bluuebunny/crossref_metadata_2025_split huggingface dataset:
An MRD-stratified pediatric protocol is as deliverable in adolescents and young adults as in children with ALL
Authors: Greenwood Matthew , Trahair Toby , Sutton Rosemary , Osborn Michael , Kwan John , Mapp Sally , Howman Rebecca , Anazodo Antoinette , Wylie Brenton , D’Rozario James , Hertzberg Mark , Irving Ian , Yeung David , Coyle Luke , Jager Amanda , Engeler Dan , Venn Nicola , Frampton Chris , Wei Andrew H. , Bradstock Kenneth , Dalla-Pozza Luciano 
Published: October 2021

Abstract
Pediatric regimens have improved outcomes in adolescent and young adult (AYA) acute lymphoblastic leukemia (ALL). However, results remain inferior to children with ALL. The Australasian Leukaemia and Lymphoma Group (ALLG) ALL06 study (anzctr.org.au/ACTRN12611000814976) was designed to assess whether a pediatric ALL regimen (Australian and New Zealand Children’s Haematology and Oncology Group [ANZCHOG] Study 8) could be administered to patients aged 15 to 39 years in a comparable time frame to children as assessed by the proportion of patients completing induction/consolidation and commencing the next phase of therapy (protocol M or high-risk [HR] treatment) by day 94. Minimal residual disease (MRD) response stratified patients to HR treatment and transplantation. From 2012 to 2018, a total of 86 patients were enrolled; 82 were eligible. Median age was 22 years (range, 16-38 years). Induction/consolidation was equally deliverable in ALL06 as in Study 8. In ALL06, 41.5% (95% confidence interval [CI], 30.7-52.9) commenced protocol M or HR therapy by day 94 vs 39.3% in Study 8 (P = .77). Median time to protocol M/HR treatment was 96 days (interquartile range, 87.5-103 days) in ALL06 vs 98 days in Study 8 (P = .80). Induction mortality was 3.6%. With a median follow-up of 44 months (1-96 months), estimated 3-year disease-free survival was 72.8% (95% CI, 62.8-82.7), and estimated 3-year overall survival was 74.9% (95% CI, 65.3-84.5). End induction/consolidation MRD negativity rate was 58.6%. Body mass index ≥30 kg/m2 and day 79 MRD positivity were associated with poorer disease-free survival and overall survival. Pediatric therapy was safe and as deliverable in AYA patients as in children with ALL. Intolerance of pediatric ALL induction/consolidation is not a major contributor to inferior outcomes in AYA ALL.
Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial
Authors: Woller Scott C. , Stevens Scott M. , Kaplan David , Wang Tzu-Fei , Branch D. Ware , Groat Danielle , Wilson Emily L. , Armbruster Brent , Aston Valerie T. , Lloyd James F. , Rondina Matthew T. , Elliott C. Greg 
Published: October 2021

Abstract
Thrombotic antiphospholipid syndrome (TAPS) is characterized by venous, arterial, or microvascular thrombosis. Patients with TAPS merit indefinite anticoagulation, and warfarin has historically been the standard treatment. Apixaban is an oral factor Xa inhibitor anticoagulant that requires no dose adjustment or monitoring. The efficacy and safety of apixaban compared with warfarin for TAPS patients remain unknown. This multicenter prospective randomized open-label blinded endpoint study assigned anticoagulated TAPS patients to apixaban or warfarin (target international normalized ratio 2-3) for 12 months. The primary efficacy outcome was clinically overt thrombosis and vascular death. Apixaban was first given at 2.5 mg twice daily. Two protocol changes were instituted based on recommendations from the data safety monitoring board. After the twenty-fifth patient was randomized, the apixaban dose was increased to 5 mg twice daily, and after the thirtieth patient was randomized, subjects with prior arterial thrombosis were excluded. Primary outcomes were adjudicated by independent experts blinded to treatment allocation. Patients randomized between 23 February 2015 and 7 March 2019 to apixaban (n = 23) or warfarin (n = 25) were similar. Among the components of the primary efficacy outcome, only stroke occurred in 6 of 23 patients randomized to apixaban compared with 0 of 25 patients randomized to warfarin. The study ended prematurely after the forty-eighth patient was enrolled. Conclusions from our study are limited due to protocol modifications and low patient accrual. Despite these limitations, our results suggest that apixaban may not be routinely substituted for warfarin to prevent recurrent thrombosis (especially strokes) among patients with TAPS. This trial was registered at www.clinicaltrials.gov as #NCT02295475.
Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multicenter cohort study
Authors: Carney Brian J. , Wang Tzu-Fei , Ren Siyang , George Gemlyn , Al Homssi Amer , Gaddh Manila , Connolly Gregory C. , Shah Vinay I. , Bogue Thomas , Bartosic Abigail , Neuberg Donna , Baumann Kreuziger Lisa , Zwicker Jeffrey I. ,   on behalf of the VENUS Network Investigators
Published: October 2021

