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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC9961050 | ||
Author Contributions | I.V., L.R., M.P. and A.V. designed the study; I.V. enrolled participants, collected and analyzed the data and drafted and revised the manuscript; L.R. performed orthopedic evaluation; L.R. and M.P. helped revise the manuscript. All authors have read and agreed to the published version of the manuscript. | PMC9961050 | ||
Institutional Review Board Statement | This study was performed in accordance with the Declaration of Helsinki and was approved by the University of Tartu Research Ethics Committee (No. 298/T-10, 18.11.2019). This study was registered at | PMC9961050 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9961050 | ||
Data Availability Statement | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC9961050 | ||
Conflicts of Interest | The authors declare that they have no competing interests. | PMC9961050 | ||
Abbreviations | PTE, musculoskeletal injury | BMI, body mass index; CI, confidence interval; CON, control; EqArea, equivalent area; H/Q, hamstring to quadriceps; INT, intervention; MSI, musculoskeletal injury; PP, prevention program; PTE, peak torque in extension; PTF, peak torque in flexion; RR, relative risk; SD, standard deviation. | PMC9961050 | |
References | injuries | Flow of participants through the study.Baseline anthropometric characteristics.Data are mean ± SD; INT, intervention group; CON, control group.Injury incidence.INT, intervention; CON, control; RR, relative risk; CI, confidence interval.Number of injuries.INT, intervention; CON, control.Motor performance and psychosocia... | PMC9961050 | |
Background | CAD | CORONARY ARTERY DISEASE, CAD | Since myocardial work (MW) and left atrial strain are valuable for screening coronary artery disease (CAD), this study aimed to develop a novel CAD screening approach based on machine learning-enhanced echocardiography. | PMC10176743 |
Methods | This prospective study used data from patients undergoing coronary angiography, in which the novel echocardiography features were extracted by a machine learning algorithm. A total of 818 patients were enrolled and randomly divided into training (80%) and testing (20%) groups. An additional 115 patients were also enrol... | PMC10176743 | ||
Results | CAD | CARDIAC EVENTS, CAD | The superior diagnosis model of CAD was optimized using 59 echocardiographic features in a gradient-boosting classifier. This model showed that the value of the receiver operating characteristic area under the curve (AUC) was 0.852 in the test group and 0.834 in the validation group, with high sensitivity (0.952) and l... | PMC10176743 |
Conclusions | CAD | CAD | Machine learning-enhanced echocardiography can improve CAD detection based on the MW and left atrial strain features. Our developed model is valuable for estimating the pre-test probability of CAD and screening CAD patients in clinical practice.
| PMC10176743 |
Keywords | PMC10176743 | |||
Introduction | CAD, death | DISEASES, CORONARY ARTERY DISEASE, CAD | Early diagnosis of coronary artery disease (CAD), a leading cause of death worldwide [The myocardial work (MW) is one of the newly developed noninvasive techniques for CAD diagnosis, which has an assessment function of deformation and afterload that provides incremental value to the evaluation of cardiac function [Alth... | PMC10176743 |
Methods | PMC10176743 | |||
Patients | CAD, stenosis | STENOSIS, CAD | This prospective clinical trial (NCT03905200, registered on 5 April 2019) included 958 cases diagnosed as clinically suspected CAD by coronary angiography in Beijing Hospital, Beijing, China. The patients with CAD were diagnosed by coronary angiography, which showed ≥ 50% stenosis in one or more coronary arteries [ | PMC10176743 |
Echocardiography | CONTRACTION | The instruments for echocardiography included Vivid E9 and Vivid E95 ultrasound systems (GE Vingmed Ultrasound, Horten, Norway). The baseline echocardiography for the admitted patients was implemented prior to their coronary angiography. The original data of echocardiography images were stored in DICOM format. EchoPac ... | PMC10176743 | |
ML classifiers | Recently, ML-based research methods have been widely used in clinical diagnostic studies [ | PMC10176743 | ||
