves costs to society while gaining QALYs in patients with T2D and advanced CKD in the Netherlands.
Prognostic value of triglyceride-glucose index in patients with chronic coronary syndrome undergoing percutaneous coronary intervention
Authors: Tao Shiyi , Yu Lintong , Li Jun , Xie Zicong , Huang Li , Yang Deshuang , Tan Yuqing , Zhang Wenjie , Huang Xuanchun , Xue Tiantian
Published: November 2023

Background

The triglyceride-glucose (TyG) index has been proposed as a reliable surrogate marker of insulin resistance and an independent predictor of major adverse cardiovascular events (MACEs). Several recent studies have shown the relationship between the TyG index and cardiovascular outcomes; however, the role of the TyG index in chronic coronary syndrome (CCS) progression has not been extensively assessed especially in population after revascularization. This study aimed to investigate the prognostic value of the TyG index in predicting MACEs in CCS patients undergoing percutaneous coronary intervention (PCI).

Methods

The data for the study were taken from the Hospital Information System database in China-Japan Friendship Hospital over the period 2019–2021. Eligible participants were divided into groups according to the TyG index tertiles. The Boruta algorithm was performed for feature selection. Multivariate Cox proportional hazards models and restricted cubic spline (RCS) analysis were applied to examine the dose–response relationship between the TyG index and endpoint, and the results were expressed with hazard ratio (HR) and 95% confidence interval (CI) values. The area under the receiver operating characteristic (ROC) curve (AUC), decision curve analysis (DCA), and clinical impact curve (CIC) were plotted to comprehensively evaluate the predictive accuracy and clinical value of the model. The goodness-of-fit of models was evaluated using the calibration curve and χ2 likelihood ratio test.

Results

After applying inclusion and exclusion criteria, 1353 patients with CCS undergoing PCI were enrolled in the study. After adjusting for all confounders, we found that those with the highest TyG index had a 59.5% increased risk of MACEs over the 1-year follow-up (HR 1.595, 95% CI 1.370 ~ 1.855). Using the lowest TyG index tertile as the reference (T1), the fully adjusted HRs (95% CIs) for endpoints was 1.343 (1.054 ~ 1.711) in the middle (T2) and 2.297 (1.842 ~ 2.864) in highest tertile (T3) (P for trend < 0.001). The TyG index had an excellent predictive performance according to the results of AUC 0.810 (0.786, 0.834) and χ2 likelihood ratio test (χ2 = 7.474, P = 0.486). DCA and CIC analysis also suggested a good overall net benefit and clinical impact of the multivariate model. The results in the subgroup analysis were consistent with the main analyses. RCS model demonstrated that the TyG index was nonlinearly associated with the risk of MACEs within one year (P for nonlinear < 0.001).

Conclusion

The elevated TyG index is associated with an increased risk of cardiovascular events and predicts future MACEs in patients with CCS undergoing PCI independently of known cardiovascular risk factors, indicating that the TyG index may be a potential marker for risk stratification and prognosis in CCS patients undergoing PCI.
Genetic deletion of MMP12 ameliorates cardiometabolic disease by improving insulin sensitivity, systemic inflammation, and atherosclerotic features in mice
Authors: Amor Melina , Bianco Valentina , Buerger Martin , Lechleitner Margarete , Vujić Nemanja , Dobrijević Anja , Akhmetshina Alena , Pirchheim Anita , Schwarz Birgit , Pessentheiner Ariane R. , Baumgartner Franziska , Rampitsch Katharina , Schauer Silvia , Klobučar Iva , Degoricija Vesna , Pregartner Gudrun , Kummer Daniel , Svecla Monika , Sommer Gerhard , Kolb Dagmar , Holzapfel Gerhard A. , Hoefler Gerald , Frank Saša , Norata Giuseppe Danilo , Kratky Dagmar
Published: November 2023

Background

Matrix metalloproteinase 12 (MMP12) is a macrophage-secreted protein that is massively upregulated as a pro-inflammatory factor in metabolic and vascular tissues of mice and humans suffering from cardiometabolic diseases (CMDs). However, the molecular mechanisms explaining the contributions of MMP12 to CMDs are still unclear.

Methods

We investigated the impact of MMP12 deficiency on CMDs in a mouse model that mimics human disease by simultaneously developing adipose tissue inflammation, insulin resistance, and atherosclerosis. To this end, we generated and characterized low-density lipoprotein receptor (Ldlr)/Mmp12-double knockout (DKO) mice fed a high-fat sucrose- and cholesterol-enriched diet for 16–20 weeks.

