BMC Medicine最新文献

{"title":"Newborn DNA methylation age differentiates long-term weight trajectories: the Boston Birth Cohort","authors":"Anat Yaskolka Meir, Guoying Wang, Xiumei Hong, Frank B. Hu, Xiaobin Wang, Liming Liang","doi":"10.1186/s12916-024-03568-9","DOIUrl":"https://doi.org/10.1186/s12916-024-03568-9","url":null,"abstract":"Gestational age (GEAA) estimated by newborn DNA methylation (GAmAge) is associated with maternal prenatal exposures and immediate birth outcomes. However, the association of GAmAge with long-term overweight or obesity (OWO) trajectories is yet to be determined. GAmAge was calculated for 831 children from a US predominantly urban, low-income, multi-ethnic birth cohort based on cord blood DNA methylation profile using Illumina EPIC array. Repeated anthropometric measurements aligned with pediatric primary care schedule allowed us to calculate body-mass-index percentiles (BMIPCT) at specific age and to define long-term weight trajectories from birth to 18 years. GAmAge was associated with BMIPCT trajectories, defined by 4 groups: stable (consistent OWO: “early OWO”; constant normal weight: “NW”) or non-stable (OWO by year 1 of follow-up: “late OWO”; OWO by year 6 of follow-up: “NW to very late OWO”). GAmAge differentiated between the group with consistently normal BMIPCT pattern and the non-stable groups with late and very late OWO development. Such differentiation was observed in the age periods of birth to 1year, 3years, 6years, 10years, and 14years (p < 0.05 for all). The findings persisted after adjusting for GEAA, maternal smoking, delivery method, and child’s sex in multivariate models. Birth weight was a mediator for the GAmAge effect on OWO status for specific groups at multiple age periods. GAmAge is associated with BMIPCT trajectories from birth to age 18 years, independent of GEAA and birth weight. If further confirmed, GAmAge may serve as an early biomarker for predicting BMI trajectory to inform early risk assessment and prevention of OWO. ClinicalTrials.gov (NCT03228875).","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends in the healthiness and nutrient composition of packaged products sold by major food and beverage companies in New Zealand 2015 to 2019","authors":"Leanne Young, Bruce Kidd, Stephanie Shen, Yannan Jiang, Helen Eyles, Josephine Marshall, Sally Schultz, Jasmine Chan, Gary Sacks, Cliona Ni Mhurchu","doi":"10.1186/s12916-024-03567-w","DOIUrl":"https://doi.org/10.1186/s12916-024-03567-w","url":null,"abstract":"Dietary risk factors are the leading cause of death globally and in New Zealand (NZ). Processed packaged foods are prevalent in the food supply and contribute excess amounts of sodium, saturated fat, and sugar in diets. Improving the nutritional quality of these foods has the potential to reduce population chronic disease risk. We aimed to evaluate the healthiness using the Australasian Health Star Rating (HSR, from 0.5 to 5 stars, with 5 being the healthiest) and nutrient composition (sodium, saturated fat, and total sugar) of packaged products manufactured by the largest NZ-based food and beverage companies in NZ 2015–2019. This analysis relates to a larger study evaluating structured engagement with food companies to improve nutrition-related policies and actions. Data was sourced from Nutritrack, a NZ-branded supermarket-sourced food composition database. The largest NZ-based companies from annual retail sales revenue (n = 35) were identified using 2019 Euromonitor data. All relevant products of the selected companies were extracted for analysis. Products included totalled 17,795 with a yearly range of 3462–3672 products. The primary outcome was a nutrient profile score estimated using HSR. Healthiness was defined as ≥ 3.5 stars. Secondary outcomes were sodium, total sugar, and saturated fat per 100 g/100 mL. All outcomes were assessed overall, by food company, and food category. Change over time was tested using linear mixed models, adjusting for major food categories and cluster effects of food companies controlling for multiple comparisons. Model-adjusted mean differences between years were estimated with 95% confidence intervals. There was a small statistically significant increase in mean HSR between 2015 and 2019 (0.08 [0.15,0.01], p = 0.024). Mean total sugar content decreased over the same period (0.78 g/100 g [0.08,1.47], p = 0.020), but there were no significant changes in mean sodium or saturated fat contents. Seven of the 13 categories showed small increases in mean HSR (0.1–0.2). Most categories (9/13) exhibited a reduction in mean total sugar content. Between 2015 and 2019, there were slight improvements in the nutritional quality of selected packaged foods and drinks in NZ. Much more substantive changes are needed to address the health-related burden of unhealthy diets, supported by stronger government action and less reliance on voluntary industry initiatives.