Model training | CAD | CAD | The tenfold cross-validation test was also applied for the model training. The CAD data set was randomly divided into two parts (80% training data set and 20% testing data set). A model for CAD prediction was built by extracting the imaging and clinical features with ML methods. | PMC10176743 |
Feature selection | The imaging and clinical features were reduced and selected using different strategies to overcome the problem of model overfitting. The importance of variables was evaluated in each classifier. For example, the correlation coefficients ( | PMC10176743 | ||
Training data set optimization | CAD | CAD | Since the randomly divided training data sets also influence the classifier accuracy, we selected a group of high-performance training data sets after hundreds of cross-validation tests. The intersection of various training data sets with an accuracy of around 80 ~ 85% was selected as a standard to build the final trai... | PMC10176743 |
Model validation | Additional 115 patients recruited from September 2021 to July 2022 were enrolled as the validation data set (out from the cross-validation test), which was used for selecting classifiers and validating the model performance. | PMC10176743 | ||
Prognostic follow-up | death | BLIND | The follow-up information was obtained through clinical visits or telephone calls by an investigator blind to clinical factors and coronary angiography data. All-cause mortality and cardiovascular hospitalization composited the study endpoint. The death documentation was obtained from hospital medical records and phone... | PMC10176743 |
Statistical analysis | The data of the continuous variables with normal distribution were expressed as mean ± standard deviation, and those without normal distribution were expressed as median (interquartile range). Chi-square or Fisher’s exact tests was used for comparing the difference between categorical variables, while the comparison of... | PMC10176743 | ||
Results | PMC10176743 | |||
Discussion | CAD, myocardial ischemia, obstructive CAD | CORONARY STENOSIS, MYOCARDIAL ISCHEMIA, CAD, STENOSES | This might be the first study on the diagnostic model of CAD using novel echocardiography tools (MW and LA strain) integrated with ML models. This superior CAD detection model showed a value of ROC AUC (0.852) with a sensitivity of 0.95 and specificity of 0.69 in the test group, while the ROC AUC value was 0.834 in the... | PMC10176743 |
Limitations | This study had several limitations. It was a single-center study due to its data collected from the same medical system. In this study, we enrolled patients who underwent coronary angiography with typical myocardial ischemia-related symptoms or positive results of examinations. In addition, a single echocardiogram vend... | PMC10176743 | ||
Conclusions | CAD | CAD | Our study demonstrated the following benefits of our model in CAD diagnosis: (1) good diagnostic performance in screening CAD patients, confirmed in the validation group; and (2) the predictive function of our model only requires the non-invasive echocardiographic and some commonly used clinical features. In summary, o... | PMC10176743 |
Acknowledgements | The authors thank Mrs. Jiangtao Wang and Mr. Zhicheng Zhu at the GE Company for their technical support. These individuals did not influence the study management or the writing of this article. | PMC10176743 | ||
Author contributions | YG, CX, YW, and FW are the major contributors to writing the manuscript. YZ, HZ, JM, GL, and YG analyzed the echocardiograms. XW, HZ, XM, and CY collected the patient information. YW, CX, and XW revised the manuscript carefully. FW conceived the study and supervised the project. All authors read and approved the final ... | PMC10176743 | ||
Funding | The study was supported by the National High-Level Hospital Clinical Research Funding (Grant No. BJ-2022–117), the National Key R&D Program of China (2020YFC2008100/2020YFC2008106), and the Key Industrial Innovation Chain Project in Shaanxi Province of China (2023-ZDLSF-21). | PMC10176743 | ||
Availability of data and materials | The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. | PMC10176743 | ||
Declarations | PMC10176743 | |||
Ethics approval and consent to participate | This study was approved by the ethics committee of Beijing Hospital (reference number: 2020BJYYEC-021–02). Our study is a post-hoc analysis of data from an IRB-approved prospective clinical trial (NCT03905200). Informed consent was obtained from all individual participants included in the study. | PMC10176743 | ||
