bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eligibility for PCSK9 inhibitors based on the 2019 ESC/EAS and 2018 ACC/AHA guidelines
Authors: Koskinas Konstantinos C , Gencer Baris , Nanchen David , Branca Mattia , Carballo David , Klingenberg Roland , Blum Manuel R , Carballo Sebastian , Muller Olivier , Matter Christian M , Lüscher Thomas F , Rodondi Nicolas , Heg Dik , Wilhelm Matthias , Räber Lorenz , Mach François , Windecker Stephan 
Published: July 2020

Abstract

Aims
The 2018 American College of Cardiology (ACC)/American Heart Association (AHA) and 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) lipid guidelines recently updated their recommendations regarding proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i). We assessed the potential eligibility for PCSK9i according to the new guidelines in patients with acute coronary syndromes.

Methods and results
We analysed a contemporary, prospective Swiss cohort of patients hospitalised for acute coronary syndromes. We modelled a statin intensification effect and an incremental ezetimibe effect on low-density lipoprotein-cholesterol levels among patients who were not on high-intensity statins or ezetimibe. One year after the index acute coronary syndrome event, treatment eligibility for PCSK9i was defined as low-density lipoprotein-cholesterol of 1.4 mmol/l or greater according to ESC/EAS guidelines. For ACC/AHA guidelines, treatment eligibility was defined as low-density lipoprotein-cholesterol of 1.8 mmol/l or greater in the presence of very high-risk atherosclerotic cardiovascular disease, defined by multiple major atherosclerotic cardiovascular disease events and/or high-risk conditions. Of 2521 patients, 93.2% were treated with statins (53% high-intensity statins) and 7.3% with ezetimibe at 1 year, and 54.9% had very high-risk atherosclerotic cardiovascular disease. Low-density lipoprotein-cholesterol levels less than 1.8 mmol/l and less than 1.4 mmol/l at 1 year were observed in 37.5% and 15.7% of patients, respectively. After modelling the statin intensification and ezetimibe effects, these numbers increased to 76.1% and 49%, respectively. The proportion of patients eligible for PCSK9i was 51% according to ESC/EAS criteria versus 14% according to ACC/AHA criteria.

Conclusions
In this analysis, the 2019 ESC/EAS guidelines rendered half of all post-acute coronary syndrome patients potentially eligible for PCSK9i treatment, as compared to a three-fold lower eligibility rate based on the 2018 ACC/AHA guidelines.
Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome
Authors: Sims Matthew C. , Mayer Louisa , Collins Janine H. , Bariana Tadbir K. , Megy Karyn , Lavenu-Bombled Cecile , Seyres Denis , Kollipara Laxmikanth , Burden Frances S. , Greene Daniel , Lee Dave , Rodriguez-Romera Antonio , Alessi Marie-Christine , Astle William J. , Bahou Wadie F. , Bury Loredana , Chalmers Elizabeth , Da Silva Rachael , De Candia Erica , Deevi Sri V. V. , Farrow Samantha , Gomez Keith , Grassi Luigi , Greinacher Andreas , Gresele Paolo , Hart Dan , Hurtaud Marie-Françoise , Kelly Anne M. , Kerr Ron , Le Quellec Sandra , Leblanc Thierry , Leinøe Eva B. , Mapeta Rutendo , McKinney Harriet , Michelson Alan D. , Morais Sara , Nugent Diane , Papadia Sofia , Park Soo J. , Pasi John , Podda Gian Marco , Poon Man-Chiu , Reed Rachel , Sekhar Mallika , Shalev Hanna , Sivapalaratnam Suthesh , Steinberg-Shemer Orna , Stephens Jonathan C. , Tait Robert C. , Turro Ernest , Wu John K. M. , Zieger Barbara ,   NIHR BioResource, Kuijpers Taco W. , Whetton Anthony D. , Sickmann Albert , Freson Kathleen , Downes Kate , Erber Wendy N. , Frontini Mattia , Nurden Paquita , Ouwehand Willem H. , Favier Remi , Guerrero Jose A. 
Published: July 2020

Abstract
Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.
Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia
Authors: Nishii Rina , Baskin-Doerfler Rebekah , Yang Wentao , Oak Ninad , Zhao Xujie , Yang Wenjian , Hoshitsuki Keito , Bloom Mackenzie , Verbist Katherine , Burns Melissa , Li Zhenhua , Lin Ting-Nien , Qian Maoxiang , Moriyama Takaya , Gastier-Foster Julie M. , Rabin Karen R. , Raetz Elizabeth , Mullighan Charles , Pui Ching-Hon , Yeoh Allen Eng-Juh , Zhang Jinghui , Metzger Monika L. , Klco Jeffery M. , Hunger Stephen P. , Newman Scott , Wu Gang , Loh Mignon L. , Nichols Kim E. , Yang Jun J. 
Published: July 2020

