bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral Blood Biomarkers Associated With Improved Functional Outcome in Patients With Chronic Left Ventricular Dysfunction: A Biorepository Evaluation of the FOCUS-CCTRN Trial
Authors: Chacon Alberty Lourdes , Perin Emerson C. , Willerson James T. , Gahremanpour Amir , Bolli Roberto , Yang Phillip C. , Traverse Jay H. , Lai Dejian , Pepine Carl J. , Taylor Doris A.
Published: September 2021

Cell therapy trials for heart failure (HF) have shown modest improvement; however, the mechanisms underlying improvement in some patients but not others are not well understood. Although immune cells are important in the course of HF, our understanding of the immune processes in HF is limited. The objective of this study was to evaluate associations between temporal changes in peripheral blood (PB) cell subpopulations and improved outcome in patients with chronic ischemic cardiomyopathy after bone marrow-derived mononuclear cell therapy or placebo in the FOCUS-CCTRN trial. Peripheral blood was collected at days 0, 1, 30, 90, and 180 from consented participants. We used flow cytometry to compare PB populations in patients with the best (cohort 1) or worst functional outcome (cohort 2) in three primary endpoints: left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption (VO2 max). A linear mixed model was used to assess changes over time in 32 cell populations. The difference between each time point and baseline was calculated as linear contrast. Compared with cohort 2, patients who improved (cohort 1) had a higher frequency of CD45+CD19+ B cells at days 0, 1, 90, and 180. CD11B+ cells increased over baseline at day 1 in both cohorts and remained higher in cohort 2 until day 30. CD45+CD133+ progenitor cells decreased over baseline at day 30 in cohort 1. We identified specific cell subpopulations associated with improved cardiac function in patients with chronic LV dysfunction. These findings may improve patient selection and prediction of outcomes in cell therapy trials.
Clustering Users Based on Hearing Aid Use: An Exploratory Analysis of Real-World Data
Authors: Pasta Alessandro , Szatmari Tiberiu-Ioan , Christensen Jeppe Høy , Jensen Kasper Juul , Pontoppidan Niels Henrik , Sun Kang , Larsen Jakob Eg
Published: September 2021

While the assessment of hearing aid use has traditionally relied on subjective self-reported measures, smartphone-connected hearing aids enable objective data logging from a large number of users. Objective data logging allows to overcome the inaccuracy of self-reported measures. Moreover, data logging enables assessing hearing aid use with a greater temporal resolution and longitudinally, making it possible to investigate hourly patterns of use and to account for the day-to-day variability. This study aims to explore patterns of hearing aid use throughout the day and assess whether clusters of users with similar use patterns can be identified. We did so by analyzing objective hearing aid use data logged from 15,905 real-world users over a 4-month period. Firstly, we investigated the daily amount of hearing aid use and its within-user and between-user variability. We found that users, on average, used the hearing aids for 10.01 h/day, exhibiting a substantial between-user (SD = 2.76 h) and within-user (SD = 3.88 h) variability. Secondly, we examined hearing aid use hourly patterns by clustering 453,612 logged days into typical days of hearing aid use. We identified three typical days of hearing aid use: full day (44% of days), afternoon (27%), and sporadic evening (26%) day of hearing aid use. Thirdly, we explored the usage patterns of the hearing aid users by clustering the users based on the proportion of time spent in each of the typical days of hearing aid use. We found three distinct user groups, each characterized by a predominant (i.e., experienced ~60% of the time) typical day of hearing aid use. Notably, the largest user group (49%) of users predominantly had full days of hearing aid use. Finally, we validated the user clustering by training a supervised classification ensemble to predict the cluster to which each user belonged. The high accuracy achieved by the supervised classifier ensemble (~86%) indicated valid user clustering and showed that such a classifier can be successfully used to group new hearing aid users in the future. This study provides a deeper insight into the adoption of hearing care treatments and paves the way for more personalized solutions.
Intermediate- and Deep-Water Oxygenation History in the Subarctic North Pacific During the Last Deglacial Period
Authors: Ovsepyan Ekaterina , Ivanova Elena , Tetard Martin , Max Lars , Tiedemann Ralf
Published: September 2021

