bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of sorafenib, lenvatinib, atezolizumab plus bevacizumab and sintilimab plus bevacizumab for the treatment of advanced hepatocellular carcinoma in China
Authors: Gong Hongyu , Ong Siew Chin , Li Fan , Weng Zhiying , Zhao Keying , Jiang Zhengyou 
Published: April 2023

Abstract
Background and Objective
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, especially in China. According to the 2021 Chinese Society of Clinical Oncology guidelines, sorafenib, lenvatinib, atezolizumab combined with bevacizumab, and sintilimab combined with bevacizumab are recommended as first-line treatment options for advanced HCC. This study provides a cost-effectiveness analysis of these treatments from the patient perspective.

Methods
A partitioned survival model was established using the TreeAge 2019 software to evaluate the cost-effectiveness. The model includes three states, namely progression-free survival, progressive disease, and death. Clinical data were derived from three randomized controlled studies involving patients with advanced HCC who received the following treatment: sorafenib and lenvatinib (NCT01761266); atezolizumab in combination with bevacizumab (NCT03434379); and sintilimab in combination with bevacizumab (NCT03794440). Cost and clinical preference data were obtained from the literature and interviews with clinicians.

Results
All compared with sorafenib therapy, lenvatinib had an incremental cost-effectiveness ratio (ICER) of US$188,625.25 per quality-adjusted life year (QALY) gained; sintilimab plus bevacizumab had an ICER of US$75,150.32 per QALY gained; and atezolizumab plus bevacizumab had an ICER of US$144,513.71 per QALY gained. The probabilistic sensitivity analysis indicated that treatment with sorafenib achieved a 100% probability of cost-effectiveness at a threshold of US$36,600/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the medical insurance reimbursement ratio and drug prices.

Conclusions
In this economic evaluation, therapy with lenvatinib, sintilimab plus bevacizumab, and atezolizumab plus bevacizumab generated incremental QALYs compared with sorafenib; however, these regimens were not cost-effective at a willingness-to-pay threshold of US$36,600 per QALY. Therefore, some patients may achieve preferred economic outcomes from these three therapies by tailoring the regimen based on individual patient factors.
HIV-1 subtype C Nef-mediated SERINC5 down-regulation significantly contributes to overall Nef activity
Authors: Naicker Delon , Sonela Nelson , Jin Steven W. , Mulaudzi Takalani , Ojwach Doty , Reddy Tarylee , Brockman Mark A. , Brumme Zabrina L. , Ndung’u Thumbi , Mann Jaclyn K. 
Published: April 2023

Abstract
Background
Nef performs multiple cellular activities that enhance HIV-1 pathogenesis. The role of Nef-mediated down-regulation of the host restriction factor SERINC5 in HIV-1 pathogenesis is not well-defined. We aimed to investigate if SERINC5 down-regulation activity contributes to HIV-1 subtype C disease progression, to assess the relative contribution of this activity to overall Nef function, and to identify amino acids required for optimal activity. We measured the SERINC5 down-regulation activity of 106 subtype C Nef clones, isolated from individuals in early infection, for which the Nef activities of CD4 and HLA-I down-regulation as well as alteration of TCR signalling were previously measured. The relationship between SERINC5 down-regulation and markers of disease progression, and the relative contribution of SERINC5 down-regulation to a Nef fitness model-derived E value (a proxy for overall Nef fitness in vivo), were assessed.

Results
No overall relationship was found between SERINC5 down-regulation and viral load set point (p = 0.28) or rate of CD4+ T cell decline (p = 0.45). CD4 down-regulation (p = 0.02) and SERINC5 down-regulation (p = 0.003) were significant determinants of E values in univariate analyses, with the greatest relative contribution for SERINC5 down-regulation, and only SERINC5 down-regulation remained significant in the multivariate analysis (p = 0.003). Using a codon-by-codon analysis, several amino acids were significantly associated with increased (10I, 11V, 38D, 51T, 65D, 101V, 188H and, 191H) or decreased (10K, 38E, 65E, 135F, 173T, 176T and, 191R) SERINC5 down-regulation activity. Site-directed mutagenesis experiments of selected mutants confirmed a substantial reduction in SERINC5 down-regulation activity associated with the mutation 173T, while mutations 10K, 135F, and 176T were associated with more modest reductions in activity that were not statistically significant.

Conclusions
These results suggest that SERINC5 down-regulation is a significant contributor to overall Nef function and identify potential genetic determinants of this Nef function that may have relevance for vaccines or therapeutics.
Screening for thyroid disease in pregnancy: a study of Danish clinical practice
Authors: Hatting Line Cleman , Kristensen Marie Østergaard , Lundgaard Maja Hjelm , Sørensen Anne , Andersen Stine Linding 
Published: April 2023

Abstract
Background
Thyroid disease in pregnant women is a matter of clinical awareness, and current clinical guidelines recommend a risk-based screening strategy. This study aimed to evaluate current clinical practice regarding screening for thyroid disease in pregnancy in Denmark.

