bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL
Authors: Zhao Yaqi , Aldoss Ibrahim , Qu Chunxu , Crawford Jeremy Chase , Gu Zhaohui , Allen Emma K. , Zamora Anthony E. , Alexander Thomas B. , Wang Jeremy , Goto Hiroaki , Imamura Toshihiko , Akahane Koshi , Marcucci Guido , Stein Anthony S. , Bhatia Ravi , Thomas Paul G. , Forman Stephen J. , Mullighan Charles G. , Roberts Kathryn G. 
Published: September 2020

Abstract
Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome–like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19− relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19− relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.
Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice
Authors: Perkins Lydia A. , Nyiranshuti Lea , Little-Ihrig Lynda , Latoche Joseph D. , Day Kathryn E. , Zhu Qin , Tavakoli Sina , Sundd Prithu , Novelli Enrico M. , Anderson Carolyn J. 
Published: September 2020

Abstract
In sickle cell disease (SCD), very late antigen-4 (VLA-4 or integrin α4β1) mediates the adhesion of reticulocytes to inflamed, proinflammatory endothelium, a key process in promoting vaso-occlusive episodes (VOEs). We hypothesized that a radionuclide tracer targeting VLA-4 could be harnessed as a positron emission tomography (PET) imaging biomarker of VOEs. We tested the VLA-4 peptidomimetic PET tracer 64Cu-CB-TE1A1P-PEG4-LLP2A (64Cu-LLP2A) for imaging hyper-adhesion–associated VOEs in the SCD Townes mouse model. With lipopolysaccharide (LPS)-induced VOEs, 64Cu-LLP2A uptake was increased in the bone marrow of the humeri and femurs, common sites of VOEs in SCD mice compared with non-SCD mice. Treatment with a proven inhibitor of VOEs (the anti-mouse anti-P-selectin monoclonal antibody [mAb] RB40.34) during LPS stimulation led to a reduction in the uptake of 64Cu-LLP2A in the humeri and femurs to baseline levels, implying blockade of VOE hyper-adhesion. Flow cytometry with Cy3-LLP2A demonstrated an increased percentage of VLA-4–positive reticulocytes in SCD vs non-SCD mice in the bone and peripheral blood after treatment with LPS, which was abrogated by anti-P-selectin mAb treatment. These data, for the first time, show in vivo imaging of VLA-4–mediated hyper-adhesion, primarily of SCD reticulocytes, during VOEs. PET imaging with 64Cu-LLP2A may serve as a valuable, noninvasive method for identifying sites of vaso-occlusion and may provide an objective biomarker of disease severity and anti-P-selectin treatment efficacy in patients with SCD.
Genomic differentiation across the speciation continuum in three hummingbird species pairs
Authors: Henderson Elisa C. , Brelsford Alan 
Published: September 2020

Abstract
Background
The study of speciation has expanded with the increasing availability and affordability of high-resolution genomic data. How the genome evolves throughout the process of divergence and which regions of the genome are responsible for causing and maintaining that divergence have been central questions in recent work. Here, we use three pairs of species from the recently diverged bee hummingbird clade to investigate differences in the genome at different stages of speciation, using divergence times as a proxy for the speciation continuum.

Results
Population measures of relative differentiation between hybridizing species reveal that different chromosome types diverge at different stages of speciation. Using FST as our relative measure of differentiation we found that the sex chromosome shows signs of divergence early in speciation. Next, small autosomes (microchromosomes) accumulate highly diverged genomic regions, while the large autosomes (macrochromosomes) accumulate genomic regions of divergence at a later stage of speciation.