Deglacial dissolved oxygen concentrations were semiquantitatively estimated for intermediate and deep waters in the western Bering Sea using the benthic foraminiferal-based transfer function developed by Tetard et al. (2017), Tetard et al. (2021a). Benthic foraminiferal assemblages were analyzed from two sediment cores, SO201-2-85KL (963 m below sea level (mbsl), the intermediate-water core) and SO201-2-77KL (2,163 mbsl, the deep-water core), collected from the Shirshov Ridge in the western Bering Sea. Intermediate waters were characterized by an oxygen content of ∼2.0 ml L−1 or more during the Last Glacial Maximum (LGM)–Heinrich 1 (H1), around 0.15 ml L−1 during the middle Bølling/Allerød (B/A)–Early Holocene (EH), and a slight increase in [O2] (∼0.20 ml L−1) at the beginning of the Younger Dryas (YD) mbsl. Deep-water oxygen concentrations ranged from 0.9 to 2.5 ml L−1 during the LGM–H1, hovered around 0.08 ml L−1 at the onset of B/A, and were within the 0.30–0.85 ml L−1 range from the middle B/A to the first half of YD and the 1.0–1.7 ml L−1 range from the middle to late Holocene. The [O2] variations remind the δ18O NGRIP record thereby providing evidence for a link between the Bering Sea oxygenation at intermediate depths and the deglacial North Atlantic climate. Changes in the deep-water oxygen concentrations mostly resemble the deglacial dynamics of the Southern Ocean upwelling intensity which is supposed to be closely coupled with the Antarctic climate variability. This coherence suggests that deglacial deep-water [O2] variations were primarily controlled by changes in the circulation of southern-sourced waters. Nevertheless, the signal from the south at the deeper site might be amplified by the Northern Hemisphere climate warming via an increase in sea-surface bioproductivity during the B/A and EH. A semi-enclosed position of the Bering Sea and sea-level oscillations might significantly contribute to the magnitude of oxygenation changes in the study area during the last deglaciation. Interregional correlation of different proxy data from a wide range of water depths indicates that deglacial oxygenation changes were more pronounced in the Bering and Okhotsk marginal seas than along the open-ocean continental margin and abyssal settings of the North Pacific.
Luminescence Dating of Relics in Ancient Cities Provides Absolute Dates for Understanding Human-Land Relationships in Qinghai Lake Basin, Northeastern Tibetan Plateau
Authors: Sun Manping , Sun Yongjuan , Wei Haicheng , Hou Guangliang , Xianba Ji , Xie Liqian , Zeng Yongxin , E Chongyi
Published: September 2021

The study of ancient city sites provides valuable evidence for understanding human-land relationships. Qinghai Lake Basin, on the northeastern Tibetan Plateau, was a key location for economic and cultural exchanges between East and West in ancient China and archaeological surveys have identified the remains of many ancient cities. Although there are relatively good historical records for some ancient cities, their absolute ages are still unclear due to a lack of systematic chronological dating. In this study, OSL dating of ceramic and tile remains from three ancient cities in Qinghai Lake Basin, Xihaijun (XHJGC), Beixiangyang (BXYGC), and Fuxi (FSC), was combined with documentary and paleoclimate evidence to investigate historical human-land relationships. Relics from XHJGC and BXYGC were dated to 0–220 AD, in the Han Dynasty, while tiles from FSC were dated to 120–520 AD, largely corresponding to the Wei Jin Southern and Northern Dynasties. Luminescence ages were generally consistent with dates recorded in historical documents, indicating that the OSL method can be reliably used to date buried tiles in ancient cities on the northeastern Tibetan Plateau. Comparing the dates with paleoclimatic records suggests that the warm and humid climate at c. 2 ka was an important driver of immigration to the region that led to the construction of cities in the Qinghai Lake area during the late Western Han Dynasty. During the Wei Jin Southern and Northern Dynasties (220–589 AD), communication between East and the West flourished, and human activities in the area were strong with the continuation of the war in Central China and Hexi Corridor. Fuxi was largely abandoned in the later Wei Jin Southern and Northern Dynasties, although it was still used intermittently until the Ming Dynasty. Pollen records confirm that humans were extensively engaged in agricultural production in the Qinghai Lake area during the Wei Jin Southern and Northern Dynasties.
The Effect of Formation Water Salinity on the Minimum Miscibility Pressure of CO2-Crude Oil for Y Oilfield
Authors: Pi Yanfu , Liu Jinxin , Liu Li , Guo Xuan , Li Chengliang , Li Zhihao
Published: September 2021