Consent for publication | Not applicable. | PMC10176743 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10176743 | ||
References | PMC10176743 | |||
Background | RHEGMATOGENOUS RETINAL DETACHMENT | This study evaluated the vascular changes in the macular and peripapillary regions before and after silicone oil (SO) removal in patients with rhegmatogenous retinal detachment. | PMC10053480 | |
Methods | tamponade | This single-center case series assessed patients who underwent SO removal at one hospital. Patients who underwent pars plana vitrectomy and perfluoropropane gas tamponade (PPV + C | PMC10053480 | |
Results | SO tamponade | Fifty eyes were administered SO tamponade, 54 SO tamponade(SOT) contralateral eyes, 29 PPV + C | PMC10053480 | |
Conclusions | SO tamponade | SVD and SPD are decreased during SO tamponade and increased in the macular region of eyes that underwent SO removal, suggesting a possible mechanism for reduced visual acuity during or after SO tamponade. | PMC10053480 | |
Trial registration | Registration date: 22/05/2019; Registration number, ChiCTR1900023322; Registration site, Chinese Clinical Trial Registry (ChiCTR). | PMC10053480 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12886-023-02868-7. | PMC10053480 | ||
Keywords | PMC10053480 | |||
Introduction | tamponade, RRD, ocular trauma, SPD, retinal detachment, macula-off rhegmatogenous | PROLIFERATIVE VITREORETINOPATHY, RETINAL TEARS, RETINAL DETACHMENT, RETINA | The combination of vitrectomy and silicone oil (SO) tamponade is widely used for treating complex retinal detachment accompanied by proliferative vitreoretinopathy, large retinal tears, and ocular trauma [Changes in macular and peripapillary microcirculation can affect vision through impaired oxygen metabolism in the r... | PMC10053480 |
Materials and methods | PMC10053480 | |||
Study design and patients | viral retinitis, keratopathy, retinal atrophy, opacity, hypotony, SO tamponade, cataract, PD, retinal redetachment, glaucoma | DIABETIC RETINOPATHY, CHRONIC UVEITIS, KERATOPATHY, RETINAL ATROPHY, OPACITY, RETINAL TEAR, RETINA, CATARACT, MAY, SECONDARY, HIGH MYOPIA, LENS, RETINAL DETACHMENT, GLAUCOMA, GIANT, MACULAR EDEMA, EYE | This single-center case series prospectively included consecutive patients who underwent SO removal from June to December 2019 at Chongqing Aier Eye Hospital. Patients who underwent SO removal combined with phacoemulsification and intraocular lens implantation were included. The inclusion criteria were (1) intravitreal... | PMC10053480 |
Surgical procedures | cataract | CATARACT, LENS | SO removal was performed under retrobulbar anesthesia by associate chief physicians (L.L. and G.W.) using the 23-G Constellation device (Alcon, Fort Worth, TX, USA) and trocars in the inferotemporal and superior quadrants 3.5 mm from the limbus. Infusion liquid was used for oil exchange. An infusion line was inserted i... | PMC10053480 |
Examinations | cataract, retinal detachment, SO tamponade | CATARACT, RETINAL DETACHMENT, INTRAOCULAR PRESSURE | The diagnosis of retinal detachment was initially confirmed by slit lamp biomicroscopy and indirect ophthalmoscopy. Perioperative data were obtained from the medical records, including age, sex, axial length, and duration of SO tamponade. BCVA (LogMAR) and intraocular pressure (IOP) in every patient were measured daily... | PMC10053480 |
Assessment of visual acuity | The BCVA assessment was performed using an international standard visual acuity chart, and data were transformed into the logarithm of the minimum angle of resolution (LogMAR) units. | PMC10053480 | ||
OCTA and analysis | SPD, tamponade | In this study, 6 × 6 mm
OCT angiography (OCTA) in a 50-year-old male with an eye administered silicone oil (SO) tamponade. The central area (1-mm diameter central circle), the mean and sector values of the inner ring between the 1-mm and 3-mm diameter circles, the outer ring between the 3-mm and 6-mm diameter circles, ... | PMC10053480 | |
Statistical analysis | Data are shown as means ± standard deviation (SD). Data analysis was performed With SPSS 23.0 (SPSS, USA). One-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test was performed to analyze the differences among multiple independent samples. SVD, SPD and BCVA before and 1 day, 7 days, 1 month, and 3... | PMC10053480 | ||