Abstract
There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.
Phase 2 study of pembrolizumab for measurable residual disease in adults with acute lymphoblastic leukemia
Authors: Cassaday Ryan D. , Garcia Kelsey-Leigh A. , Fromm Jonathan R. , Percival Mary-Elizabeth M. , Turtle Cameron J. , Nghiem Paul T. , Stevenson Phillip A. , Estey Elihu H. 
Published: July 2020

Abstract
The presence of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) confers a poor prognosis. CD19-targeted immunotherapy is effective against MRD but is logistically challenging, potentially toxic, and not applicable to T-cell ALL. We thus hypothesized that inhibition of PD-1 with pembrolizumab could also be effective for MRD, but without lineage restriction. The primary objective of this phase 2 study was to evaluate the efficacy of pembrolizumab in patients with ALL and MRD. Key eligibility criteria included adults with B- or T-cell ALL and MRD detectable by multiparameter flow cytometry or quantitative polymerase chain reaction from bone marrow aspirate (BMA) despite chemotherapy (plus ABL kinase inhibitor if Philadelphia chromosome positive). Pembrolizumab 200 mg IV was given every 3 weeks. Response was assessed by BMA using methods that previously detected MRD. The primary end point was complete MRD response rate. We stopped enrollment early; only 1 of 12 (8%) experienced a complete MRD response, which lasted 3 weeks. Interestingly, this patient had previously received hematopoietic cell transplantation and CD19-targeted chimeric antigen receptor–modified T-cell therapy and was the only patient to experience an immune-related adverse event from pembrolizumab (grade 3 Stevens-Johnson syndrome). Median overall survival from enrollment was 12.7 months. In summary, pembrolizumab had minimal activity against MRD but was generally well tolerated. These data can be compared with ongoing anti-PD-1 combination studies in ALL, and they further establish the role of trials specifically for patients with MRD. This trial was registered at www.clinicaltrials.gov as #NCT02767934.
Seed characterization and early nitrogen metabolism performance of seedlings from Altiplano and coastal ecotypes of Quinoa
Authors: Pinto-Irish Katherine , Coba de la Peña Teodoro , Ostria-Gallardo Enrique , Ibáñez Cristian , Briones Vilbett , Vergara Alexander , Alvarez Rodrigo , Castro Catalina , Sanhueza Carolina , Castro Patricio A. , Bascuñán-Godoy Luisa 
Published: July 2020

Abstract
Background
Early seed germination and a functional root system development during establishment are crucial attributes contributing to nutrient competence under marginal nutrient soil conditions. Chenopodium quinoa Willd (Chenopodiaceae) is a rustic crop, able to grow in marginal areas. Altiplano and Coastal/Lowlands are two representative zones of quinoa cultivation in South America with contrasting soil fertility and edaphoclimatic conditions.
In the present work, we hypothesize that the ecotypes of Quinoa from Altiplano (landrace Socaire) and from Coastal/Lowland (landrace Faro) have developed differential adaptive responses in order to survive under conditions of low availability of N in their respective climatic zones of Altiplano and Lowlands. In order to understand intrinsic differences for N competence between landraces, seed metabolite profile and germinative capacity were studied. Additionally, in order to elucidate the mechanisms of N uptake and assimilation at limiting N conditions during establishment, germinated seeds of both landraces were grown at either sufficient nitrate (HN) or low nitrate (LN) supply. We studied the photosynthetic performance, protein storage, root morphometrical parameters, activity and expression of N-assimilating enzymes, and the expression of nitrate transporters of roots in plants submitted to the different treatments.

Results
Seeds from Socaire landrace presented higher content of free N-related metabolites and faster seed germination rate compared to Faro landrace. Seedlings of both ecotypes presented similar physiological performance at HN supply, but at LN supply their differences were exalted. At LN, Socaire plants showed an increased root biomass (including a higher number and total length of lateral roots), a differential regulation of a nitrate transporter (a NPF6.3-like homologue) belonging to the Low Affinity Transport System (LATS), and an upregulation of a nitrate transporter (a NRT2.1-like homologue) belonging to the High Affinity nitrate Transport System (HATS) compared to Faro. These responses as a whole could be linked to a higher amount of stored proteins in leaves, associated to an enhanced photochemical performance in Altiplano plants, in comparison to Lowland quinoa plants.