Results

DKO mice showed lower cholesterol and plasma glucose concentrations and improved insulin sensitivity compared with LdlrKO mice. Untargeted proteomic analyses of epididymal white adipose tissue revealed that inflammation- and fibrosis-related pathways were downregulated in DKO mice. In addition, genetic deletion of MMP12 led to alterations in immune cell composition and a reduction in plasma monocyte chemoattractant protein-1 in peripheral blood which indicated decreased low-grade systemic inflammation. Aortic en face analyses and staining of aortic valve sections demonstrated reduced atherosclerotic plaque size and collagen content, which was paralleled by an improved relaxation pattern and endothelial function of the aortic rings and more elastic aortic sections in DKO compared to LdlrKO mice. Shotgun proteomics revealed upregulation of anti-inflammatory and atheroprotective markers in the aortas of DKO mice, further supporting our data. In humans, MMP12 serum concentrations were only weakly associated with clinical and laboratory indicators of CMDs.

Conclusion

We conclude that the genetic deletion of MMP12 ameliorates obesity-induced low-grade inflammation, white adipose tissue dysfunction, biomechanical properties of the aorta, and the development of atherosclerosis. Therefore, therapeutic strategies targeting MMP12 may represent a promising approach to combat CMDs.
Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors
Authors: Llinàs-Arias Pere , Ensenyat-Mendez Miquel , Íñiguez-Muñoz Sandra , Orozco Javier I. J. , Valdez Betsy , Salomon Matthew P. , Matsuba Chikako , Solivellas-Pieras Maria , Bedoya-López Andrés F. , Sesé Borja , Mezger Anja , Ormestad Mattias , Unzueta Fernando , Strand Siri H. , Boiko Alexander D. , Hwang E Shelley , Cortés Javier , DiNome Maggie L. , Esteller Manel , Lupien Mathieu , Marzese Diego M.
Published: November 2023

Background

Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.

Methods

We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.

Results

We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 − 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 − 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01).

Conclusion

Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.
Breaking barriers: exploring mechanisms behind opening the blood–brain barrier
Authors: Stamp Melanie E. M. , Halwes Michael , Nisbet David , Collins David J.
Published: November 2023

The blood–brain barrier (BBB) is a selectively permeable membrane that separates the bloodstream from the brain. While useful for protecting neural tissue from harmful substances, brain-related diseases are difficult to treat due to this barrier, as it also limits the efficacy of drug delivery. To address this, promising new approaches for enhancing drug delivery are based on disrupting the BBB using physical means, including optical/photothermal therapy, electrical stimulation, and acoustic/mechanical stimulation. These physical mechanisms can temporarily and locally open the BBB, allowing drugs and other substances to enter. Focused ultrasound is particularly promising, with the ability to focus energies to targeted, deep-brain regions. In this review, we examine recent advances in physical approaches for temporary BBB disruption, describing their underlying mechanisms as well as evaluating the utility of these physical approaches with regard to their potential risks and limitations. While these methods have demonstrated efficacy in disrupting the BBB, their safety, comparative efficacy, and practicality for clinical use remain an ongoing topic of research.
Much room for change: access to surgical care for stateless individuals in Pakistan
Authors: Thobani Humza , Shah Mashal Murad , Ehsan Anam N , Khan Sadaf
Published: November 2023

Background

As developing countries take steps towards providing universal essential surgery, ensuring the equitable distribution of such care for underrepresented populations is a vital function of the global surgery community. Unfortunately, in the context of the global “stateless”, there remains much room for improvement.

Key issues

Inherent structural deficiencies, such as lack of adequate population data on stateless communities, absent health coverage policies for stateless individuals, and minimal patient-reported qualitative data on barriers to surgical service delivery prevent stateless individuals from receiving the care they require – even when healthcare infrastructure to provide such care exists. The authors therefore propose more research and targeted interventions to address the systemic issues that prevent stateless individuals from accessing surgical care.

Conclusion

It is essential to address the aforementioned barriers in order to improve stateless populations’ access to surgical care. Rigorous empirical and qualitative research provides an important avenue through which these structural issues may be addressed.
Findings from a Malaysian multicentre study on oropharyngeal squamous cell carcinoma
Authors: Sathasivam Hans Prakash , Davan Sangeetha Passu , Chua Szu May , Rohaizat Rahmuna Fazlina , Japar Rohaizam , Zakaria Zahirrudin , Ahmad Abd Razak , Hashim Hasmah , Marimuthu Shashi Gopalan , Liew Yew Toong , Yong Doh Jeing , Vairavan Pappathy , Mohan Singh Avatar Singh , Goh Benjamin Hong Beng , Yusof Zulkifli , Abu Dahari Khairul Azlan Shahril , Haron Ali , Mansor Masaany , Ibrahim Mohd Zambri , Muhammad Abdul Kadar Shiraz Qamil , Hamal Mohamad Hazri , Wan Mohamad Wan Emelda ,   Malaysian Head & Neck Cancer Research Group
Published: November 2023