Abstract
Venous thromboembolism (VTE) with concurrent thrombocytopenia is frequently encountered in patients with cancer. Therapeutic anticoagulation in the setting of thrombocytopenia is associated with a high risk of hemorrhage. Retrospective analyses suggest the utility of modified-dose anticoagulation in this population. To assess the incidence of hemorrhage or thrombosis according to anticoagulation strategy, we performed a prospective, multicenter, observational study. Patients with active malignancy, acute VTE, and concurrent thrombocytopenia (platelet count &lt;100 000/µL) were enrolled. The cumulative incidences of hemorrhage or recurrent VTE were determined considering death as a competing risk. Primary outcomes were centrally adjudicated and comparisons made according to initial treatment with full-dose or modified-dose anticoagulation. A total of 121 patients were enrolled at 6 hospitals. Seventy-five patients were initially treated with full-dose anticoagulation (62%) and 33 (27%) with modified-dose anticoagulation; 13 (11%) patients received no anticoagulation. Most patients who received modified-dose anticoagulation had a hematologic malignancy (31 of 33 [94%]) and an acute deep vein thrombosis (28 of 33 [85%]). In patients who initially received full-dose anticoagulation, the cumulative incidence of major hemorrhage at 60 days was 12.8% (95% confidence interval [CI], 4.9-20.8) and 6.6% (95% CI, 2.4-15.7) in those who received modified-dose anticoagulation (Fine-Gray hazard ratio, 2.18; 95% CI, 1.21-3.93). The cumulative incidence of recurrent VTE at 60 days in patients who initially received full-dose anticoagulation was 5.6% (95% CI, 0.2-11) and 0% in patients who received modified-dose anticoagulation. In conclusion, modified-dose anticoagulation appears to be a safe alternative to therapeutic anticoagulation in patients with cancer who develop deep vein thrombosis in the setting of thrombocytopenia.
Diffuse large B-cell lymphomas in adults with aberrant coexpression of CD10, BCL6, and MUM1 are enriched in IRF4 rearrangements
Authors: Frauenfeld Leonie , Castrejon-de-Anta Natalia , Ramis-Zaldivar Joan Enric , Streich Sebastian , Salmerón-Villalobos Julia , Otto Franziska , Mayer Annika Katharina , Steinhilber Julia , Pinyol Magda , Mankel Barbara , Ramsower Colleen , Bonzheim Irina , Fend Falko , Rimsza Lisa M. , Salaverria Itziar , Campo Elias , Balagué Olga , Quintanilla-Martinez Leticia 
Published: October 2021

Abstract
Diffuse large B-cell lymphoma (DLBCL) with aberrant coexpression of CD10+BCL6+MUM1+ (DLBCL-AE), classified as germinal center B cell (GCB) type by the Hans algorithm (HA), was genetically characterized. To capture the complexity of DLBCL-AE, we used an integrated approach that included gene expression profiling (GEP), fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. According to GEP, 32/54 (59%) cases were classified as GCB-DLBCL, 16/54 (30%) as activated B-cell (ABC) DLBCL, and 6/54 (11%) as unclassifiable. The discrepancy between HA and GEP was 41%. Three genetic subgroups were identified. Group 1 included 13/50 (26%) cases without translocations and mainly showing and ABC/MCD molecular profile. Group 2 comprised 11/50 (22%) cases with IRF4 alterations (DLBCL-IRF4), frequent mutations in IRF4 (82%) and NF-κB pathway genes (MYD88, CARD11, and CD79B), and losses of 17p13.2. Five cases each were classified as GCB- or ABC-type. Group 3 included 26/50 (52%) cases with 1 or several translocations in BCL2/BCL6/MYC/IGH, and GCB/EZB molecular profile predominated. Two cases in this latter group showed complex BCL2/BCL6/IRF4 translocations. DLBCL-IRF4 in adults showed a similar copy number profile and shared recurrent CARD11 and CD79B mutations when compared with LBCL-IRF4 in the pediatric population. However, adult cases showed higher genetic complexity, higher mutational load with frequent MYD88 and KMT2D mutations, and more ABC GEP. IRF4 mutations were identified only in IRF4-rearranged cases, indicating its potential use in the diagnostic setting. In conclusion, DLBCL-AE is genetically heterogeneous and enriched in cases with IRF4 alterations. DLBCL-IRF4 in adults has many similarities to the pediatric counterpart.
Improved detection of disease-associated gut microbes using 16S sequence-based biomarkers
Authors: Chrisman Brianna S. , Paskov Kelley M. , Stockham Nate , Jung Jae-Yoon , Varma Maya , Washington Peter Y. , Tataru Christine , Iwai Shoko , DeSantis Todd Z. , David Maude , Wall Dennis P. 
Published: October 2021