Methods
A cross-sectional study was performed in the North Denmark Region with consecutive inclusion of 150 pregnant women from Aalborg University Hospital each year in 2020 and 2021. Medical records were reviewed according to the recommended risk-based screening criteria for thyroid disease in pregnancy. Any measurement of thyroid-stimulating hormone (TSH) was assessed 3 months prior to and in pregnancy.

Results
Altogether 292 pregnant women who received no current treatment for thyroid disease were included. A total of 81 (27.7%) had a measurement of TSH before or during the pregnancy, and 30 women (10.3%) in the early pregnancy specifically. One or more of the screening criteria for thyroid disease recommended in the Danish clinical practice guideline were fulfilled in 37 of the 81 women (45.7%) with thyroid function tested and among 41 of the 211 (19.4%) women who did not have thyroid function tested before or during pregnancy.

Conclusion
In a Danish regional investigation, 1 in 4 women had their thyroid function tested in relation to a pregnancy. However, recommended risk-based screening criteria for thyroid disease in pregnancy were heterogeneously distributed. Results encourage considerations on the current practice for the screening of thyroid function in Danish pregnant women and inform the general debate.
Methylglyoxal: a novel upstream regulator of DNA methylation
Authors: Dube Gaurav , Tiamiou Assia , Bizet Martin , Boumahd Yasmine , Gasmi Imène , Crake Rebekah , Bellier Justine , Nokin Marie-Julie , Calonne Emilie , Deplus Rachel , Wissocq Tom , Peulen Olivier , Castronovo Vincent , Fuks François , Bellahcène Akeila 
Published: April 2023

Abstract
Background
Aerobic glycolysis, also known as the Warburg effect, is predominantly upregulated in a variety of solid tumors, including breast cancer. We have previously reported that methylglyoxal (MG), a very reactive by-product of glycolysis, unexpectedly enhanced the metastatic potential in triple negative breast cancer (TNBC) cells. MG and MG-derived glycation products have been associated with various diseases, such as diabetes, neurodegenerative disorders, and cancer. Glyoxalase 1 (GLO1) exerts an anti-glycation defense by detoxifying MG to D-lactate.

Methods
Here, we used our validated model consisting of stable GLO1 depletion to induce MG stress in TNBC cells. Using genome-scale DNA methylation analysis, we report that this condition resulted in DNA hypermethylation in TNBC cells and xenografts.

Results
GLO1-depleted breast cancer cells showed elevated expression of DNMT3B methyltransferase and significant loss of metastasis-related tumor suppressor genes, as assessed using integrated analysis of methylome and transcriptome data. Interestingly, MG scavengers revealed to be as potent as typical DNA demethylating agents at triggering the re-expression of representative silenced genes. Importantly, we delineated an epigenomic MG signature that effectively stratified TNBC patients based on survival.

Conclusion
This study emphasizes the importance of MG oncometabolite, occurring downstream of the Warburg effect, as a novel epigenetic regulator and proposes MG scavengers to reverse altered patterns of gene expression in TNBC.
FYN/TOPK/HSPB1 axis facilitates the proliferation and metastasis of gastric cancer
Authors: Peng SanFei , Yin YuHan , Zhang YiZheng , Zhu Feng , Yang Ge , Fu Yang 
Published: April 2023

AbstractBackgroundFYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown.MethodsIn vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting,32p-labeled isotope radioautography assays, vitro kinase assays, and TOPK knockout mice.ResultsFYN was found to be significantly upregulated in GC tissues as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice.ConclusionsFYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC.
Unicompartmental knee arthroplasty vs. high tibial osteotomy for medial knee osteoarthritis (UNIKORN): a study protocol of a randomized controlled trial
Authors: Siren Juuso , Rämö Lasse , Rantasalo Mikko , Komulainen Olli , Skants Noora , Reito Aleksi , Kosola Jussi , Lindahl Jan 
Published: April 2023

Abstract

Background

Medial knee osteoarthritis (OA) is a common health problem resulting in knee pain and limiting patients’ physical activity. After failed conservative treatment, unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) are possible surgical treatment options for this condition. There is a paucity of high-quality evidence in the literature comparing objective and subjective outcomes of these procedures. Also, there is no common agreement on whether these procedures provide comparable results in late-stage medial knee OA patients.