Conclusions
These differential characteristics of Socaire over Faro plants could involve an adaptation to enhanced nitrate uptake under the brutal unfavorable climate conditions of Altiplano.
How do people in China think about causes of their back pain? A predominantly qualitative cross-sectional survey
Authors: Li YiJun , Coppieters Michel W. , Setchell Jenny , Hodges Paul W. , Scholten-Peeters Gwendolyne G. M. 
Published: July 2020

Abstract
Background
Low back pain (LBP) is the second highest cause of health burden in China. Delayed recovery, poor clinical outcomes and persistence of LBP are associated with negative pain beliefs about LBP. Chinese philosophies are nested into the daily life of people in China, which is likely to influence pain beliefs. However, there is lack of knowledge about people’s discourses regarding their LBP in China. The primary aim of this study was to explore the discourses underlying the beliefs of people in China about what causes their persistent or recurrent LBP. The secondary aim was to investigate the sources of these pain beliefs.

Methods
People (n = 152) from South Central, East and North Mainland China with LBP completed an online survey about what they believed caused their persistent or recurrent LBP and where these understandings came from. Potential causes of persistent or recurrent LBP were explored qualitatively using discourse analysis. The sources of these discourses were assessed by descriptive statistics with conventional content analysis.

Results
Five discourses were identified to underpin participants’ beliefs about what caused their persistent or recurrent LBP, namely: (1) biomedical problems (66.4%), (2) unbalanced lifestyle (48.7%), (3) menstruation and ‘kidney’ status (9.2%), (4) the ‘Five Elements’ imbalance (7.9%), and (5) energy status (5.9%). Most participants responded that their pain beliefs were based on information derived from healthcare professionals (59.2%), followed by the internet (24.3%) and family (23.0%).

Conclusions
People from moderately and well-developed parts of Mainland China think predominantly in line with a Western biomedical viewpoint about their LBP. Traditional Chinese medicine related pain beliefs mainly to the concept of ‘balance’ were evident on contemporary Chinese society’s understandings of LBP. These cultural beliefs could be relevant to consider in LBP management and involve healthcare professionals, family and patient in this process.
A feasibility study of individual 3D-printed navigation template for the deep external fixator pin position on the iliac crest
Authors: Liang Bin , Chen Qiang , Liu Shuai , Chen Shuo , Yao Qingqiang , Wei Bo , Xu Yan , Tang Cheng , Wang Liming 
Published: July 2020

AbstractBackgroundThe aim of this study was to investigate the feasibility of an individual navigation template for the deep pin position on the iliac crest, based on digital design and 3D printing technology.MethodsThe preoperative CT images of 8 patients with pelvic fractures were collected. The data were reconstructed using a 3D imaging reconstruction workstation. An individual navigation template for the deep pin position on the iliac crest was designed on a virtual 3D model. The individual drill template and the solid pelvic model were produced using the 3D printing technology. The individual drill template was used for intraoperative deep pin position on the iliac crest after the preoperative simulation was completed.ResultsThirty-two external fixator pins were inserted using the individual drill template. The average depth of pins was 84.82 mm. The trajectories were appropriate based on the postoperative X-ray and CT scan. No significant difference in the entry point, convergence angle, and caudal angle of the pins were noted before and after the operation (allP > 0.05). Finite element analysis indicated that the deep external fixator pin position could more reasonably distribute the stress in the cortical and spongy bones in the pelvis. All patients could perform partial weight-bearing activity 6 weeks postoperatively. No loosening and rupture of the pin, infection, and no damage of blood vessels and nervous tissue were found during the entire follow-up period.ConclusionsThe individual drill template technique is an improvement of the traditional technique, which could increase precision and the depth of pin position. In addition, good mechanical stability and low risk of pin-related complications occurred due to the individual drill template, which makes the external fixation technique a potential alternative.
Fixing tacks induced bladder erosion and recurrent stones following laparoscopic inguinal hernia repair: a case report
Authors: Liu Wan-Zhang , Qian Jun-Hai , Shen Zhi-Jiu , Yang Bin-Bin , Cheng Yue 
Published: July 2020

Abstract
Background
Hernia mesh erosion into the urinary bladder is a rare complication of hernioplasty, and mesh immigration is the most probable pathophysiology. There is no report describing mesh erosion induced by fixing tacks in inguinal hernia repair.

Case presentation
A 37-year-old man was admitted to our hospital with frequency, urgency and odynuria for 3 months. He received open right inguinal hernia repair in September 2014, and right laparoscopic hernioplasty for recurrence of the inguinal hernia in May 2015. In February 2019, he underwent a day-case transurethral cystoscopic operation for urethral and bladder stones. Cystoscopy revealed the existence of bladder stones and part of the eroded mesh on the right anterior wall, for which an open partial cystectomy was performed. The patient was followed up for 3 months postoperatively, during which no further mesh erosion or stone recurrence was detected by cystoscopy.