\u0000","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential deprescribing indications for antidepressants between 2012 and 2019: repeated cross-sectional analysis in two Scottish health boards","authors":"Vita Brisnik, Marietta Rottenkolber, Jochen Vukas, Miriam Schechner, Karoline Lukaschek, Caroline Jung-Sievers, Jochen Gensichen, Ulrich Thiem, Michael Drey, Nils Krüger, Alpana Mair, Bruce Guthrie, Sebastian Fischer, Tobias Dreischulte","doi":"10.1186/s12916-024-03584-9","DOIUrl":"https://doi.org/10.1186/s12916-024-03584-9","url":null,"abstract":"Antidepressants have a pivotal role in the treatment of many psychiatric disorders, but there are concerns about long-term use and adverse effects. The objectives of this study were (1) to examine time trends in antidepressant use, (2) to estimate the prevalence of long-term and potential high-risk antidepressant use, and (3) to examine patient characteristics associated with potential deprescribing indications (PDIs) (i.e., simultaneous long-term and potential high-risk antidepressant use). Repeated population-based cross-sectional study for all 609,299 people aged ≥ 18 years resident in the Tayside or Fife regions of Scotland. The prevalence of antidepressant use was examined on June 30th (index date) of each year from 2012 to 2019, while the prevalence of long-term and potential high-risk use as well as PDIs was assessed and compared on the same dates in 2012 and 2019. Binary logistic regression modeling was used to examine patient characteristics associated with PDIs. Antidepressant use increased by 27% from 12.0 to 15.3% among adult residents between 2012 and 2019. While the proportion of antidepressants users dispensed ≥ 1 antidepressant for > 2 years increased from 54.3 to 61.9% between 2012 and 2019, the proportion of antidepressant users triggering ≥ 1 indicator of potential high-risk use decreased slightly from 37.9 to 34.7%. In 2019, potential high-risk use most commonly related to indicators targeting fall risk (16.0%), cardiovascular risks (14.1%), insomnia (10.6%), and risk of orthostatic hypotension (8.6%). More than 1 in 4 (25.8%) antidepressant users had PDIs. The main risk factors associated with PDIs included increasing age (65–79, adjusted OR 14.12; 95% CI, 13.15–15.17), increasing number of drugs taken concomitantly (≥ 15 drugs, adjusted OR 7.37; 95% CI, 6.71–8.10), use of tricyclic antidepressants (≥ 50 mg) (adjusted OR 5.49; 95% CI, 5.02–6.01), and concomitant use of ≥ 2 antidepressants (adjusted OR 5.52; 95% CI, 5.20–5.85). Long-term and potential high-risk use of antidepressants is widespread, and potential deprescribing indications (PDIs) are increasing, suggesting the need for a critical review of their ongoing use by clinicians. If deemed necessary, future deprescribing interventions may use the criteria applied here for identification of patients with PDIs and for evaluating intervention effectiveness.","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A deep learning model for differentiating paediatric intracranial germ cell tumour subtypes and predicting survival with MRI: a multicentre prospective study","authors":"Yanong Li, Zhizheng Zhuo, Jinyuan Weng, Sven Haller, Harrison X. Bai, Bo Li, Xing Liu, Mingwang Zhu, Zheng Wang, Jane Li, Xiaoguang Qiu, Yaou Liu","doi":"10.1186/s12916-024-03575-w","DOIUrl":"https://doi.org/10.1186/s12916-024-03575-w","url":null,"abstract":"The pretherapeutic differentiation of subtypes of primary intracranial germ cell tumours (iGCTs), including germinomas (GEs) and nongerminomatous germ cell tumours (NGGCTs), is essential for clinical practice because of distinct treatment strategies and prognostic profiles of these diseases. This study aimed to develop a deep learning model, iGNet, to assist in the differentiation and prognostication of iGCT subtypes by employing pretherapeutic MR T2-weighted imaging. The iGNet model, which is based on the nnUNet architecture, was developed using a retrospective dataset of 280 pathologically confirmed iGCT patients. The training dataset included 83 GEs and 117 NGGCTs, while the retrospective internal test dataset included 31 GEs and 49 NGGCTs. The model’s diagnostic performance was then assessed with the area under the receiver operating characteristic curve (AUC) in a prospective internal dataset (n = 22) and two external datasets (n = 22 and 20). Next, we compared the diagnostic performance of six neuroradiologists with or without the assistance of iGNet. Finally, the predictive ability of the output of iGNet for progression-free and overall survival was assessed and compared to that of the pathological diagnosis. iGNet achieved high diagnostic performance, with AUCs between 0.869 and 0.950 across the four test datasets. With the assistance of iGNet, the six neuroradiologists’ diagnostic AUCs (averages of