bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sonographic evaluation of the degree of medial meniscal extrusion during Thessaly test in healthy knees
Authors: Cho John C. , Tollefson Lauren , Reckelhoff Kenneth 
Published: August 2021

Abstract
Objective
The Thessaly test is a commonly used orthopedic test for meniscus tear evaluation. The study’s objective is to evaluate the degree of medial meniscal extrusion during different loading phases of the Thessaly test.

Methods
A convenience sample of 60 healthy knees (35 participants) was examined and the data sets were collected from October 8, 2018 through February 8, 2019. Sonographic measurement of the degree of physiologic extrusion of the medial meniscus deep to the medial collateral ligament was taken by two examiners at six different loading phases: supine, standing, 5° knee-flexion with internal (IR)/external (ER) rotation and 20° knee-flexion with IR/ER. The difference in meniscal extrusion by knee position was compared with ANOVA. Interexaminer reproducibility assessment was analyzed using limits of agreement.

Results
The mean meniscal extrusion for each position was—supine: 2.3 ± 0.5 mm, standing: 2.8 ± 0.8 mm, 5° IR: 2.3 ± 0.9 mm, 5° ER: 2.4 ± 0.7 mm, 20° IR: 1.9 ± 0.8 mm, and 20° ER: 2.3 ± 0.7 mm. Significant increase in extrusion was observed from supine to standing (p < 0.05) and from 20° IR to 20° ER (p = 0.015). Significant decreased measurement was observed from standing to 5° IR (p < 0.05), 5° ER (p < 0.05), 20° IR (p < 0.05) and 20° ER (p < 0.05). There is no significant change between 5° IR and 5° ER (p = 1.0). Agreement parameters revealed that the differences between examiner measurements were minimal; 75% of both examiners’ meniscal extrusion measurements were within 1.0 mm with 97% of measurements falling within 2.0 mm.

Conclusion
Our study’s novel findings showed various degrees of physiological extrusion of the medial meniscus in asymptomatic knees during the loading phases involved in the Thessaly test. Physiological MME does exist and should not be defaulted to pathologic meniscus as previously described. Agreement parameters suggest that measurement of meniscal extrusion during the Thessaly test is reproducible between different examiners.
Deep learning method for prediction of patient-specific dose distribution in breast cancer
Authors: Ahn Sang Hee , Kim EunSook , Kim Chankyu , Cheon Wonjoong , Kim Myeongsoo , Lee Se Byeong , Lim Young Kyung , Kim Haksoo , Shin Dongho , Kim Dae Yong , Jeong Jong Hwi 
Published: August 2021

Abstract
Background
Patient-specific dose prediction improves the efficiency and quality of radiation treatment planning and reduces the time required to find the optimal plan. In this study, a patient-specific dose prediction model was developed for a left-sided breast clinical case using deep learning, and its performance was compared with that of conventional knowledge-based planning using RapidPlan™.

Methods
Patient-specific dose prediction was performed using a contour image of the planning target volume (PTV) and organs at risk (OARs) with a U-net-based modified dose prediction neural network. A database of 50 volumetric modulated arc therapy (VMAT) plans for left-sided breast cancer patients was utilized to produce training and validation datasets. The dose prediction deep neural network (DpNet) feature weights of the previously learned convolution layers were applied to the test on a cohort of 10 test sets. With the same patient data set, dose prediction was performed for the 10 test sets after training in RapidPlan. The 3D dose distribution, absolute dose difference error, dose-volume histogram, 2D gamma index, and iso-dose dice similarity coefficient were used for quantitative evaluation of the dose prediction.

Results
The mean absolute error (MAE) and one standard deviation (SD) between the clinical and deep learning dose prediction models were 0.02 ± 0.04%, 0.01 ± 0.83%, 0.16 ± 0.82%, 0.52 ± 0.97, − 0.88 ± 1.83%, − 1.16 ± 2.58%, and − 0.97 ± 1.73% for D95%, Dmean in the PTV, and the OARs of the body, left breast, heart, left lung, and right lung, respectively, and those measured between the clinical and RapidPlan dose prediction models were 0.02 ± 0.14%, 0.87 ± 0.63%, − 0.29 ± 0.98%, 1.30 ± 0.86%, − 0.32 ± 1.10%, 0.12 ± 2.13%, and − 1.74 ± 1.79, respectively.