Conclusions
Our finding that genomic windows of elevated FST accumulate on small autosomes earlier in speciation than on larger autosomes is counter to the prediction that FST increases with size of chromosome (i.e. with decreased recombination rate), and is not represented when weighted average FST per chromosome is compared with chromosome size. The results of this study suggest that multiple chromosome characteristics such as recombination rate and gene density combine to influence the genomic locations of signatures of divergence.
De novo transcriptome assembly and population genetic analyses of an important coastal shrub, Apocynum venetum L
Authors: Yuan Na , Li Mimi , Jia Chunlin 
Published: September 2020

Abstract
Background
Apocynum venetum L. is an important medicinal plant that is mainly distributed in the coastal areas and northwest of China. In addition to its high medical and economic value, its adaptation to saline-alkali and coastal saline lands makes A. venetum an ideal candidate for use in vegetation restoration. To date, the study of A. venetum has been limited in the northwest region of China, little attention has been paid to the genetic diversity and population structure of A. venetum populations in the coastal region. Here, we performed transcriptome sequencing of total RNA from A. venetum leaves and developed efficient expressed sequence tag-simple sequence repeat (EST-SSR) markers for analyzing the genetic diversity and population structure of A. venetum in the coastal region.

Results
A total of 86,890 unigenes were generated after de novo assembly, and 68,751 of which were successfully annotated by searching against seven protein databases. Furthermore, 14,072 EST-SSR loci were detected and 10,243 primer pairs were successfully designed from these loci. One hundred primer pairs were randomly selected and synthesized, twelve primer pairs were identified as highly polymorphic and further used for population genetic analysis. Population genetic analyses showed that A. venetum exhibited low level of genetic diversity (mean alleles per locus, NA = 3.3; mean expected heterozygosity, HE = 0.342) and moderate level of genetic differentiation among the populations (genetic differentiation index, FST = 0.032–0.220) in the coastal region. Although the contemporary (mean mc = 0.056) and historical (mean mh = 0.106) migration rates among the six A. venetum populations were moderate, a decreasing trend over the last few generations was detected. Bayesian structure analysis clustered six populations into two major groups, and genetic bottlenecks were found to have occurred in two populations (QG, BH).

Conclusions
Using novel EST-SSR markers, we evaluated the genetic variation of A. venetum in the coastal region and determined conservation priorities based on these findings. The large dataset of unigenes and SSRs identified in our study, combining samples from a broader range, will support further research on the conservation and evolution of this important coastal plant and its related species.
Ultrasound-guided versus Shikani optical stylet-aided tracheal intubation: a prospective randomized study
Authors: Ma Yuanyuan , Wang Yan , Shi Ping , Cao Xue , Ge Shengjin 
Published: September 2020

Abstract
Background
To compare ultrasound-guided tracheal intubation (UGTI) versus Shikani optical stylet (SOS)-aided tracheal intubation in patients with anticipated normal airway.

Methods
Sixty patients aged 18–65 years old who presented for elective surgery under general anesthesia were recruited in this prospective randomized study. They were assigned into two equal groups, either an ultrasound-guided group (Group UG, n = 30) or an SOS-aided group (Group SOS, n = 30). After the induction of anesthesia, the tracheal intubation was performed by a specified skilled anesthesiologist. The number of tracheal intubation attempt and the duration of successful intubation on the first attempt were recorded. Complications relative to tracheal intubation including desaturation, hoarseness and sore throat were also recorded.

Results
The first-attempt success rate is 93.3% (28/30) in Group UG and 90% (27/30) in Group SOS (P = 0.640). The second-attempt was all successful for the 2 and 3 patients left in the two groups, and the overall success rate of both groups was 100%. The duration of successful intubation on the first attempt of Group UG was not significantly different from that of Group SOS (34.0 ± 20.8 s vs 35.5 ± 23.2 s, P = 0.784). One patient in Group SOS had desaturation (P = 0.313), and there was none hoarseness in the two groups. Sore throat was detected in both group (4 in Group UG, 5 in Group SOS, P = 0.718).

Conclusion
Ultrasound-guided tracheal intubation was as effective as Shikani optical stylet-aided tracheal intubation in adult patients with anticipated normal airway.