Abstract
Background
Sequencing partial 16S rRNA genes is a cost effective method for quantifying the microbial composition of an environment, such as the human gut. However, downstream analysis relies on binning reads into microbial groups by either considering each unique sequence as a different microbe, querying a database to get taxonomic labels from sequences, or clustering similar sequences together. However, these approaches do not fully capture evolutionary relationships between microbes, limiting the ability to identify differentially abundant groups of microbes between a diseased and control cohort. We present sequence-based biomarkers (SBBs), an aggregation method that groups and aggregates microbes using single variants and combinations of variants within their 16S sequences. We compare SBBs against other existing aggregation methods (OTU clustering and Microphenoor DiTaxa features) in several benchmarking tasks: biomarker discovery via permutation test, biomarker discovery via linear discriminant analysis, and phenotype prediction power. We demonstrate the SBBs perform on-par or better than the state-of-the-art methods in biomarker discovery and phenotype prediction.

Results
On two independent datasets, SBBs identify differentially abundant groups of microbes with similar or higher statistical significance than existing methods in both a permutation-test-based analysis and using linear discriminant analysis effect size. . By grouping microbes by SBB, we can identify several differentially abundant microbial groups (FDR <.1) between children with autism and neurotypical controls in a set of 115 discordant siblings. Porphyromonadaceae, Ruminococcaceae, and an unnamed species of Blastocystis were significantly enriched in autism, while Veillonellaceae was significantly depleted. Likewise, aggregating microbes by SBB on a dataset of obese and lean twins, we find several significantly differentially abundant microbial groups (FDR<.1). We observed Megasphaera andSutterellaceae highly enriched in obesity, and Phocaeicola significantly depleted. SBBs also perform on bar with or better than existing aggregation methods as features in a phenotype prediction model, predicting the autism phenotype with an ROC-AUC score of .64 and the obesity phenotype with an ROC-AUC score of .84.

Conclusions
SBBs provide a powerful method for aggregating microbes to perform differential abundance analysis as well as phenotype prediction. Our source code can be freely downloaded from http://github.com/briannachrisman/16s_biomarkers.
Identification and prediction of developmental enhancers in sea urchin embryos
Authors: Arenas-Mena César , Miljovska Sofija , Rice Edward J. , Gurges Justin , Shashikant Tanvi , Wang Zihe , Ercan Sevinç , Danko Charles G. 
Published: October 2021

Abstract
Background
The transcription of developmental regulatory genes is often controlled by multiple cis-regulatory elements. The identification and functional characterization of distal regulatory elements remains challenging, even in tractable model organisms like sea urchins.

Results
We evaluate the use of chromatin accessibility, transcription and RNA Polymerase II for their ability to predict enhancer activity of genomic regions in sea urchin embryos. ATAC-seq, PRO-seq, and Pol II ChIP-seq from early and late blastula embryos are manually contrasted with experimental cis-regulatory analyses available in sea urchin embryos, with particular attention to common developmental regulatory elements known to have enhancer and silencer functions differentially deployed among embryonic territories. Using the three functional genomic data types, machine learning models are trained and tested to classify and quantitatively predict the enhancer activity of several hundred genomic regions previously validated with reporter constructs in vivo.