Background

In addition to the conventional aetiologic agents of oropharyngeal squamous cell carcinoma (OPSCC) such as tobacco usage, alcohol consumption and betel quid usage, it has been established that a proportion of OPSCC are driven by persistent oncogenic human papillomavirus (HPV) infections. Currently, there is a lack of data on the burden of HPV- associated OPSCC in Asian countries including Malaysia.

Methods

A cross-sectional multicentre study with tissue analysis of Malaysian patients diagnosed with primary OPSCC within a five-year period, from 2015 to 2019 between 01/01/2015 to 31/12/2019 was undertaken. Determination of HPV status was carried out using p16INK4a immunohistochemistry on tissue microarrays constructed from archived formalin-fixed paraffin-embedded tissue.

Results

From the cases identified, 184 cases had sufficient tissue material for analysis. Overall, median age at diagnosis was 63.0 years (IQR = 15) and 76.1% of patients were males. In our cohort, 35.3% of patients were Indian, 34.2% were Chinese, 21.2% were Malay and 9.2% were from other ethnicities. The estimated prevalence of HPV-associated OPSCC in our cohort was 31.0% (CI 24.4–38.2%). The median age for the HPV-associated OPSCC sub-group of patients was not significantly lower than the median age of patients with HPV-independent OPSCC. More than half of HPV-associated OPSCC was seen in patients of Chinese ethnicity (54.4%). Patients with HPV-associated OPSCC had a much better overall survival than patients with HPV-independent OPSCC (Log rank test; p < 0.001). Patients with HPV-associated OPSCC with no habit-related risk factors such as smoking, were found to have much better overall survival when compared to all other sub-groups.

Conclusions

The findings from our study suggests that prevalence of HPV-associated OPSCC in Malaysia, though not as high as some developed countries, is however on an upward trend. HPV-associated OPSCC appears to be more frequently encountered in patients of Chinese ethnicity. Conventional risk-factors associated with OPSCC such as smoking, alcohol consumption and betel quid chewing should still be considered when estimating prognosis of patients with HPV-associated OPSCC.
External validation of the modified sepsis renal angina index for prediction of severe acute kidney injury in children with septic shock
Authors: Stanski Natalja L. , Basu Rajit K. , Cvijanovich Natalie Z. , Fitzgerald Julie C. , Bigham Michael T. , Jain Parag N. , Schwarz Adam J. , Lutfi Riad , Thomas Neal J. , Baines Torrey , Haileselassie Bereketeab , Weiss Scott L. , Atreya Mihir R. , Lautz Andrew J. , Zingarelli Basilia , Standage Stephen W. , Kaplan Jennifer , Chawla Lakhmir S. , Goldstein Stuart L.
Published: November 2023

Background

Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort.

Methods

A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 103/µL.

Results

Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5–16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6–49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2–5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82–0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0–10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5–21.5, p = 0.01).

Conclusions

Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population.
Methylation-directed regulatory networks determine enhancing and silencing of mutation disease driver genes and explain inter-patient expression variation
Authors: Edrei Yifat , Levy Revital , Kaye Daniel , Marom Anat , Radlwimmer Bernhard , Hellman Asaf
Published: November 2023

Background

Common diseases manifest differentially between patients, but the genetic origin of this variation remains unclear. To explore possible involvement of gene transcriptional-variation, we produce a DNA methylation-oriented, driver-gene-wide dataset of regulatory elements in human glioblastomas and study their effect on inter-patient gene expression variation.

Results

In 175 of 177 analyzed gene regulatory domains, transcriptional enhancers and silencers are intermixed. Under experimental conditions, DNA methylation induces enhancers to alter their enhancing effects or convert into silencers, while silencers are affected inversely. High-resolution mapping of the association between DNA methylation and gene expression in intact genomes reveals methylation-related regulatory units (average size = 915.1 base-pairs). Upon increased methylation of these units, their target-genes either increased or decreased in expression. Gene-enhancing and silencing units constitute cis-regulatory networks of genes. Mathematical modeling of the networks highlights indicative methylation sites, which signified the effect of key regulatory units, and add up to make the overall transcriptional effect of the network. Methylation variation in these sites effectively describe inter-patient expression variation and, compared with DNA sequence-alterations, appears as a major contributor of gene-expression variation among glioblastoma patients.