Trial registration
Chinese Clinical Trial Registry, ChiCTR-IIC-17010875. Date of Registration: 15 March 2017.
The low fresh gas flow anesthesia and hypothermia in neonates undergoing digestive surgeries: a retrospective before-after study
Authors: Cui Yu , Wang Yu , Cao Rong , Li Gen , Deng Lingmei , Li Jia 
Published: September 2020

Abstract
Background
Based on the previous investigation in our institution, the incidence of intraoperative hypothermia in neonates was high. Since September 1st, 2019, the recommendation had been launched to utilize ≤1 L/min fresh gas flow during the neonates’ surgical procedure. We therefore intended to evaluate the association between low fresh gas flow anesthesia and the occurrence of hypothermia in neonates undergoing digestive surgeries.

Methods
A retrospective chart review, before-after study was conducted for neonates who underwent digestive surgeries. The primary outcomes were the incidence of hypothermia. The secondary outcomes included hospital mortality, the value of lowest temperature, blood loss, mean body temperature during the surgery, the length of hypothermia during the surgery and postoperative hospital length-of- stay (PLOS).

Results
249 neonates fulfilled the eligibility criteria. The overall incidence of intraoperative hypothermia was 81.9%. The low fresh gas flow anesthesia significantly reduced the odds of hypothermia [routine group: 149 (87.6%) versus low flow group: 55 (69.6%); p < 0.01]. Moreover, the low fresh gas flow anesthesia could reduce the length of hypothermia [routine group: 104 mins (50, 156) versus low flow group: 30 mins (0,100); p < 0.01], as well as elevate the value of lowest temperature for neonates [routine group: 35.1 °C (34.5, 35.7) versus low flow group: 35.7 °C (35.3, 36); p < 0.01]. After adjustment for confounding, low fresh gas flow anesthesia and the length of surgical time were independently associated with intraoperative hypothermia.

Conclusions
Low fresh gas flow anesthesia is an effective way to alleviate hypothermia in neonates undergoing open digestive surgery.
Quantification of myocardial strain in patients with isolated left ventricular non-compaction and healthy subjects using deformable registration algorithm: comparison with feature tracking
Authors: Liu Jia , Li Yumin , Cui Yue , Cao Yukun , Yao Sheng , Zhou Xiaoyue , Wetzl Jens , Zeng Wenjuan , Shi Heshui 
Published: September 2020

Abstract
Background
Systolic dysfunction of the left ventricle is frequently associated with isolated left ventricular non-compaction (iLVNC). Clinically, the ejection fraction (EF) is the primary index of cardiac function. However, changes of EF usually occur later in the disease course. Feature tracking (FT) and deformable registration algorithm (DRA) have become appealing techniques for myocardial strain assessment.

Methods
Thirty patients with iLVNC (36.7 ± 13.3 years old) and fifty healthy volunteers (42.3 ± 13.6 years old) underwent cardiovascular magnetic resonance (CMR) examination on a 1.5 T MR scanner. Strain values in the radial, circumferential, longitudinal directions were analyzed based on the short-axis and long-axis cine images using FT and DRA methods. The iLVNC patients were further divided based on the ejection fraction, into EF ≥ 50% group (n = 11) and EF < 50% group (n = 19). Receiver-operating-characteristic (ROC) analysis was performed to assess the diagnostic performance of the global strain values. Intraclass correlation coefficient (ICC) analysis was used to evaluate the intra- and inter-observer agreement.

Results
Global radial strain (GRS) was statistically lower in EF ≥ 50% group compared with control group [GRS (DRA)/% vs. controls: 34.6 ± 7.0 vs. 37.6 ± 7.2, P < 0.001; GRS (FT)/% vs. controls: 37.4 ± 13.2 vs. 56.9 ± 16.4, P < 0.01]. ROC analysis of global strain values derived from DRA and FT demonstrated high area under curve (range, 0.743–0.854). DRA showed excellent intra- and inter-observer agreement of global strain in both iLVNC patients (ICC: 0.995–0.999) and normal controls (ICC: 0.934–0.996). While for FT analysis, global radial strain of normal controls showed moderate intra-observer (ICC: 0.509) and poor inter-observer agreement (ICC: 0.394).