Conclusions
Overall, chromatin accessibility and transcription have substantial power for predicting enhancer activity. For promoter-overlapping cis-regulatory elements in particular, the distribution of Pol II is the best predictor of enhancer activity in blastula embryos. Furthermore, ATAC- and PRO-seq predictive value is stage dependent for the promoter-overlapping subset. This suggests that the sequence of regulatory mechanisms leading to transcriptional activation have distinct relevance at different levels of the developmental gene regulatory hierarchy deployed during embryogenesis.
coreSCD: multi-stakeholder consensus on core outcomes for sickle cell disease clinical trials
Authors: Tambor Ellen , Robinson Matoya , Hsu Lewis , Chang Hsing-Yuan , Al Naber Jennifer ,   on behalf of the coreSCD Panel
Published: October 2021

Abstract
Background
With the dramatic increase in the pipeline for new sickle cell disease (SCD) therapies in recent years, the time is ripe to ensure a robust body of evidence is available for decision making by regulators, payers, clinicians, and patients. Harmonization of the outcomes selected across interventional trials enables optimal post-trial appraisal and decision making through valid pooled analyses and indirect comparisons. We employed a structured, multi-stakeholder consensus process to develop core outcome sets (COS) for use in clinical trials of SCD interventions.

Methods
CoreSCD utilized a modified Delphi method adapted from the standards recommended by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. An initial list of candidate outcomes was developed through a targeted literature review and input from an 11-member advisory committee. A 44-member multi-stakeholder Delphi Panel was established and included patients and family members, advocates, clinicians, researchers, payers, health technology assessors, representatives from government agencies, and industry representatives. Patients/advocates comprised 25% of the Delphi Panel and orientation and training was provided prior to the consensus process to ensure all were prepared to participate meaningfully. Panelists completed three rounds of an online survey to rate the importance of candidate outcomes for inclusion in the COS. Summary data was provided between each voting round and an in-person consensus meeting was held between the second and third round of voting. Consensus rules were applied following each round of voting to eliminate outcomes that did not meet predetermined criteria for retention.

Results
Consensus was reached for two core outcome sets. The final COS for trials of disease-modifying therapies includes ten outcomes and the COS for trials of acute interventions includes six outcomes. Both core sets include clinical outcomes as well as outcomes related to functioning/quality of life, resource utilization, and survival/mortality.

Conclusions
Use of the COS in clinical development programs for SCD will help to ensure that relevant, consistent outcomes are available for decision making across the product lifecycle.
Implementing advance care planning in early dementia care: results and insights from a pilot interventional trial
Authors: Bosisio Francesca , Sterie Anca-Cristina , Rubli Truchard Eve , Jox Ralf J. 
Published: October 2021

Abstract
Background
Advance care planning (ACP) is particularly appropriate for persons with early dementia (PWED) since it promotes conversations about dementia-specific illness scenarios, addresses inconsistencies between advance directives and patients’ observed behavior, emphasizes prospective and relational autonomy, and may be generally consistent with older persons’ decision-making needs. However, despite evidence of its benefits, ACP is yet to become widely used among PWED. In this paper, we present a dementia-specific tool developed in Western Switzerland, discuss results of a pilot trial designed to promote ACP among PWED and their relatives, and discuss the feasibility and acceptability of the intervention and the study protocol in prevision of a large scale trial.

Methods
This one-arm pre-post pilot trial consisted of four visits, with visits 2 and 3 being the ACP intervention. Quantitative outcome measures during visit 1 and 4 assessed the aptitude of the intervention to support PWED autonomy and relatives’ knowledge of PWED’s preferences. Feasibility was explored according to how the recruitment procedure unfurled and based on the necessary revisions to the study protocol and healthcare providers’ reason for excluding a PWED from the study. Acceptability was assessed according to pre-post evaluations, difficulties regarding the intervention or trial participation, and pre-post qualitative interviews regarding participants’ reasons to participate to the study, satisfaction with the tool and difficulties perceived.

Results
The ACP intervention itself was well received by PWED and their relatives that expressed satisfaction with the procedure, especially regarding the opportunity to discuss a sensitive topic with the help of a facilitator. Five main challenges in terms of feasibility were 1) to locate eligible patients, 2) to tailor recruitment procedures to recruitment locations, 3) to adapt inclusion criteria to clinical routines, 4) to engage PWED and their relatives in ACP, and 5) to design a trial that does not burden PWED. Despite these challenges, the intervention increased the number of advance directives, the concordance between PWED’s preferences and relatives’ decision on their behalf, and relatives’ perceived control over healthcare decisions.