the four test datasets) increased by 9.22% to 17.90%. There was no significant difference between the output of iGNet and the results of pathological diagnosis in predicting progression-free and overall survival (P = .889). By leveraging pretherapeutic MR imaging data, iGNet accurately differentiates iGCT subtypes, facilitating prognostic evaluation and increasing the potential for tailored treatment. ","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of machine-learning models of diet management for hyperphenylalaninemia: a multicenter retrospective study","authors":"Yajie Su, Yaqiong Wang, Jinfeng He, Huijun Wang, Xian A, Haili Jiang, Wei Lu, Wenhao Zhou, Long Li","doi":"10.1186/s12916-024-03602-w","DOIUrl":"https://doi.org/10.1186/s12916-024-03602-w","url":null,"abstract":"Assessing dietary phenylalanine (Phe) tolerance is crucial for managing hyperphenylalaninemia (HPA) in children. However, traditionally, adjusting the diet requires significant time from clinicians and parents. This study aims to investigate the development of a machine-learning model that predicts a range of dietary Phe intake tolerance for children with HPA over 10 years following diagnosis. In this multicenter retrospective observational study, we collected the genotypes of phenylalanine hydroxylase (PAH), metabolic profiles at screening and diagnosis, and blood Phe concentrations corresponding to dietary Phe intake from over 10 years of follow-up data for 204 children with HPA. To incorporate genetic information, allelic phenotype value (APV) was input for 2965 missense variants in the PAH gene using a predicted APV (pAPV) model. This model was trained on known pheno-genotype relationships from the BioPKU database, utilizing 31 features. Subsequently, a multiclass classification model was constructed and trained on a dataset featuring metabolic data, genetic data, and follow-up data from 3177 events. The final model was fine-tuned using tenfold validation and validated against three independent datasets. The pAPV model achieved a good predictive performance with root mean squared error (RMSE) of 1.53 and 2.38 on the training and test datasets, respectively. The variants that cause amino acid changes in the region of 200–300 of PAH tend to exhibit lower pAPV. The final model achieved a sensitivity range of 0.77 to 0.91 and a specificity range of 0.8 to 1 across all validation datasets. Additional assessment metrics including positive predictive value (0.68–1), negative predictive values (0.8–0.98), F1 score (0.71–0.92), and balanced accuracy (0.8–0.92) demonstrated the robust performance of our model. Our model integrates metabolic and genetic information to accurately predict age-specific Phe tolerance, aiding in the precision management of patients with HPA. This study provides a potential framework that could be applied to other inborn errors of metabolism.","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Has multimorbidity and frailty in adult hospital admissions changed over the last 15 years? A retrospective study of 107 million admissions in England","authors":"Puji Faitna, Alex Bottle, Bob Klaber, Paul P. Aylin","doi":"10.1186/s12916-024-03572-z","DOIUrl":"https://doi.org/10.1186/s12916-024-03572-z","url":null,"abstract":"Few studies have quantified multimorbidity and frailty trends within hospital settings, with even fewer reporting how much is attributable to the ageing population and individual patient factors. Studies to date have tended to focus on people over 65, rarely capturing older people or stratifying findings by planned and unplanned activity. As the UK’s national health service (NHS) backlog worsens, and debates about productivity dominate, it is essential to understand these hospital trends so health services can meet them. Hospital Episode Statistics inpatient admission records were extracted for adults between 2006 and 2021. Multimorbidity and frailty was measured using Elixhauser Comorbidity Index and Soong Frailty Scores. Yearly proportions of people with Elixhauser conditions (0, 1, 2, 3 +) or frailty syndromes (0, 1, 2 +) were reported, and the prevalence between 2006 and 2021 compared. Logistic regression models measured how much patient factors impacted the likelihood of having three or more Elixhauser conditions or two or more frailty syndromes. Results were stratified by age groups (18–44, 45–64 and 65 +) and admission type (emergency or elective). The study included 107 million adult inpatient hospital episodes. Overall, the proportion of admissions with one or more Elixhauser conditions rose for acute and elective admissions, with the trend becoming more prominent as age increased. This was most striking among acute admissions for people aged 65 and over, who saw a 35.2% absolute increase in the proportion of admissions who had three or more Elixhauser conditions. This means there