CO2 miscible flooding is an important technology for enhancing oil recovery and greenhouse gas storage in the world. As a tertiary recovery technology, it is usually applied after water flooding. Therefore, the actual reservoirs usually contain a lot of injected water in addition to connate water. The salinity of these formation waters varies from place to place. CO2 is an acid gas. After it is injected into the reservoir, it easily reacts with formation water and rock and affects the physical properties of the reservoir. However, no research results have been reported whether this reaction affects the minimum miscibility pressure (MMP) of CO2-crude oil, a key parameter determining miscible flooding in formation water. Based on CO2-formation water–rock interaction experiments, this paper uses the core flooding method to measure the CO2-crude oil MMP under different salinity in formation water. Results show that CO2 causes a formation water pH decrease from 7.4 to 6.5 due to its dissolution in formation water. At the same time, CO2 reacts with formation water, albite, potassium feldspar, and carbonate minerals in the cores to generate silicate and carbonate precipitates, which could migrate to the pore throat together with the released clay particles. Overall, CO2 increased core porosity by 5.63% and reduced core permeability by 7.43%. In addition, when the salinity of formation water in cores was 0, 4,767, and 6,778 mg/L, the MMP of CO2-crude oil was 20.58, 19.85, and 19.32 MPa, respectively. In other words, the MMP of CO2-crude oil decreased with the increase of salinity of formation water.
An Operational Earthquake Forecasting Experiment for Israel: Preliminary Results
Authors: Falcone Giuseppe , Spassiani Ilaria , Ashkenazy Yosef , Shapira Avi , Hofstetter Rami , Havlin Shlomo , Marzocchi Warner
Published: September 2021

Operational Earthquake Forecasting (OEF) aims to deliver timely and reliable forecasts that may help to mitigate seismic risk during earthquake sequences. In this paper, we build the first OEF system for the State of Israel, and we evaluate its reliability. This first version of the OEF system is composed of one forecasting model, which is based on a stochastic clustering Epidemic Type Earthquake Sequence (ETES) model. For every day of the forecasting time period, January 1, 2016 - November 15, 2020, the OEF-Israel system produces a weekly forecast for target earthquakes with local magnitudes greater than 4.0 and 5.5 in the entire State of Israel. Specifically, it provides space-time-dependent seismic maps of the weekly probabilities, obtained by using a fixed set of the model’s parameters, which are estimated through the maximum likelihood technique based on a learning period of about 32 years (1983–2015). According to the guidance proposed by the Collaboratory for the Study of Earthquake Predictability (CSEP), we also perform the N- and S-statistical tests to verify the reliability of the forecasts. Results show that the OEF system forecasts a number of events comparable to the observed one, and also captures quite well the spatial distribution of the real catalog with the exception of two target events that occurred in low seismicity regions.
Sparse Constrained Least-Squares Reverse Time Migration Based on Kirchhoff Approximation
Authors: Hong-Qiao Xu , Xiao-Yi Wang , Chen-Yuan Wang , Jiang-Jie Zhang
Published: September 2021