Conclusions
In this study, a deep learning method for dose prediction was developed and was demonstrated to accurately predict patient-specific doses for left-sided breast cancer. Using the deep learning framework, the efficiency and accuracy of the dose prediction were compared to those of RapidPlan. The doses predicted by deep learning were superior to the results of the RapidPlan-generated VMAT plan.
Heuristic algorithms for best match graph editing
Authors: Schaller David , Geiß Manuela , Hellmuth Marc , Stadler Peter F. 
Published: August 2021

Abstract
Background
Best match graphs (BMGs) are a class of colored digraphs that naturally appear in mathematical phylogenetics as a representation of the pairwise most closely related genes among multiple species. An arc connects a gene x with a gene y from another species (vertex color) Y whenever it is one of the phylogenetically closest relatives of x. BMGs can be approximated with the help of similarity measures between gene sequences, albeit not without errors. Empirical estimates thus will usually violate the theoretical properties of BMGs. The corresponding graph editing problem can be used to guide error correction for best match data. Since the arc set modification problems for BMGs are NP-complete, efficient heuristics are needed if BMGs are to be used for the practical analysis of biological sequence data.

Results
Since BMGs have a characterization in terms of consistency of a certain set of rooted triples (binary trees on three vertices) defined on the set of genes, we consider heuristics that operate on triple sets. As an alternative, we show that there is a close connection to a set partitioning problem that leads to a class of top-down recursive algorithms that are similar to Aho’s supertree algorithm and give rise to BMG editing algorithms that are consistent in the sense that they leave BMGs invariant. Extensive benchmarking shows that community detection algorithms for the partitioning steps perform best for BMG editing.

Conclusion
Noisy BMG data can be corrected with sufficient accuracy and efficiency to make BMGs an attractive alternative to classical phylogenetic methods.
4-Methylumbelliferone suppresses catabolic activation in anterior cruciate ligament-derived cells via a mechanism independent of hyaluronan inhibition
Authors: Idota Masaru , Ishizuka Shinya , Hiraiwa Hideki , Yamashita Satoshi , Oba Hiroki , Kawamura Yusuke , Sakaguchi Takefumi , Haga Takahiro , Mizuno Takafumi , Kawashima Itaru , Kuriyama Kanae , Imagama Shiro 
Published: August 2021

Abstract
Background
The anterior cruciate ligament (ACL) has a key role as a dynamic stabilizer of the knee joints, and ACL dysfunction caused by traumatic or degenerative rupture accelerates osteoarthritis progression. Thus, it is important to prevent the degenerative rupture of the ACL. 4-Methylumbelliferone (4-MU), a pre-approved drug, exerts anti-inflammatory effects in osteoarthritis chondrocytes. It was originally used as an inhibitor of hyaluronan synthesis in chondrocytes.

Methods
In this study, we investigated whether 4-MU affects the expression of catabolic factors, such as matrix metalloproteinase (MMP)-1, MMP-3, and interleukin (IL)-6, in ACL-derived cells and ACL explant cultures using immunohistochemistry, real-time RT-qPCR, and capillary western immunoassay. Furthermore, the hyaluronan concentration was evaluated using a colorimetric assay. Statistical analyses were conducted using analysis of variance for multi-group comparisons, followed by Tukey or Tukey-Kramer post hoc test.

Results
Our results revealed, for the first time, that 4-MU suppressed the IL-β-induced upregulation of pro-catabolic factors, such as MMP-1, MMP-3, and IL-6, in ACL-derived cells. This suppressive effect was also observed in the cultured ligament tissues in ex vivo experiments. 4-MU also reversed an enhanced dependence on glycolysis in IL-1β-activated ACL-derived cells. Furthermore, we found that the suppressive effects of 4-MU were exerted directly and not through the inhibition of hyaluronan synthesis.