Conclusions
In patients with iLVNC, DRA can be used to quantitatively analyze the strain of left ventricle, with global radial strain being an earlier marker of LV systolic dysfunction. DRA has better reproducibility in evaluating both the global and segmental strain.
Potential associated factors of functional disability in Chinese older inpatients: a multicenter cross-sectional study
Authors: Liu Hongpeng , Jiao Jing , Zhu Chen , Zhu Minglei , Wen Xianxiu , Jin Jingfen , Wang Hui , Lv Dongmei , Zhao Shengxiu , Wu Xinjuan , Xu Tao 
Published: September 2020

Abstract
Background
There is still controversy about the relationship between aging and changes in functional ability. This study aims to describe the level of basic activities of daily living (ADL) and higher-level instrumental activities of daily living (IADL) in different age groups and explore the factors associated with functional disability in Chinese older inpatients.

Methods
This cross-sectional study surveyed 9996 older inpatients aged 65 years and older from six tertiary hospitals in China from October 2018 to February 2019. The levels of ADL and IADL were measured by scores of the Barthel index and Instrumental Activities of Daily Living Scale. A mixed-effect generalized linear model was used to examine the association between functional disability and covariates.

Results
The average ADL score was 89.51 ± 19.29 and the mean IADL score 6.76 ± 2.01 for all participants. There was a trend of decreasing scores along with aging, and significant differences between age groups were also observed (P < 0.001). The most affected ADL and IADL was stair climbing and shopping, respectively. Sociodemographic characteristics (such as age), physical health variables (frailty, emaciation, hearing dysfunction, urinary dysfunction, defecation dysfunction, falling accidents in the past 12 months), and mental health variables (cognitive dysfunction, depression) were associated with functional disability. Patients from the emergency department or transferred from other hospitals and former alcohol drinkers are at risk of ADL disability. Former smoking is a risk factor for IADL disability, whereas current drinking, higher-level education, and residing in a building without elevators were likely to maintain a better IADL performance.

Conclusions
Functional ability declines with aging, older inpatients are low dependency upon ADL and IADL. There are several associated factors among the participants derived from this investigation of a large-scale, multicenter, nationally representative Chinese older inpatient population. These findings potentially have major importance for the planning of hospital services, discharge planning, and post-discharge care.

Trial registration
Chinese Clinical Trial Registry, ChiCTR1800017682, registered August 9, 2018.
Rapid multiplex MinION nanopore sequencing workflow for Influenza A viruses
Authors: King Jacqueline , Harder Timm , Beer Martin , Pohlmann Anne 
Published: September 2020

Abstract
Background
Due to the frequent reassortment and zoonotic potential of influenza A viruses, rapid gain of sequence information is crucial. Alongside established next-generation sequencing protocols, the MinION sequencing device (Oxford Nanopore Technologies) has become a serious competitor for routine whole-genome sequencing. Here, we established a novel, rapid and high-throughput MinION multiplexing workflow based on a universal RT-PCR.

Methods
Twelve representative influenza A virus samples of multiple subtypes were universally amplified in a one-step RT-PCR and subsequently sequenced on the MinION instrument in conjunction with a barcoding library preparation kit from the rapid family and the MinIT performing live base-calling. The identical PCR products were sequenced on an IonTorrent platform and, after final consensus assembly, all data was compared for validation. To prove the practicability of the MinION-MinIT method in human and veterinary diagnostics, we sequenced recent and historical influenza strains for further benchmarking.

Results
The MinION-MinIT combination generated over two million reads for twelve samples in a six-hour sequencing run, from which a total of 72% classified as quality screened, trimmed and mapped influenza reads to produce full genome sequences. Identities between the datasets of > 99.9% were achieved, with 100% coverage of all segments alongside a sufficient confidence and 4492fold mean depth. From RNA extraction to finished sequences, only 14 h were required.

Conclusions
Overall, we developed and validated a novel and rapid multiplex workflow for influenza A virus sequencing. This protocol suits both clinical and academic settings, aiding in real time diagnostics and passive surveillance.
Modeling the relative role of human mobility, land-use and climate factors on dengue outbreak emergence in Sri Lanka
Authors: Zhang Ying , Riera Jefferson , Ostrow Kayla , Siddiqui Sauleh , de Silva Harendra , Sarkar Sahotra , Fernando Lakkumar , Gardner Lauren 
Published: September 2020

Abstract
Background
More than 80,000 dengue cases including 215 deaths were reported nationally in less than 7 months between 2016 and 2017, a fourfold increase in the number of reported cases compared to the average number over 2010–2016. The region of Negombo, located in the Western province, experienced the greatest number of dengue cases in the country and is the focus area of our study, where we aim to capture the spatial-temporal dynamics of dengue transmission.

