bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis
Authors: Xing Puyuan , Hao Xuezhi , Zhang Xin , Li Junling 
Published: November 2022

BackgroundBrigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC.MethodsThe pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model.ResultsThe pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events.ConclusionBrigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types.Systematic Review Registrationhttps://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).
Dosimetric impact of mechanical movements of the Linac gantry during treatments with small fields
Authors: McCallum-Hee Broderick Ivan , Milan Thomas , White Rohen , Rowshanfarzad Pejman 
Published: November 2022

ObjectiveCurrent accepted linac Quality Assurance (QA) guidelines used for Volumetric Modulated Arc Therapy (VMAT) suggest a mechanical isocentre tolerance level of 1 mm. However, this tolerance level has not been well-established for the specific case of small field stereotactic VMAT. This study aims to evaluate the clinical impact of mechanical uncertainty on this treatment modality by modelling systematic gantry sag derived isocentre variance in the Treatment Planning System (TPS).ApproachA previously reported dataset of gantry sag values in the literature served as a starting point for this study. Using an in-house developed VMAT arc splitting algorithm, isocentre shifts were applied at a Control Point (CP) level to DICOM-RT treatment plans. Dose distributions for varying isocentre shift magnitudes were calculated for a set of 29 stereotactic VMAT plans using the Eclipse Acuros XB dose algorithm. These plans had a range of Planning Target Volume (PTV) sizes. A quantitative comparison of each plan was conducted by evaluating five Dose Volume Histogram (DVH)-derived plan quality metrics.ResultsAll metrics exhibited a deterioration in plan quality with increasing magnitudes of isocentre shift. At small PTV sizes, these effects were amplified, exhibiting significant changes at 1 mm of average shift when typical targets and tolerances were considered. For plans with PTVs between 0 and 5 cm3, a 1 mm shift reduced PTV coverage by 6.6 ± 2.2% and caused a 12.1 ± 3.8% deterioration in the conformity index. Based on the results of this study, the prevalent tolerance of 1 mm may not be suitable for treatments of small PTVs with small fields.SignificanceIn contrast to commonly accepted values, an absolute mechanical isocentre of 0.5 mm with action level at 0.75 mm is recommended for stereotactic VMAT of PTV sizes below 10 cm3.
Treatment adherence and associated factors among glaucoma patients attending Ophthalmic units of referral hospitals in North West Ethiopia, 2019
Authors: Birhanie Setarg Ayenew , Getie Girma Alem , Tesfa Mulugeta , Mulugeta Henok , Gedfew Mihretie , Mekete Yeshimareg Shita , Liknaw Tiliksew , Teshale Mikiyas Muche , Tilahun Melkamu , Amlak Baye Tsegaye , Yitayew Fentahun Minwuyelet , Ayenew Temesgen , Bewket Bekalu , Tsegaye Dejen 
Published: November 2022

ObjectiveGlaucoma is one of the common eye disorders resulting from optic neuropathy, which leads to irreversible blindness if left untreated. Poor adherence to glaucoma medical treatments typically leads to some serious consequences, such as progressive visual impairment and blindness. The aim of this study was to assess adherence to treatment and associated factors among patients with glaucoma attending at Northwest Ethiopia referral hospitals.MethodFrom March 1st to April 30th, 2019, an institution-based cross-sectional study was conducted on 382 consecutive glaucoma patients attending at Northwest Ethiopia referral hospitals. Data about adherence to glaucoma treatment was collected by using a standardized tool, the Morisky Medication Adherence Scale-8, through an interviewer-administered questionnaire. Each collected data set was coded and entered into Epi-Data version 4.2, and analysis was done by using STATA version 14.0 statistical software. A logistic regression model was fitted to assess the effect of an independent variable on the dependent variable. A p-value &lt; 0.05 was considered to declare a statistically significant association. The study proposal was approved by the Debre Markos University ethical review committee.ResultsAmong the study participants, 189 (49.5%) were adherent to glaucoma treatment. In this study, occupation (farmer), good knowledge, favorable attitude, a short distance from patients’ homes to hospitals, and scheduling problems for glaucoma medical follow-up visits were significant factors associated with adherence to glaucoma treatments.ConclusionThe study has identified the adherence level as being low. Patient related factors and health care system related factors were significantly associated with adherence to glaucoma treatments. Appropriate patient education and planning a patient follow-up strategy might improve patients’ adherence to glaucoma treatment. Care providers should place emphasis on the importance of adherence.
Evaluation of the effectiveness and efficiency of the East African community joint assessment procedure by pharmaceutical companies: Opportunities for improvement
Authors: Ngum Nancy , Mashingia Jane , Ndomondo-Sigonda Margareth , Walker Stuart , Salek Sam 
Published: November 2022