Results | PMC10053480 | |||
Characteristics of the patients | vitreous hemorrhage | RETINA, VITREOUS HEMORRHAGE, MACULAR HOLE, MACULAR EDEMA, INTRAOCULAR PRESSURE | Ninety-four patients were enrolled initially, among whom 54 SOT contralateral eyes with BCVA (LogMAR) < 0.1 and OCTA signal strength > 8 were selected as control eyes. Among the treated eyes, 44 were excluded due to loss to follow-up (n = 21), scans with signal strength < 6 in OCTA (n = 13), ERM (n = 3), macular edema ... | PMC10053480 |
OCTA parameters of the macular region before SO removal | SO tamponade | Compared with the SOT contralateral eyes, eyes with SO tamponade showed reduced SVD and SPD in the macular region (all | PMC10053480 | |
OCTA parameters of the peripapillary region before SO removal | SO tamponade | The SVD and SPD in the central area of the peripapillary region in the eyes with SO tamponade and SOT contralateral eyes were not significantly different ( | PMC10053480 | |
OCTA parameters of the macular region of eyes administered SO tamponade and SO removal | After SO removal, both SVD and SPD in the central area, inner ring, outer ring, and full area of the macular region showed significant improvements compared with the preoperative values (repeated measures analysis of variance,
Line charts illustrating SVD and SPD in the macular region before and after SO removal. (A) ... | PMC10053480 | ||
OCTA parameters of the peripapillary region of eyes administered SO tamponade and SO removal | There were significant differences in SVD and SPD in the peripapillary region among the groups (pre-operation and postoperative 1 day, 7 days, 1 month, and 3 months), as shown in Supplementary Table | PMC10053480 | ||
Visual acuity of eyes administered SO tamponade | SO tamponade | The average BCVA (LogMAR) was higher during SO tamponade (0.69 ± 0.27) compared with the SOT contralateral control eyes (0.05 ± 0.07,
Line chart illustrating BCVA (LogMAR) before and after SO removal. BCVA (LogMAR) showed a trend of time-dependent decrease from postoperative 1 day to 3 months ( | PMC10053480 | |
Pearson correlation analysis of BCVA (LogMAR), SVD, and SPD | SPD | In the eyes with SO removal, BCVA (LogMAR) was significantly correlated with SVD and SPD in the central area, inner ring, outer ring, and full area of the macular region. The Pearson correlation test showed that SVD and SPD in the central area, inner ring, outer ring, and full area of the macular region were negatively... | PMC10053480 | |
Discussion | neuronal damage, might damage retinal structures, ischemia, SO tamponade, avascular | ISCHEMIA, STILL, RETINA | The SVD and SPD in the central area, inner ring, outer ring, and full area were lower in the eyes with SO tamponade compared with the control eyes. It is unclear whether the decrease in macular microcirculation was due to RRD damage or SO tamponade duration. Agarwal et al. [The present study showed that SO might have a... | PMC10053480 |
Conclusion | SO tamponade, tamponade | RETINA | This research indicated that SVD and SPD were lower in eyes with SO tamponade than in contralateral eyes. SVD and SPD were increased in the macular region of the eyes with SO tamponade and removal. BCVA (LogMAR) decreased while SVD and SPD increased in the macular region after SO removal; BCVA (LogMAR) was negatively c... | PMC10053480 |
Acknowledgements | The authors acknowledge all patients who participated in this study, as well as all individuals who helped perform examinations but are not listed as authors. | PMC10053480 | ||
Authors’ contributions | Conceptualization, YN H and Y W; Methodology, YN H and L L; Formal analysis and investigation, L L and G W; Writing - original draft preparation, YN H and JW X; Writing - review and editing, Y W and G W; Funding acquisition, Y W; Resources, YN H and Y W; Supervision, Y W. | PMC10053480 | ||
Funding | EYE | This study was funded by the Clinic Research Foundation of Aier Eye Hospital Group [grant number AF2018007]. | PMC10053480 | |
Data availability | All data relevant to the study are included in the article. | PMC10053480 | ||
Declarations | PMC10053480 | |||