Conclusion
This is the first case report describing mesh erosion into the urinary bladder by fixing tacks following laparoscopic inguinal hernia repair. In such a case, the eroded mesh and tacks need to be removed completely, but the effectiveness of a single transurethral procedure needs to be verified in more cases.
LandmarkNet: a 2D digital radiograph landmark estimator for registration
Authors: Wang Zhen , Liu Cong , Ma Longhua 
Published: July 2020

Abstract
Background
Radiation therapy requires precision to target and escalate the doses to affected regions while reducing the adjacent normal tissue exposed to high radiotherapy doses. Image guidance has become the start of the art in the treating process. Registering the digital radiographs megavoltage x ray (MV-DRs) and the kilovoltage digital reconstructed radiographs (KV-DRRs) is difficult because of the poor quality of MV-DRs. We simplify the problem by registering between landmarks instead of entire image information, thence we propose a model to estimate the landmark accurately.

Methods
After doctors’ analysis, it is proved that it is effective to register through several physiological features such as spinous process, tracheal bifurcation, Louis angle. We propose the LandmarkNet, a novel keypoint estimation architecture, can automatically detect keypoints in blurred medical images. The method applies the idea of Feature Pyramid Network (FPN) twice to merge the cross-scale and cross-layer features for feature extraction and landmark estimation successively. Intermediate supervision is used at the end of the first FPN to ensure that the underlying parameters are updated normally. The network finally produces heatmap to display the approximate location of landmarks and we obtain accurate position estimation after non-maximum suppression (NMS) processing.

Results
Our method could obtain accurate landmark estimation in the dataset provided by several cancer hospitals and labeled by ourselves. The standard percentage of correct keypoints (PCK) within 8 pixels of estimation for the spinous process, tracheal bifurcation and Louis angle is 81.24%, 98.95% and 85.61% respectively. For the above three landmarks, the mean deviation between the predicted location of each landmark and corresponding ground truth is 2.38, 0.98 and 2.64 pixels respectively.

Conclusion
Landmark estimation based on LandmarkNet has high accuracy for different kinds of landmarks. Our model estimates the location of tracheal bifurcation especially accurately because of its obvious features. For the spinous process, our model performs well in quantity estimation as well as in position estimation. The wide application of our method assists doctors in image-guided radiotherapy (IGRT) and provides the possibility of precise treatment in the true sense.
Privately computing set-maximal matches in genomic data
Authors: Sotiraki Katerina , Ghosh Esha , Chen Hao 
Published: July 2020

Abstract
Background
Finding long matches in deoxyribonucleic acid (DNA) sequences in large aligned genetic sequences is a problem of great interest. A paradigmatic application is the identification of distant relatives via large common subsequences in DNA data. However, because of the sensitive nature of genomic data such computations without security consideration might compromise the privacy of the individuals involved.

Methods
The secret sharing technique enables the computation of matches while respecting the privacy of the inputs of the parties involved. This method requires interaction that depends on the circuit depth needed for the computation.

Results
We design a new depth-optimized algorithm for computing set-maximal matches between a database of aligned genetic sequences and the DNA of an individual while respecting the privacy of both the database owner and the individual. We then implement and evaluate our protocol.

Conclusions
Using modern cryptographic techniques, difficult genomic computations are performed in a privacy-preserving way. We enrich this research area by proposing a privacy-preserving protocol for set-maximal matches.
Genomic landscape in acute myeloid leukemia and its implications in risk classification and targeted therapies
Authors: Hou Hsin-An , Tien Hwei-Fang 
Published: July 2020

AbstractAcute myeloid leukemia (AML) is a heterogeneous hematologic malignancy in terms of clinical features, underlying pathogenesis and treatment outcomes. Recent advances in genomic techniques have unraveled the molecular complexity of AML leukemogenesis, which in turn have led to refinement of risk stratification and personalized therapeutic strategies for patients with AML. Incorporation of prognostic and druggable genetic biomarkers into clinical practice to guide patient-specific treatment is going to be the mainstay in AML therapeutics. Since 2017 there has been an explosion of novel treatment options to tailor personalized therapy for AML patients. In the past 3 years, the U.S. Food and Drug Administration approved a total of eight drugs for the treatment of AML; most specifically target certain gene mutations, biological pathways, or surface antigen. These novel agents are especially beneficial for older patients or those with comorbidities, in whom the treatment choice is limited and the clinical outcome is very poor. How to balance efficacy and toxicity to further improve patient outcome is clinically relevant. In this review article, we give an overview of the most relevant genetic markers in AML with special focus on the therapeutic implications of these aberrations.