Conclusions
We conclude that 4-MU could be an effective and useful treatment for knee osteoarthritis, owing to its anti-inflammatory effect on, not only chondrocytes but also on ligament cells.
Targeting the tumor microenvironment in B-cell lymphoma: challenges and opportunities
Authors: Liu Yingyue , Zhou Xiangxiang , Wang Xin 
Published: August 2021

AbstractB-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.
Making clinical decisions based on measurable residual disease improves the outcome in multiple myeloma
Authors: Martinez-Lopez Joaquin , Alonso Rafael , Wong Sandy W. , Rios Rafael , Shah Nina , Ruiz-Heredia Yanira , Sanchez-Pina Jose Maria , Sanchez Ricardo , Bahri Natasha , Zamanillo Irene , Poza Maria , Buenache Natalia , Encinas Cristina , Juarez Luis , Miras Fatima , Collado Luis , Barrio Santiago , Martin Thomas , Cedena Maria Teresa , Wolf Jeffrey 
Published: August 2021

AbstractThe assessment of measurable residual disease (MRD) in bone marrow has proven of prognostic relevance in patients with multiple myeloma (MM). Nevertheless, and unlike other hematologic malignancies, the use of MRD results to make clinical decisions in MM has been underexplored to date. In this retrospective study, we present the results from a multinational and multicenter series of 400 patients with MRD monitoring during front-line therapy with the aim of exploring how clinical decisions made based on those MRD results affected outcomes. As expected, achievement of MRD negativity at any point was associated with improved PFS versus persistent MRD positivity (median PFS 104 vs. 45 months, p < 0.0001). In addition, however, 67 out of 400 patients underwent a clinical decision (treatment discontinuation, intensification or initiation of a new therapy) based on MRD results. Those patients in whom a treatment change was made showed a prolonged PFS in comparison with those 333 patients in which MRD results were not acted upon (respectively, mPFS 104 vs. 62 months, p = 0.005). In patients who achieved MRD negativity during maintenance (n = 186) on at least one occasion, stopping therapy in 24 patients vs. continuing in 162 did not alter PFS (mPFS 120 months vs. 82 months, p = 0.1). Most importantly, however, in patients with a positive MRD during maintenance (n = 214), a clinical decision (either intensification or change of therapy) (n = 43) resulted in better PFS compared to patients in whom no adjustment was made (n = 171) (mPFS NA vs. 39 months, p = 0.02). Interestingly, there were no significant differences when MRD was assessed by flow cytometry or by next-generation sequencing. Herein, we find that MRD is useful in guiding clinical decisions during initial therapy and has a positive impact on PFS in MM patients. This potentially opens a new dimension for the use of MRD in MM, but this role still remains to be confirmed in prospective, randomized clinical trials.
Zelen design clinical trials: why, when, and how
Authors: Simon Gregory E. , Shortreed Susan M. , DeBar Lynn L. 
Published: August 2021

Abstract
Background
In 1979, Marvin Zelen proposed a new design for randomized clinical trials intended to facilitate clinicians’ and patients’ participation. The defining innovation of Zelen’s proposal was random assignment of treatment prior to patient or participant consent. Following randomization, a participant would receive information and asked to consent to the assigned treatment.

Methods
This narrative review examined recent examples of Zelen design trials evaluating clinical and public health interventions.

Results
Zelen designs have often been applied to questions regarding real-world treatment or intervention effects under conditions of incomplete adherence. Examples include evaluating outreach or engagement interventions (especially for stigmatized conditions), evaluating treatments for which benefit may vary according to participant motivation, and situations when assignment to a control or usual care condition might prompt a disappointment effect. Specific practical considerations determine whether a Zelen design is scientifically appropriate or practicable. Zelen design trials usually depend on identifying participants automatically from existing records rather than by advertising, referral, or active recruitment. Assessments of baseline or prognostic characteristics usually depend on available records data rather than research-specific assessments. Because investigators must consider how exposure to treatments or interventions might bias ascertainment of outcomes, assessment of outcomes from routinely created records is often necessary. A Zelen design requires a waiver of the usual requirement for informed consent prior to random assignment of treatment. The Revised Common Rule includes specific criteria for such a waiver, and those criteria are most often met for evaluation of a low-risk and potentially beneficial intervention added to usual care. Investigators and Institutional Review Boards must also consider whether the scientific or public health benefit of a Zelen design trial outweighs the autonomy interests of potential participants. Analysis of Zelen trials compares outcomes according to original assignment, regardless of any refusal to accept or participate in the assigned treatment.