Methods
We will perform a prospective randomized controlled trial comparing HTO and UKA in patients with late-stage medial knee OA. 100 patients with isolated medial knee OA (KL III–IV) are assigned to either UKA (n = 50) or HTO (n = 50) procedure in patients 45–65 years of age. Our primary outcome will be KOOS5 at one year postoperatively. Secondary outcomes include OARSI physical assessment, length of stay, wearable activity watch, radiographs (OA progression according to Kellgren-Lawrence classification), patient-reported outcomes (KOOS subscales, pain visual analog scale [VAS], Lysholm, and Oxford knee scores), and adverse events (conversion to total knee arthroplasty, surgery-related complications, need for revision surgery) outcomes. Our hypothesis is that neither of the interventions is superior as measured with KOOS5 at 12 months.

Ethics and dissemination
The institutional review board of the Helsinki and Uusimaa Hospital District has approved the protocol. We will disseminate the findings through peer-reviewed publications.

Trial registration
ClinicalTrials.gov/TooloH NCT05442242. Registered on 7/1/2022.
Stratified distribution of Th17 and Treg cells in patients with multi-stage rheumatoid arthritis
Authors: Su Rui , Li Baochen , Wu Ruihe , Xie Yuhuan , Gao Anqi , Gao Chong , Li Xiaofeng , Wang Caihong 
Published: April 2023

Abstract
Objective
Rheumatoid arthritis (RA) is a typical, progressive autoimmune disease. Its occurrence and development are associated with dysregulation of T and B cell numbers. However, the specific immune characteristics of different RA courses remain incompletely defined. Here, we describe the peripheral blood lymphocyte subsets, particularly CD4 + T subsets, of different RA courses with a focus on early RA (Ea-RA).

Methods
In all, 131 patients with Ea-RA, 117 with advanced RA (Ad-RA), and 109 with treated RA (Tr-RA) were enrolled. We collected general clinical data. Whole blood samples obtained from the patients and 97 healthy controls (HCs) were analysed via flow cytometry.

Results
Decreased absolute NK cell numbers and increased CD4/CD8 T cell ratios were observed in different RA groups, including Ea-RA, compared to healthy controls. In Ea-RA patients, the Th17 and Treg cell numbers were similar to those in HCs. We performed k-means clustering based on the profiles of Th17 and Treg cells for patients with multi-stage of RA. We identified three patient types: type A characterised by relatively low Treg and Th17 cell numbers, type B with moderate levels of Treg cells and levels of Th17 cells similar to that of type C patients, and type C with high levels of Treg cells and levels of Th17 cells similar to that of type B patients.

Conclusion
The immune characteristics of Ea-RA patients differ from those of HCs; an immune system disorder is apparent although no differences in Th17 and Treg levels were evident between Ea-RA patients and HCs. We found distributional heterogeneities of Th17 and Treg cells in patients with multi-stage of RA. Stratified management based on such heterogeneity may serve as a useful novel immunotherapy allowing of early intervention.
Effect of interval and continuous small-sided games training on the bio-motor abilities of young soccer players: a comparative study
Authors: Daryanoosh Farhad , Alishavandi Hossein , Nemati Javad , Basereh Aref , Jowhari Alireza , Asad-manesh Enayatollah , Oliveira Rafael , Brito João Paulo , Prieto-González Pablo , García-Calvo Tomás , Khoramipour Kayvan , Nobari Hadi 
Published: April 2023

Abstract
Objective
The present study compared the effects of two different small-sided game (SSG) training methods, interval (ISSG) and continuous (CSSG) on the bio-motor abilities of young soccer players.

Methods
Sixteen young soccer players (age: 19.5 ± 0.5 years; height: 177 ± 4.72 cm) were ranked based on the result of a running-based anaerobic sprint test (RAST) and randomly divided into two groups: CSSG (n = 8) and ISSG (n = 8). The training protocols were performed for eight weeks, three sessions per week. Participants were assessed twice (pre- and post-intervention) to estimate their anaerobic capacity with the RAST, aerobic capacity with Yo-Yo intermittent recovery test, body fat percentage with a bioimpedance analysis, speed with a 30-meter run test, and agility with the Illinois agility test. During the training session, the rating of the perceived exertion (RPE) and heart rate (mean and maximum) were recorded to assess the training load.

Results
In general, aerobic and anaerobic capacities improved after ISSG (p < 0.05, for all). The between-group analysis with repeated measures ANOVA revealed higher values for ISSG than CSSG groups post-intervention in anaerobic power (p = 0.042, ηp2 = 0.264). In addition, the independent t-test results indicated that ISSG presented lower values of mean heart rate (p = 0.023, effect size [ES] = 0.85) and RPE (p < 0.05, ES = 0.88) than CSSG. Moreover, higher values for maximum heart rate were revealed for ISSG than for the CSSG group (p = 0.004, ES = 0.85).