were 915,221 extra hospital episodes in the last 12 months of the study, by people who had at least three Elixhauser conditions compared with 15 years ago. The findings were similar for people who had one or more frailty syndromes. Overall, year, age and socioeconomic deprivation were found to be strongly and positively associated with having three or more Elixhauser conditions or two or more frailty syndromes, with socioeconomic deprivation showing a strong dose–response relationship. Overall, the proportion of hospital admissions with multiple conditions or frailty syndromes has risen over the last 15 years. This matches smaller-scale and anecdotal reports from hospitals and can inform how hospitals are reimbursed.","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addressing the credibility crisis in Mendelian randomization","authors":"Stephen Burgess, Benjamin Woolf, Amy M. Mason, Mika Ala-Korpela, Dipender Gill","doi":"10.1186/s12916-024-03607-5","DOIUrl":"https://doi.org/10.1186/s12916-024-03607-5","url":null,"abstract":"Genome-wide association studies have enabled Mendelian randomization analyses to be performed at an industrial scale. Two-sample summary data Mendelian randomization analyses can be performed using publicly available data by anyone who has access to the internet. While this has led to many insightful papers, it has also fuelled an explosion of poor-quality Mendelian randomization publications, which threatens to undermine the credibility of the whole approach. We detail five pitfalls in conducting a reliable Mendelian randomization investigation: (1) inappropriate research question, (2) inappropriate choice of variants as instruments, (3) insufficient interrogation of findings, (4) inappropriate interpretation of findings, and (5) lack of engagement with previous work. We have provided a brief checklist of key points to consider when performing a Mendelian randomization investigation; this does not replace previous guidance, but highlights critical analysis choices. Journal editors should be able to identify many low-quality submissions and reject papers without requiring peer review. Peer reviewers should focus initially on key indicators of validity; if a paper does not satisfy these, then the paper may be meaningless even if it is technically flawless. Performing an informative Mendelian randomization investigation requires critical thought and collaboration between different specialties and fields of research.","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global acute malnutrition is associated with geography, season and malaria incidence in the conflict-affected regions of Ouham and Ouham Pendé prefectures, Central African Republic","authors":"Nicola Stambach, Helen Lambert, Katie Eves, Blaise Alenwi Nfornuh, Emily Bowler, Peter Williams, Marcel Lama, Pascal Bakamba, Richard Allan","doi":"10.1186/s12916-024-03603-9","DOIUrl":"https://doi.org/10.1186/s12916-024-03603-9","url":null,"abstract":"Ongoing conflict between multiple armed groups, including pastoralist herders in the Central African Republic (CAR) causes frequent population displacements, food insecurity and scarcity of healthcare services. The inaccessibility and insecurity of many areas of CAR limit data collection and assessments from national nutritional surveys. Community health workers (CHWs) trained by an international non-governmental organisation, The MENTOR Initiative, deliver basic healthcare to children under 5 years old living in hard-to-reach and conflict-affected areas in eight subprefectures of north-west CAR. Their nutritional status and its associations with geography, malaria, season and conflict are unknown. CHW monthly records (October 2015–August 2021), Armed Conflict Location and Event Data project conflict data and The World Bank Group meteorological data for eight subprefectures of north-west CAR were analysed. Associations between counts of global acute malnutrition (GAM) assessed by mid-upper arm circumference and malaria, season and conflict were investigated using negative binomial regression. Of the 457,325 consultations with children aged 6–59 months, 6.2% and 0.4% were classified as moderately or severely malnourished, respectively. The negative binomial model demonstrated differences in counts of GAM by subprefecture. Counts of GAM were positively associated with the case rate of severe malaria (IRR = 1.045; 95% CI: 1.04–1.06) and the rainy season (July–September) (IRR = 1.10; 95% CI: 1.03–1.17). Conflict events coded as Battles in ACLED were associated with lower counts of GAM (IRR = 0.78; 95% CI: 0.62–0.97). This analysis shows geographical differences in levels of malnutrition in north-west CAR and demonstrates clear associations between malnutrition, season and malaria. It provides evidence that levels of GAM may be underestimated in north-west CAR in areas experiencing