Conclusion
Misconceptions about dementia and ACP, in the patient, relatives, and healthcare providers, combined with structural and institutional challenges, have the power to impede research and implementation of ACP in dementia care. For this reason, we conclude that a large scale trial to test a dementia-specific tool of ACP is currently not feasible in Western Switzerland and should be endorsed in a systemic approach of ACP.

Trial registration
This trial was registered in the database clinicaltrial.gov with the number NCT03615027.
Classification of moving coronary calcified plaques based on motion artifacts using convolutional neural networks: a robotic simulating study on influential factors
Authors: Dobrolińska Magdalena , van der Werf Niels , Greuter Marcel , Jiang Beibei , Slart Riemer , Xie Xueqian 
Published: October 2021

Abstract
Background
Motion artifacts affect the images of coronary calcified plaques. This study utilized convolutional neural networks (CNNs) to classify the motion-contaminated images of moving coronary calcified plaques and to determine the influential factors for the classification performance.

Methods
Two artificial coronary arteries containing four artificial plaques of different densities were placed on a robotic arm in an anthropomorphic thorax phantom. Each artery moved linearly at velocities ranging from 0 to 60 mm/s. CT examinations were performed with four state-of-the-art CT systems. All images were reconstructed with filtered back projection and at least three levels of iterative reconstruction. Each examination was performed at 100%, 80% and 40% radiation dose. Three deep CNN architectures were used for training the classification models. A five-fold cross-validation procedure was applied to validate the models.

Results
The accuracy of the CNN classification was 90.2 ± 3.1%, 90.6 ± 3.5%, and 90.1 ± 3.2% for the artificial plaques using Inception v3, ResNet101 and DenseNet201 CNN architectures, respectively. In the multivariate analysis, higher density and increasing velocity were significantly associated with higher classification accuracy (all P < 0.001). The classification accuracy in all three CNN architectures was not affected by CT system, radiation dose or image reconstruction method (all P > 0.05).

Conclusions
The CNN achieved a high accuracy of 90% when classifying the motion-contaminated images into the actual category, regardless of different vendors, velocities, radiation doses, and reconstruction algorithms, which indicates the potential value of using a CNN to correct calcium scores.
The impact of the COVID-19 Pandemic on rhegmatogenous retinal detachment treatment patterns
Authors: Li Jipeng , Zhao Meng , She Haicheng 
Published: October 2021

Abstract
Backgrounds
To describe changes in rhegmatogenous retinal detachment (RRD) surgical procedures in Beijing during the COVID-19 Pandemic.

Methods
A retrospective cohort of RRD patients was analyzed. Patients were divided into the COVID-19 pandemic group and pre-COVID-19 group according to their presentation. The presurgery characteristics, surgical procedures, and surgery outcomes were collected. The potential factors related to the choice of pars plana vitrectomy (PPV) or scleral buckling (SB) were analyzed using logistic regression. The differences in the procedure choice under specific conditions were compared. Surgery outcomes were compared between the two groups.

Results
In the COVID-19 pandemic group, less patients received SB (27.8, 41.3%, p = 0.02) while more patients received PPV (72.2, 58.6%, p = 0.02); in patients who received SB, fewer patients received subretinal fluid drainage (45.4,75.7%, p = 0.01); in patients who received PPV, fewer patients received phacovitrectomy (7.0, 21.0%, p = 0.02). The choice of PPV was related to older age (1.03, p = 0.005), the presence of RRD with choroidal detachment (RRD-CD) (2.92, p = 0.03), pseudophakia (5.0, p = 0.002), retinal breaks located posterior to the equator (4.87, p < 0.001), macular holes (9.76, p = 0.005), and a presurgery visual acuity (VA) less than 0.02 (0.44, p = 0.03). Fewer phakia patients with retinal breaks located posterior to the equator (1/28, 11/30, p = 0.01) and fewer patients with chronic RRD and subretinal strand (1/9, 9/16, p = 0.03) received SB in the COVID-19 pandemic group. There were more patients with improved VA (55.7, 40.2%, p = 0.03) in the COVID-19 pandemic group. The overall single-surgery retinal attachment rate was similar in the two groups (94.9, 94.5%, p = 0.99).

Conclusions
During the COVID-19 Pandemic, the main reason for the increased number of PPV in RRD treatment was that more complicated cases were presented. However, the surgeons were conservative in procedure choice in specific cases. The adjustments on RRD treatments lead to comparable surgery outcomes.