Ethics approval and consent to participate | EYE | All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This study was approved by the Ethics Committee of Chongqing Aier Eye Hospital (EC approval number: IRB2019009). All participants provided signed informed consent. All methods w... | PMC10053480 | |
Consent for publication | Not applicable. | PMC10053480 | ||
Competing interests | The authors have no conflicts of interest to declare that are relevant to the content of this article. | PMC10053480 | ||
References | PMC10053480 | |||
Keywords | Based on the premise that physical activity/exercise impacts hippocampal structure and function, we investigated if hippocampal metabolites for neuronal viability and cell membrane density (i.e., N-acetyl aspartate (NAA), choline (Cho), creatine (Cr)) were higher in older adults performing supervised exercise compared ... | PMC10400748 | ||
Introduction | dementia | MRS, CORTEX | Physical activity and/or exercising are suggested as avenues to preserve brain function and structure in older adults and even to stave off dementia [Investigations into the molecular characteristics of the hippocampus might provide new insight into mechanisms through which physical activity and/or exercise impact both... | PMC10400748 |
Methods | PMC10400748 | |||
Ethics | The RCT and the substudy were approved by the Regional Committee for Medical Research Ethics (REK 2012/381 B and REK 2012/849, respectively). Both studies adhered to the Helsinki Declaration and participants gave their written informed consent to both. | PMC10400748 | ||
The RCT study | MRS | Participants were from the RCT Generation 100 study (NCT01666340, ClinicalTrials.gov registry) which originally set out to evaluate the effect of 3 years of supervised exercise training versus following the national physical activity guidelines on morbidity and mortality in older adults. The MRS acquisition was planned... | PMC10400748 | |
The Generation 100 MRI study | DISORDERS | A total of 111 (55 men, 56 women) agreed to participate. Six were excluded due to MRI contraindications or previous neurosurgical disorders, leaving 105 participants (53 men, 52 women). The participants underwent a standardized structural MRI protocol [Flowchart describing inclusion of participants. Number ( | PMC10400748 | |
Interventions | Participants in the SEG were randomized to twice weekly MICT or HIIT sessions. The MICT sessions consisted of 50 min of continuous exercise at about 70% of peak heart rate corresponding to a rating of perceived exertion of about 13 on the Borg scale [ | PMC10400748 | ||
Sociodemographic, health, fitness, and exercise variables | Date of birth, sex, and level of education (primary school, high school, and university) were obtained at baseline [Clinical measurements, including body mass index (BMI), blood pressure, and resting heart rate, were acquired at baseline and after 3 years of intervention using standard practices [Cardiorespiratory fitn... | PMC10400748 | ||
Brain MRI and MRSI | MRI/MRSI data were acquired on 3T Magnetom Skyra scanner (Siemens AG, Erlangen, Germany) equipped with a 32-channel head coil for homogenous signal-to-noise ratio (SNR) due to radio frequency (RF or BMagnetic resonance spectroscopic imaging (MRSI) acquisition and representative spectra. | PMC10400748 | ||
Statistics | MRS | Mean, standard deviation (SD), 95% confidence intervals (CI), and % were used as appropriate to display the distribution of variables. Statistical comparisons of sociodemographic, health, fitness, and exercise variables were performed with Group differences in NAA/Cr and Cho/Cr in the hippocampal head and body were ass... | PMC10400748 | |
Results | Usable spectral data were obtained in 63 (32 SEG/31 CG) of the 79 participants in whom MRSI scans were conducted. Motion, small hippocampal volumes, and technical processing/analysis issues were reasons for lack and exclusion of MRSI data. There were no significant differences in sociodemographic variables or VOSociode... | PMC10400748 | ||
Sociodemographic, health and fitness, and exercise variables | An overview of the sociodemographic and health characteristics of the included participants in the two groups at baseline and after 3 years is presented in Table Sociodemographic and clinical variables for the supervised exercise (SEG) and control groups (CG) at inclusion and after 3 years of interventionThe continuous... | PMC10400748 | ||