Conclusion
In conclusion, the findings of this study suggests that ISSG can lead to better improvements in anaerobic power and aerobic capacity than CSSG. Additionally, the ISSG led to a lower mean heart rate and RPE than the CSSG. Therefore, coaches and trainers may want to consider incorporating ISSG into their training programs for young soccer players to enhance their bio-motor abilities.
It all depends on which side of the fence you are standing: agent and recipient perspectives are differently linked with job crafting
Authors: Roczniewska Marta , Marszałek Magdalena 
Published: April 2023

Abstract
Background
In social contexts, people may view themselves as agents, who are in control of the environment, or recipients, who succumb to what others have decided. Here, we investigated how these perspectives determine job crafting (JC)—self-initiated employee behaviors targeted at altering job characteristics to fit them with one’s needs.

Methods
Study 1 tested the relationships between chronic agent–recipient tendencies and JC in a cross-lagged panel design. Study 2 was a randomized experiment where agent–recipient perspectives were manipulated to predict JC intentions in the week to follow.

Results
Supporting our predictions, while agents sought structural job resources and increased challenging demands, recipients resorted to reducing hindering demands (Study 1). Study 2 revealed that activating an agent perspective led to stronger intentions to increase structural job resources and challenging demands.

Conclusions
We conclude that agent and recipient perspectives are linked with differential patterns of JC behaviors. Strengthening agency is a vital step in forming job redesign goals during JC interventions.
Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents
Authors: Moreno Lucas , DuBois Steven G. , Glade Bender Julia , Mauguen Audrey , Bird Nick , Buenger Vickie , Casanova Michela , Doz François , Fox Elizabeth , Gore Lia , Hawkins Douglas S. , Izraeli Shai , Jones David T.W. , Kearns Pamela R. , Molenaar Jan J. , Nysom Karsten , Pfister Stefan , Reaman Gregory , Smith Malcolm , Weigel Brenda , Vassal Gilles , Zwaan Christian Michel , Paoletti Xavier , Iasonos Alexia , Pearson Andrew D.J. 
Published: April 2023

PURPOSE There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.
Tracheostomy, Feeding-Tube, and In-Hospital Postoperative Mortality in Children: A Retrospective Cohort Study
Authors: Brown Sydney E. S. , Hall Matt , Cassidy Ruth B. , Zhao Xinyi , Kheterpal Sachin , Feudtner Chris 
Published: April 2023

BACKGROUND:
Neuromuscular/neurologic disease confers increased risk of perioperative mortality in children. Some patients require tracheostomy and/or feeding tubes to ameliorate upper airway obstruction or respiratory failure and reduce aspiration risk. Empiric differences between patients with and without these devices and their association with postoperative mortality have not been previously assessed.

METHODS:
This retrospective cohort study using the Pediatric Health Information System measured 3- and 30-day in-hospital postsurgical mortality among children 1 month to 18 years of age with neuromuscular/neurologic disease at 44 US children’s hospitals, from April 2016 to October 2018. We summarized differences between patients presenting for surgery with and without these devices using standardized differences. Then, we calculated 3- and 30-day mortality among patients with tracheostomy, feeding tube, both, and neither device, overall and stratified by important exposures, using Fisher exact test to test whether differences were significant.

RESULTS:
There were 43,193 eligible patients. Unadjusted 3-day mortality was 1.3% (549/43,193); 30-day mortality was 2.7% (1168/43,193). Most (79.1%) used neither a feeding tube or tracheostomy, 1.2% had tracheostomy only, 15.5% had feeding tube only, and 4.2% used both devices. Compared to children with neither device, children using either or both devices were more likely to have multiple CCCs, dysphagia, chronic pulmonary disease, cerebral palsy, obstructive sleep apnea, or malnutrition, and a prolonged intensive care unit (ICU) stay within the previous year. They were less likely to present for high-risk surgeries (33% vs 57%). Having a feeding tube was associated with decreased 3-day mortality overall compared to having neither device (0.9% vs 1.3%, P = .003), and among children having low-risk surgery, and surgery during urgent or emergent hospitalizations. Having both devices was associated with decreased 3-day mortality among children having low-risk surgery (0.8% vs 1.9%; P = .013), and during urgent or emergent hospitalizations (1.6% vs 2.9%; P = .023). For 30-day mortality, having a feeding tube or both devices was associated with lower mortality when the data were stratified by the number of CCCs.

CONCLUSIONS:
Patients requiring tracheostomy, feeding tube, or both are generally sicker than patients without these devices. Despite this, having a feeding tube was associated with lower 3-day mortality overall and lower 30-day mortality when the data were stratified by the number of CCCs. Having both devices was associated with lower 3-day mortality in patients presenting for low-risk surgery, and surgery during urgent or emergent hospitalizations.