Conclusions

We describe complex cis-regulatory networks, which determine gene expression by summing the effects of positive and negative transcriptional inputs. In these networks, DNA methylation induces both enhancing and silencing effects, depending on the context. The revealed mechanism sheds light on the regulatory role of DNA methylation, explains inter-individual gene-expression variation, and opens the way for monitoring the driving forces behind deferential courses of cancer and other diseases.
Supporting physical activity for mobility in older adults with mobility limitations (SuPA Mobility): study protocol for a randomized controlled trial
Authors: Rice Jordyn , Li Linda C. , Davis Jennifer C. , Pahor Marco , Madden Kenneth , Wei Nathan , Wong Hubert , Skelton Dawn A. , McCormick Sioban , Falck Ryan S. , Barha Cindy K. , Rhodes Ryan E. , Loomba Sohail , Sadatsafavi Mohsen , Liu-Ambrose Teresa
Published: November 2023

Background

Limited mobility in older adults consistently predicts both morbidity and mortality. As individuals age, the rates of mobility disability increase from 1.0% in people aged 15–24 to 20.6% in adults over 65 years of age. Physical activity can effectively improve mobility in older adults, yet many older adults do not engage in sufficient physical activity. Evidence shows that increasing physical activity by 50 min of moderate intensity physical activity in sedentary older adults with mobility limitations can improve mobility and reduce the incidence of mobility disability. To maximize the healthy life span of older adults, it is necessary to find effective and efficient interventions that can be delivered widely to prevent mobility limitations, increase physical activity participation, and improve quality of life in older adults. We propose a randomized controlled trial to assess the effect of a physical activity health coaching intervention on mobility in older adults with mobility limitations.

Methods

This randomized controlled trial among 290 (145 per group) community-dwelling older adults with mobility limitations, aged 70–89 years old, will compare the effect of a physical activity health coaching intervention versus a general healthy aging education program on mobility, as assessed with the Short Physical Performance Battery. The physical activity health coaching intervention will be delivered by exercise individuals who are trained in Brief Action Planning. The coaches will use evidence-based behavior change techniques including goal-setting, action planning, self-monitoring, and feedback to improve participation in physical activity by a known dose of 50 min per week. There will be a total of 9 health coaching or education sessions delivered over 26 weeks with a subsequent 26-week follow-up period, wherein both groups will receive the same duration and frequency of study visits and activities.

Discussion

The consequences of limited mobility pose a significant burden on the quality of life of older adults. Our trial is novel in that it investigates implementing a dose of physical activity that is known to improve mobility in older adults utilizing a health coaching intervention.

Trial registration

ClinicalTrials.gov Protocol Registration System: NCT05978336; registered on 28 July 2023.
Natural compound targeting BDNF V66M variant: insights from in silico docking and molecular analysis
Authors: Sakhawat Azra , Khan Muhammad Umer , Rehman Raima , Khan Samiullah , Shan Muhammad Adnan , Batool Alia , Javed Muhammad Arshad , Ali Qurban
Published: November 2023

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin gene family gene that encodes proteins vital for the growth, maintenance, and survival of neurons in the nervous system. The study aimed to screen natural compounds against BDNF variant (V66M), which affects memory, cognition, and mood regulation. BDNF variant (V66M) as a target structure was selected, and Vitamin D, Curcumin, Vitamin C, and Quercetin as ligands structures were taken from PubChem database. Multiple tools like AUTODOCK VINA, BIOVIA discovery studio, PyMOL, CB-dock, IMOD server, Swiss ADEMT, and Swiss predict ligands target were used to analyze binding energy, interaction, stability, toxicity, and visualize BDNF-ligand complexes. Compounds Vitamin D3, Curcumin, Vitamin C, and Quercetin with binding energies values of − 5.5, − 6.1, − 4.5, and − 6.7 kj/mol, respectively, were selected. The ligands bind to the active sites of the BDNF variant (V66M) via hydrophobic bonds, hydrogen bonds, and electrostatic interactions. Furthermore, ADMET analysis of the ligands revealed they exhibited sound pharmacokinetic and toxicity profiles. In addition, an MD simulation study showed that the most active ligand bound favorably and dynamically to the target protein, and protein–ligand complex stability was determined. The finding of this research could provide an excellent platform for discovering and rationalizing novel drugs against stress related to BDNF (V66M). Docking, preclinical drug testing and MD simulation results suggest Quercetin as a more potent BDNF variant (V66M) inhibitor and forming a more structurally stable complex.