Hippocampal metabolite ratios, intervention groups, VO | The observed mean, SD, 95% CI, and Cohen’s Mean, standard deviation (SD), and 95% confidence interval for the raw observations of NAA/Cr and Cho/Cr ratios in the hippocampal body and head in the control group (CG) and supervised exercise group (SEG)CGThe general linear model revealed a significant effect of group on NA... | PMC10400748 | ||
Hippocampal metabolite ratios and associations with HADS and MoCA scores | A significant negative association was present between HADS score and NAA/Cr in the hippocampal body but not hippocampal head, with lower NAA/Cr associated with poorer psychological health (Fig. Scatter plot of rawHADS and MoCA scores versus raw NAA/Cr level in the hippocampal body and headGeneral linear model results ... | PMC10400748 | ||
Discussion | hippocampal head volume, dementia | STILL | This is the first exercise RCT in older adults examining metabolites in the hippocampus, a region considered highly modifiable by training and physical activity and a key structure in dementia. Opposed to our predictions, the CG had a higher NAA/Cr in the hippocampal body than the SEG after 3 years of intervention. Lik... | PMC10400748 |
Strengths and Limitations | RECRUITMENT, STILL | The main strength was the study design with recruitment from the general population into an RCT, the detailed clinical assessment from baseline, objective VOAll statistical models were corrected for variables known to be connected to hippocampal size such as age [A limitation of the study was the low number of particip... | PMC10400748 | |
Acknowledgements | RECRUITMENT | The authors thank all the participants for taking part in this study, and Torill E. Sjøbakk for help with the recruitment. We thank Hanne Nikkels, Stine Bjøralt, and the radiographers at the 3T scanner for help with the MRI/MRSI data collection. We also thank those involved with the clinical testing, including VO | PMC10400748 | |
Author contribution | Line Skarsem Reitlo contributed to the data quality control, statistical analysis, figures, drafting, and revision of the manuscript. Jelena Mihailovic performed the MRSI data analyses, wrote methods, and revised the manuscript. Dorthe Stensvold and Ulrik Wisløff supervised the RCT Generation 100 study; were responsibl... | PMC10400748 | ||
Funding | Open access funding provided by NTNU Norwegian University of Science and Technology (incl St. Olavs Hospital - Trondheim University Hospital) The Generation 100 study was supported by the Research Council of Norway; The K.G. Jebsen Foundation for medical research, Norway; Norwegian University of Science and Technology ... | PMC10400748 | ||
Data Availability | Data used in this manuscript can be accessed by contacting the corresponding author. Access to data by qualified investigators will be subject to ethical and scientific review (to ensure the data is being requested for valid scientific research) and must comply with the European Union General Data Protection Regulation... | PMC10400748 | ||
Declarations | PMC10400748 | |||
Conflict of interest | The authors declare no competing interests. | PMC10400748 | ||
References | PMC10400748 | |||
Abstract | PMC10417045 | |||
Introduction | NSCLC | LUNG CANCER, NSCLC | Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non‐squamous, non‐small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. | PMC10417045 |
Methods | NSCLC | NSCLC | Eligibility criteria included: no prior chemotherapy; advanced, non‐squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation‐negative. Patients ( | PMC10417045 |
Results | Thirty‐five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34–0.93], log‐rank | PMC10417045 | ||
Conclusions | NSCLC | NSCLC | Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non‐squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M‐MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin an... | PMC10417045 |
INTRODUCTION | NSCLC, death, non‐squamous cell lung cancer, (PD‐1)/programmed cell death, Non‐small cell lung cancer, PD‐L1 | LUNG CANCERS, NSCLC | Non‐small cell lung cancer (NSCLC) has been one of the most common causes of cancer‐related death.NSCLC accounts for 80%–90% of all lung cancers, and non‐squamous cell lung cancer accounts for 70%–80% of all NSCLC cases.Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor (VEGF).Recently... | PMC10417045 |
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