Conclusions
A Zelen design trial assesses the real-world consequences of a specific strategy to prompt or promote uptake of a specific treatment. While such trials are poorly suited to address explanatory or efficacy questions, they are often preferred for addressing pragmatic or policy questions.
Efficacy and safety of secukinumab in patients with giant cell arteritis: study protocol for a randomized, parallel group, double-blind, placebo-controlled phase II trial
Authors: Venhoff Nils , Schmidt Wolfgang A. , Lamprecht Peter , Tony Hans-Peter , App Christine , Sieder Christian , Legeler Carolin , Jentzsch Claudia , Thiel Jens 
Published: August 2021

Abstract
Background
One key pathological finding in giant cell arteritis (GCA) is the presence of interferon-gamma and interleukin (IL)-17 producing T helper (Th) 1 and Th17 cells in affected arteries. There is anecdotal evidence of successful induction and maintenance of remission with the monoclonal anti-IL-17A antibody secukinumab. Inhibition of IL-17A could therefore represent a potential new therapeutic option for the treatment of GCA.

Methods
This is a randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase II study in which patients, treating physicians, and the associated clinical staff as well as the sponsor clinical team are blinded. It is designed to evaluate efficacy and safety of secukinumab compared to placebo in combination with an open-label prednisolone taper regimen. Patients included are naïve to biological therapy and have newly diagnosed or relapsing GCA. Fifty patients are randomly assigned in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously at baseline, weeks 1, 2 and 3, and every 4 weeks from week 4. Patients in both treatment arms receive a 26-week prednisolone taper regimen. The study consists of a maximum 6-week screening period, a 52-week treatment period (including the 26-week tapering), and an 8-week safety follow-up, with primary and secondary endpoint assessments at week 28. Patients who do not achieve remission by week 12 experience a flare after remission or cannot adhere to the prednisolone tapering will enter the escape arm and receive prednisolone at a dose determined by the investigator’s clinical judgment. The blinded treatment is continued. Two optional imaging sub-studies are included (ultrasound and contrast-media enhanced magnetic resonance angiography [MRA]) to assess vessel wall inflammation and occlusion before and after treatment. The primary endpoint is the proportion of patients in sustained remission until week 28 in the secukinumab group compared to the proportion of patients in the placebo group. A Bayesian approach is applied.

Discussion
The trial design allows the first placebo-controlled data collection on the efficacy and safety of secukinumab in patients with GCA.

Trial registration
ClinicalTrials.gov NCT03765788. Registration on 5 December 2018, prospective registration, EudraCT number 2018-002610-12; clinical trial protocol number CAIN457ADE11C.
Discrepancy between PCR based SARS-CoV-2 tests suggests the need to re-evaluate diagnostic assays
Authors: Mushtaq Muhammad Zain , Shakoor Sadia , Kanji Akbar , Shaheen Najma , Nasir Asghar , Ansar Zeeshan , Ahmed Imran , Mahmood Syed Faisal , Hasan Rumina , Hasan Zahra 
Published: August 2021

Abstract
Objective
We investigated the discrepancy between clinical and PCR-based diagnosis of COVID-19. We compared results of ten patients with mild to severe COVID-19. Respiratory samples from all cases were tested on the Roche SARS-CoV-2 (Cobas) assay, Filmarray RP2.1 (bioMereiux) and TaqPath™ COVID19 (Thermofisher) PCR assays.