Background: A 2021 study to determine the viewpoints among the seven member countries regarding the effectiveness (i.e., achieving the intended outcomes) and efficiency (i.e., achieving the intended outcomes in timely manner with the resources available) of the East African Community Medicine Regulatory Harmonisation (EAC-MRH) Joint Assessment Procedure recommended the conduct of a similar study among pharmaceutical company applicants. The aim of this study then was to evaluate the effectiveness and efficiency of the current EAC-MRH operating model from the applicants’ perspective, including the challenges and opportunities for improvement.Methods: Using the Process Effectiveness and Efficiency Rating for Industry questionnaire developed by the authors, data were collected from company representatives responsible for EAC joint procedure submissions.Results: Responses from 14 study participants underlined the support of pharmaceutical companies for the EAC-MRH initiative, which has facilitated the harmonisation of registration requirements across the EAC region leading to one registration for all countries and a reduction of the workload for both applicants and assessors. In addition, it is expected that shorter timelines for approval will lead to improved access to quality-assured essential medicines in the region. Access to various markets at the same time was also noted as an important benefit to pharmaceutical companies. Noted challenges include a lack of process information, a lack of centralised submission and tracking process and a lack of mandated central registration. A key strategy proposed by participants is the establishment of a regional administrative body to centrally receive and track EAC applications and the eventual establishment of a Regional EAC Medicines Authority.Conclusion: This is the first study evaluating the performance of the EAC work-sharing initiative from the point of view of the applicants. In general, the applicants believe that the system performs efficiently and fulfils its promise. However, some participants indicated that in some countries an EAC positive recommendation does not directly result in an individual country approvals. Following the recommendations listed in this report may mitigate identified areas for improvement and facilitate the overall goal of the EAC-MRH initiative to expedite the availability of needed quality-assured medicines to patients in the region.
The effects of levosimendan in patients undergoing transcatheter aortic valve replacement- a retrospective analysis
Authors: Zhao Zhenyan , Meng Zhen , Song Guangyuan , Wang Chunrong , Shi Sheng , Zhao Jie , Zhang Hongliang , Wang Moyang , Niu Guannan , Zhou Zheng , Wang Jianhui , Wu Yongjian 
Published: November 2022

Background: Aortic stenosis (AS) increases left ventricular afterload, leading to cardiac damage and heart failure (HF). Transcatheter aortic valve replacement (TAVR) is an effective therapy for AS. No inotropic agents including levosimendan have been evaluated in patients undergoing TAVR.Methods: A total of 285 patients underwent TAVR between 2014 and 2019; 210 were included in the matched analysis and 105 received 0.1 μg/kg body weight/min levosimendan immediately after the prosthesis had been successfully implanted. Medical history, laboratory tests, and echocardiography results were analyzed. Endpoints including 2-year all-cause mortality, stroke, or HF-related hospitalization, and a combination of the above were analyzed by Cox proportional hazard models.Results: The levosimendan group had no difference in 2-year mortality compared with the control group (hazard ratio [HR]: 0.603, 95% confidence interval [CI]: 0.197–1.844; p = 0.375). However, levosimendan reduced stroke or HF-related hospitalization (HR: 0.346; 95% CI: 0.135–0.884; p = 0.027) and the combined endpoint (HR: 0.459, 95% CI: 0.215–0.980; p = 0.044). After adjusting for multiple variants, levosimendan still reduced stroke or HF-related hospitalization (HR: 0.346, 95% CI: 0.134–0.944; p = 0.038).Conclusion: Prophylactic levosimendan administration immediately after valve implantation in patients undergoing TAVR can reduce stroke or HF-related hospitalization but does not lower all-cause mortality.
Circulating microparticles are associated with plaque burden and cause eNOS uncoupling in patients with carotid atherosclerosis
Authors: Han Xiaowan , Li Tong , Wang Tieshan , Wang Baofu , Li Yang , Wang Lei , Lu Ziwen , Wu Aiming , Liu Lisong , Pan Guozhong , Zhao Mingjing 
Published: November 2022