conflict. These findings highlight the need for targeted nutritional support to reach children most at risk of malnutrition. CHWs are a proven effective means of delivering essential primary healthcare services in hard-to-reach, conflict-affected areas.","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori seropositivity associates with hyperglycemia, but not obesity, in Danish children and adolescents","authors":"Sigri Kløve, Sara E. Stinson, Fie O. Romme, Julia Butt, Katrine B. Graversen, Morten A. V. Lund, Cilius E. Fonvig, Tim Waterboer, Guillermo I. Perez-Perez, Torben Hansen, Jens-Christian Holm, Sandra B. Andersen","doi":"10.1186/s12916-024-03591-w","DOIUrl":"https://doi.org/10.1186/s12916-024-03591-w","url":null,"abstract":"Helicobacter pylori colonizes the human stomach and may affect the inflammatory response, hormone production related to energy regulation, and gastrointestinal microbiota composition. Previous studies have explored a potential association between H. pylori infection and pediatric obesity with varying results. Considering the immunomodulatory effects of early-life infection with H. pylori that can confer beneficial effects, we hypothesized that we would find an inverse relationship between H. pylori seropositivity and obesity among Danish children and adolescents. We assessed H. pylori seroprevalence in 713 subjects from an obesity clinic cohort and 990 subjects from a population-based cohort, aged 6 to 19 years, and examined its association with obesity and other cardiometabolic risk factors. No association was found between H. pylori and body mass index standard deviation score (BMI SDS). H. pylori seropositivity was, however, significantly associated with higher fasting plasma glucose levels and the prevalence of hyperglycemia. While we did not find an association between H. pylori seropositivity and BMI SDS, we observed a significant association with higher fasting plasma glucose levels and increased prevalence of hyperglycemia, suggesting that H. pylori infection may contribute to impaired glucose regulation in Danish children and adolescents. ","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-17A exacerbates corpus cavernosum fibrosis and neurogenic erectile dysfunction by inducing CSMC senescence via the mTORC2-ACACA pathway","authors":"Wende Yang, Jiafeng Fang, Jiancheng Zhai, Chen Qiu, Zhenkang Liang, Qianhui Liu, Hongbo Wei","doi":"10.1186/s12916-024-03609-3","DOIUrl":"https://doi.org/10.1186/s12916-024-03609-3","url":null,"abstract":"Neurogenic erectile dysfunction, characterized by neurological repair disorders and progressive corpus cavernosum fibrosis (CCF), is an unbearable disease with limited treatment success. IL-17A exhibits a complex role in tissue remodelling. Nevertheless, the precise role and underlying mechanisms of IL-17A in CCF under denervation remain unclear. PCR array was employed to identified differentially expressed genes between neurogenic ED and normal rats. IL-17A expression and its main target cells were analyzed using Western blotting, immunofluorescence and immunohistochemistry. The phenotypic regulation of IL-17A on corpus cavernosum smooth muscle cells (CSMCs) was evaluated by cell cycle experiments and SA-β-Gal staining. The mechanism of IL-17A was elucidated using non-target metabolomics and siRNA technique. Finally, IL-17A antagonist and ABT-263 (an inhibitor of B-cell lymphoma 2/w/xL) were utilized to enhance the therapeutic effect in a rat model of neurogenic ED. IL-17A emerged as the most significantly upregulated gene in the corpus cavernosum of model rats. It augmented the senescence transformation and fibrotic response of CSMCs, and exhibited a strong correlation with CCF. Mechanistically, IL-17A facilitated CCF by activating the mTORC2-ACACA signalling pathway, upregulating of CSMCs lipid synthesis and senescence transition, and increasing the secretion of fibro-matrix proteins. In vivo, the blockade of IL-17A-senescence signalling improved erectile function and alleviated CCF in neurogenic ED. IL-17A assumes a pivotal role in denervated CCF by activating the mTORC2-ACACA signalling pathway, presenting itself as a potential therapeutic target for effectively overcoming CCF and erection rehabilitation in neurogenic ED. IL-17A is significantly upregulated in the corpus cavernosum under denervated conditions, promoting the senescence transformation and fibrotic response of corpus cavernosum smooth muscle cells, primarily through the activation of the mTORC2-ACACA signalling pathway. Blocking the IL-17A-senescence signalling axis can improve erectile function and alleviate corpus cavernosum fibrosis, suggesting that this pathway represents a potential therapeutic target for neurogenic erectile dysfunction. ","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142193652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}