Results
Laboratory records of ten patients with mild to severe COVID-19 were examined. Initially, respiratory samples from the patients were tested as negative on the SARS-CoV-2 Roche® assay. Further investigation using the BIOFIRE® Filmarray RP2.1 assay identified SARS-CoV-2 as the pathogen in all ten cases. To investigate possible discrepancies between PCR assays, additional testing was conducted using the TaqPath™ COVID19 PCR. Eight of ten samples were positive for SARS-CoV-2 on the TaqPath assay. Further, Spike gene target failures (SGTF) were identified in three of these eight cases. Discrepancy between the three PCR assays could be due to variation in PCR efficiencies of the amplification reactions or, variation at primer binding sites. Strains with SGTF indicate the presence of new SARS-CoV-2 variant strains. Regular modification of gene targets in diagnostic assays may be necessary to maintain robustness and accuracy of SARS-CoV-2 diagnostic assays to avoid reduced case detection, under-surveillance, and missed opportunities for control.
Lipoprotein lipase hydrolysis products induce pro-inflammatory cytokine expression in triple-negative breast cancer cells
Authors: Tobin Alexandria J. , Noel Nicholas P. , Christian Sherri L. , Brown Robert J. 
Published: August 2021

Abstract
Objectives
Breast cancer cell growth and proliferation requires lipids for energy production, cell membrane synthesis, or as signaling molecules. Lipids can be delivered to cells by lipoprotein lipase (LPL), an extracellular lipase that hydrolyzes triacylglycerols and phospholipids from lipoproteins, that is expressed by adipose tissue and some breast cancer cell lines. Studies have shown that lipoprotein hydrolysis products induce pro-inflammatory cytokine secretion by endothelial cells. Thus, our objective was to determine if hydrolysis products generated by LPL from total lipoproteins can also promote pro-inflammatory cytokine secretion from breast cancer cells.

Results
Using cytokine arrays, we found that MDA-MB-231 cells increased secretion of seven cytokines in response to treatment with lipoprotein hydrolysis products. In contrast, MCF-7 cells showed decreased secretion of two cytokines. Expanding the analysis to additional cell lines by ELISA, we found increased secretion of TNF-α and IL-6 by MDA-MB-468 cells, and increased secretion of IL-4 by MDA-MB-468 and SKBR3 cells. The changes to cytokine secretion profiles of the breast cancer cell types examined, including the non-cancerous MCF-10a breast cells, were independent of increased cell metabolic activity. These results provide information on how lipoprotein hydrolysis products within the tumor microenvironment might affect breast cancer cell viability and progression.
Combination of white matter hyperintensities and Aβ burden is related to cognitive composites domain scores in subjective cognitive decline: the FACEHBI cohort
Authors: Ortega G. , Espinosa A. , Alegret M. , Monté-Rubio GC. , Sotolongo-Grau O. , Sanabria A. , Tartari JP. , Rodríguez-Gómez O. , Marquié M. , Vivas A. , Gómez-Chiari M. , Alarcón-Martín E. , Pérez-Cordón A. , Roberto N. , Hernández I. , Rosende-Roca M. , Vargas L. , Mauleón A. , Abdelnour C. , Esteban De Antonio E. , López-Cuevas R. , Alonso-Lana S. , Moreno-Grau S. , de Rojas I. , Orellana A. , Montrreal L. , Tárraga L. , Ruiz A. , Boada M. , Valero S. ,   FACEHBI group, Aguilera N. , Alonso-Lana S. , Berthier M. , Buendia M. , Bullich S. , Campos F. , Cañabate P. , Cañada L. , Cuevas C. , Diego S. , Gailhajenet A. , García P. , Giménez J. , Gismondi R. , Guitart M. , Ibarria M. , Lafuente A. , Lomeña F. , Masip E. , Martín E. , Martínez J. , Moreno M. , Niñerola A. , Nogales A. B. , Núñez L. , Páez A. , Pancho A. , Pelejà E. , Pérez-Grijalba V. , Perissinotti A. , Pesini P. , Preckler S. , Roé-Vellvé N. , Romero J. , Ramis M. I. , Sarasa M. , Tejero M. A. , Torres M. 
Published: August 2021

AbstractBackgroundTo explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aβ) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD).MethodsTwo hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI),18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables.ResultsAdjusted multiple linear regression models showed that FreeSurfer (B − .245; 95% CI − .1.676, − .393,p = .016) and β burden (SUVR) (B − .180; 95% CI − 2.140, − .292;p = .070) were associated with face–name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face–name associative performance indicated that those individuals with either higher WMH load or higher Aβ burden showed the worst performance on the face–name associative memory CCs domain score.ConclusionsOur results suggest that increased WMH load and increased Aβ are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.