Methods
We present a statistical modeling framework to evaluate the spatial-temporal dynamics of the 2016–2017 dengue outbreak in the Negombo region of Sri Lanka as a function of human mobility, land-use, and climate patterns. The analysis was conducted at a 1 km × 1 km spatial resolution and a weekly temporal resolution.

Results
Our results indicate human mobility to be a stronger indicator for local outbreak clusters than land-use or climate variables. The minimum daily temperature was identified as the most influential climate variable on dengue cases in the region; while among the set of land-use patterns considered, urban areas were found to be most prone to dengue outbreak, followed by areas with stagnant water and then coastal areas. The results are shown to be robust across spatial resolutions.

Conclusions
Our study highlights the potential value of using travel data to target vector control within a region. In addition to illustrating the relative relationship between various potential risk factors for dengue outbreaks, the results of our study can be used to inform where and when new cases of dengue are likely to occur within a region, and thus help more effectively and innovatively, plan for disease surveillance and vector control.
Association of retinal venular tortuosity with impaired renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing
Authors: O’Neill R. A. , Maxwell A. P. , Kee F. , Young I. , McGuinness B. , Hogg R. E. , GJ McKay 
Published: September 2020

Abstract
Background
Previous studies have identified retinal microvascular features associated with renal dysfunction. Biopsies are necessary to confirm kidney microvascular damage and retinal imaging may enable evaluation of microangiopathic characteristics reflecting renal changes associated with chronic kidney disease (CKD). We evaluated retinal microvascular parameters (RMPs) for associations with renal function in a cross-sectional analysis of the Northern Ireland Cohort for the Longitudinal Study of Ageing.

Methods
RMPs (central retinal arteriolar/ venular equivalents [CRAE/CRVE], arteriolar to venular ratio [AVR], fractal dimension and tortuosity) were measured from optic disc centred fundus images using semi-automated software. Associations were assessed with multivariable regression analyses between RMPs and estimated glomerular filtration rate (eGFR) defined by serum creatinine (eGFRscr) and cystatin C (eGFRcys) and also CKD status characterised by eGFR < 60 mL/min/1.73m2. Regression models were adjusted for potential confounders including age, sex, diabetes, smoking status, educational attainment, cardiovascular disease, body mass index, antihypertensive medication, systolic blood pressure, triglycerides, high- and low-density lipoprotein levels.

Results
Data were included for 1860 participants that had measures of renal function and retinal fundus images of sufficient quality for analysis. Participants had a mean age of 62.0 ± 8.5 yrs. and 53% were female. The mean eGFR for scr and cys were 82.2 ± 14.9 mL/min/1.73m2 and 70.7 ± 18.6 mL/min/1.73m2 respectively. eGFRcys provided lower estimates than eGFRscr resulting in a greater proportion of participants categorised as having CKD stages 3–5 (eGFRcys 26.8%; eGFRscr 7.9%). Multivariable regression analyses showed that increased venular tortuosity (OR = 1.30; 95%CI: 1.10, 1.54; P < 0.01) was associated with CKD stages 3–5 characterised by eGFRscr < 60 mL/min/1.73 m2. No additional associations between CKD status characterised by eGFRscr or with eGFRcys, were detected (P > 0.05). Multivariable regression failed to detect associations between CRAE, CRVE, AVR, fractal dimension or tortuosity and eGFRscr or eGFRcys (P > 0.05).

Conclusion
Increased retinal venular tortuosity was associated with CKD stages 3–5 defined by eGFRscr < 60 mL/min/1.73 m2, in an older population independent of potential confounding factors. These retinal measures may provide non-invasive microvascular assessment of associations with CKD.