Aims: The study aimed to evaluate the correlation of different microparticle (MP) phenotypes with plaque burden and their diagnostic value and preliminarily explore the role of MPs in atherosclerosis (AS).Methods: Carotid intima-media thickness (CIMT) and maximal plaque area in 23 patients with carotid atherosclerosis (CAS) and 22 healthy subjects were measured by ultrasound. Transmission electron microscopy, nanoparticle tracking analysis and western blot were used to identify MPs. Flow cytometry assay measured absolute number of MPs, and receiver operating characteristic (ROC) analysis was used to assess the relationship between plaque burden and MPs. To study the preliminary mechanism of MPs in AS, MPs were administered to 32 male Kunming mice, which were randomly divided into control, CAS, healthy, and tetrahydrobiopterin (BH4) groups. Hematoxylin-eosin staining, immunohistochemistry staining, and Western blot were adopted to detect relevant indexes 24 h after the injection.Results: The plasma levels of CD45+ leukocyte-derived microparticle (LMP), CD11a+ LMP, CD11a+/CD45+ LMP, and CD31+/CD42b+ platelet-derived microparticle (PMP) in CAS patients were significantly higher than those in healthy subjects, and were positively correlated with the maximal plaque area. Moreover, the levels of CD11a+ LMP, CD11a+/CD45+ LMP were also positively correlated with CIMT. The area under the ROC curve of the four MPs was 0.689, 0.747, 0.741, and 0.701, respectively. Compared with healthy subjects, MPs from CAS patients resulted in a significantly lower expression of endothelial nitric oxide synthase (eNOS) dimer/monomer, and BH4 could improve eNOS uncoupling. Moreover, the level of VCAM-1 in intima in the CAS group was significantly higher than in the other three groups.Conclusion: CD11a+ LMP and CD11a+/CD45+ LMP might be potential biomarkers for CAS prediction. BH4-related eNOS uncoupling occurs in CAS patients, and circulating MPs from them lead to endothelial dysfunction through eNOS uncoupling.
Changes in peripheral T-lymphocyte subsets and serum cytokines in patients with systemic sclerosis
Authors: Guo Rong-Hong , Cheng Hao , Zhang Xiao-Ying , Yu Zhen , Wang Guang-Hui , Hao Shu-Ya , Gao Xiao-Peng , Wen Hong-Yan 
Published: November 2022

Objective: T cells represent a predominant cell type in autoimmune disease. However, their exact roles are not fully clear in systemic sclerosis (SSc). This study aimed to mainly investigate the alteration in the absolute numbers of T-lymphocyte subsets and the serum levels of cytokines in SSc patients.Methods: A total of 76 patients with SSc and 76 age- and sex-matched healthy controls (HCs) were enrolled. The levels of circulating T cell subsets and serum cytokines were measured by flow cytometry. T cell subsets or serum cytokines correlations with disease activity and organ involvement were analyzed.Results: The absolute numbers of Th2 and Treg cells in SSc patients were lower than those in HCs (p &lt; 0.05), resulting in the ratios of Th1/Th2 [25.01 (12.24, 38.61) vs. 11.64 (6.38, 20.34)] and Th17/Treg [0.42 (0.17, 0.66) vs. 0.17 (0.13, 0.29)] were increased significantly (p &lt; 0.001). The absolute numbers of total T, Th, and Treg cells were negatively correlated with CRP (r = -0.406, p = 0.002; r = -0.263, p &lt; 0.05; r = -0.367 p &lt; 0.01). The serum levels of IL-2, SIL-2R, IL-6, IL-10, INF-γ, and TNF-α were significantly higher than those in HCs (p &lt; 0.001). Increasing IL-2 in the wake of the augment of ESR (r = 0.671, p = 0.004), so did IL-6 (r = 0.378, p &lt; 0.05). The ratio of Th17/Treg in SSc-ILD patients had lower levels than that in other patients [0.35 (0.14, 0.53) vs. 0.64 (0.26, 0.93) p = 0.028]; Treg cells were lessened in patients with Raynaud’s phenomenon relative to controls [3.00 (2.41, 4.28) vs. 3.55 (2.86, 4.53) p &lt; 0.05]. The levels of IL-2, IL-10 and INF-γ [3.32 (1.05,11.73) vs. 2.32 (0.44,6.45), p = 0.045], [8.08 (3.63, 355,77) vs. 4.89 (0.78, 21.44), p = 0.02], [6.31 (2.66, 44.03) vs. 4.03 (0.22, 16.96), p = 0.009] were elevated in patients with arthralgia, while the level of Th17 was decreased [0.62 (0.20,2.16) vs. 1.26 (0.22,10.93), p = 0.026]. ROC curve analysis yielded an optimal cut-off IL-2, IL-10, and INF-γ levels of 2.67, 5.93, and 5.32 pg/ml for the presence of arthralgia.Conclusion: We exhibited abnormalities in T subsets and the production of their cytokines in SSc, as compared with those in HCs. This may allow the pathogenesis of SSc and the development of novel therapeutic interventions aimed at targeting these cells and the cytokines they produce.
Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts
Authors: Blokland Kaj E. C. , Nizamoglu Mehmet , Habibie Habibie , Borghuis Theo , Schuliga Michael , Melgert Barbro N. , Knight Darryl A. , Brandsma Corry-Anke , Pouwels Simon D. , Burgess Janette K. 
Published: November 2022

In fibrosis remodelling of ECM leads to changes in composition and stiffness. Such changes can have a major impact on cell functions including proliferation, secretory profile and differentiation. Several studies have reported that fibrosis is characterised by increased senescence and accumulating evidence suggests that changes to the ECM including altered composition and increased stiffness may contribute to premature cellular senescence. This study investigated if increased stiffness could modulate markers of senescence and/or fibrosis in primary human lung fibroblasts. Using hydrogels representing stiffnesses that fall within healthy and fibrotic ranges, we cultured primary fibroblasts from non-diseased lung tissue on top of these hydrogels for up to 7 days before assessing senescence and fibrosis markers. Fibroblasts cultured on stiffer (±15 kPa) hydrogels showed higher Yes-associated protein-1 (YAP) nuclear translocation compared to soft hydrogels. When looking at senescence-associated proteins we also found higher secretion of receptor activator of nuclear factor kappa-B ligand (RANKL) but no change in transforming growth factor-β1 (TGF-β1) or connective tissue growth factor (CTGF) expression and higher decorin protein deposition on stiffer matrices. With respect to genes associated with fibrosis, fibroblasts on stiffer hydrogels compared to soft had higher expression of smooth muscle alpha (α)-2 actin (ACTA2), collagen (COL) 1A1 and fibulin-1 (Fbln1) and higher Fbln1 protein deposition after 7 days. Our results show that exposure of lung fibroblasts to fibrotic stiffness activates genes and secreted factors that are part of fibrotic responses and part of the Senescence-associated secretory phenotype (SASP). This overlap may contribute to the creation of a feedback loop whereby fibroblasts create a perpetuating cycle reinforcing progression of a fibrotic response.
The recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure: Five years of data based on a population pharmacokinetic model and Monte-Carlo simulations
Authors: Yang Qianting , Zhang Tao , Zhang Ying , Sun Dan , Zheng Xiaowei , Du Qian , Wang Xue , Cheng Xiaoliang , Xing Jianfeng , Dong Yalin 
Published: November 2022

Background: To develop a population pharmacokinetic (PPK) model for caspofungin, identify parameters influencing caspofungin pharmacokinetics, and assess the required probability of target attainment (PTA) and cumulative fraction of response (CFR) for various dosing regimens of caspofungin in all patients and intensive care unit (ICU)-subgroup patients.Method: The general PPK model was developed based on data sets from all patients (299 patients). A ICU-subgroup PPK model based on data sets from 136 patients was then analyzed. The effects of demographics, clinical data, laboratory data, and concomitant medications were tested. Monte-Carlo simulations (MCS) were used to evaluate the effectiveness of different caspofungin dosage regimens.Results: One-compartment model best described the data of all patients and ICU patients. Clearances (CL) were 0.32 L/h and 0.40 L/h and volumes of distribution (V) were 13.31 L and 10.20 L for the general and ICU-subgroup PPK models, respectively. In the general model, CL and V were significantly associated with albumin (ALB) concentration and body weight (WT). In the ICU-subgroup model, CL was associated with WT. The simulated exposure in ICU patients was lower than that in all patients (p &lt; 0.05). MCS indicated that higher caspofungin maintenance doses of 70–150 mg may achieve target CFR of &gt;90% for patients with higher WT (&gt;70 kg) or with C. albicans or C. parapsilosis infections, and especially for ICU patients with hypoalbuminaemia.Conclusion: The PPK model and MCS presented in the study demonstrated that the recommended dosage regimen for caspofungin in patients with higher body weight or hypoalbuminaemia will result in low exposure.
RNA-seq and qRT-PCR analyses reveal the physiological response to acute hypoxia and reoxygenation in Epinephelus coioides
Authors: Lai Xingxing , Zhong Zhongxuan , Lin Bing , Wu Yuxin , Ma Yonghao , Zhang Cuiping , Yang Yang , Zhang Mingqing , Qin Weijian , Fu Xiaoqin , Shu Hu 
Published: November 2022

Hypoxia is a critical problem in intensive Epinephelus coioides aquaculture systems. In the present study, the physiological responses of E. coioides muscle to acute hypoxic stress (DO = 0.6 ± 0.1 mg/L) and reoxygenation (DO = 6.0 ± 0.1 mg/L) were analyzed by transcriptome sequencing (RNA-seq) and quantitative real-time PCR (qRT–PCR). RNA-seq was conducted on the muscle tissues of E. coioides in the hypoxia-tolerant (EMS), hypoxia-sensitive (EMW), and normoxic (CM) groups. Among the three groups, a total of 277 differentially expressed genes (DEGs) were identified. KEGG analysis revealed that the pathways significantly enriched after hypoxic stress are involved in the immune response, glycolysis/gluconeogenesis, energy metabolism, vasodilation and proliferation, cell proliferation, and apoptosis. qRT‒PCR verified that the differentially expressed genes FIH-1, PHD-2, PPARα, BCL-XL, LDH-A, and Flt-1 were significantly upregulated after hypoxic stress and returned to normal levels after reoxygenation, suggesting that these DEGs play important roles in responding to hypoxia treatment. In addition, the HIF-1 signaling pathway was also activated under hypoxic stress, and qRT‒PCR confirmed that the expression level of HIF-1α was significantly elevated under acute hypoxic stress, indicating that the HIF-1 signaling pathway is the central pathway in the E. coioides hypoxic response mechanism and activates other related pathways to adapt to hypoxic stress. These pathways jointly regulate energy metabolism, substance synthesis, blood vessel proliferation, cell proliferation, and differentiation and prolong survival time. These results provide ideas for understanding physiological regulation after hypoxic stress and reoxygenation and provide basic insights for the future breeding of hypoxia-tolerant E. coioides.