Least-squares reverse time migration (LSRTM) is powerful for imaging complex geological structures. Most researches are based on Born modeling operator with the assumption of small perturbation. However, studies have shown that LSRTM based on Kirchhoff approximation performs better; in particular, it generates a more explicit reflected subsurface and fits large offset data well. Moreover, minimizing the difference between predicted and observed data in a least-squares sense leads to an average solution with relatively low quality. This study applies L1-norm regularization to LSRTM (L1-LSRTM) based on Kirchhoff approximation to compensate for the shortcomings of conventional LSRTM, which obtains a better reflectivity image and gets the residual and resolution in balance. Several numerical examples demonstrate that our method can effectively mitigate the deficiencies of conventional LSRTM and provide a higher resolution image profile.
Enhanced Quaternary Exhumation in the Central Three Rivers Region, Southeastern Tibet
Authors: Shen Xiaoming , Tian Yuntao , Wang Ying , Wu Lin , Jia Yingying , Tang Xiudang , Lei Haijia , Yuan Xiaoping , Ge Yukui , Liu-Zeng Jing
Published: September 2021

The roles of tectonics and climate in the global increased erosion rates during the Quaternary have been the subject of active debate. The Three Rivers Region, strongly influenced by continental convergence between India and Eurasia and change in Asian monsoon climate, is an ideal place to study the interactions between tectonics and surface processes. Here we report new apatite (U-Th)/He data from an elevation transect that reveal a phase of rapid exhumation since ∼2.6 Ma in the Dulong batholith in the central Three Rivers Region, southeastern Tibetan Plateau. Based on stream profile analysis and compiled thermochronological data in the region, we demonstrate that the tectonic uplift caused by the high-strain at the corner of Indian-Eurasia convergence is responsible for the enhanced exhumation in the central Three Rivers Region in the Quaternary. Our new results highlight that the continuous plate convergence towards the plateau interior has dominated the uplift and deformation in the southeastern Tibet in the Quaternary.
Program Design Principles to Support Teen-Adult Community Conservation Efforts
Authors: Cisneros Laura M. , Simmons Jonathan , Campbell Todd , Freidenfelds Nicole , Arnold Chester , Chadwick Cary , Dickson David , Moss David , Rodriguez Laura , Volin John C.
Published: September 2021

Researchers and practitioners have identified numerous outcomes of place-based environmental action (PBEA) programs at both individual and community levels (e.g., promoting positive youth development, fostering science identity, building social capital, and contributing to environmental quality improvement). In many cases, the primary audience of PBEA programs are youth, with less attention given to lifelong learners or intergenerational (e.g., youth and adult) partnerships. However, there is a need for PBEA programs for lifelong learners as local conservation decisions in the United States are often carried out by volunteer boards and commissions, which often have little formal conservation training. Intergenerational PBEA programs can provide an opportunity to bring together, in the case of this study, the unique skills and knowledge of teens (e.g., tech-savvy) and adults (e.g., knowledgeable of local community issues) that can lead to innovative ways of addressing real world endeavors that are relevant to participants and their communities.

This study describes a program model that offers structured learning opportunities that support intergenerational partnerships (teens and adults) as they contribute to community conservation efforts. We used a design-based research approach to develop and refine program design principles and communication pillars for the purpose of supporting successful teen-adult conservation projects, positive participant experiences, and science identity authoring. The principles and pillars drew on identity, cultural learning pathways, and community conservation research literature as well as previously collected participant interview data from our intergenerational PBEA program. We outline four design principles and four communication pillars that are critical to facilitate collaborative teen-adult environmental action efforts and serve dual functions of providing program guidance and participant support. The aim of these principles and pillars are to establish collaborative team partnership norms that resist traditional hierarchical teen-adult relationships. Further, the principles and pillars consider how partners can draw on their interests, experiences, and knowledge of community, and utilize these assets along with conservation science disciplinary practices to accomplish meaningful science pursuits; thus facilitating how they identify themselves as contributing to science endeavors. Exemplar data and literature that support each principle and pillar are provided, and future extensions of these principles are discussed.
Teachers’ Professional Vision: Teachers’ Gaze During the Act of Teaching and After the Event
Authors: Minarikova Eva , Smidekova Zuzana , Janik Miroslav , Holmqvist Kenneth
Published: September 2021

To date most of our knowledge on professional vision has relied on verbal data or questionnaires that used classroom videos as prompts. This has been used to tell us about a teacher’s professional vision. Recently, however, new studies explore professional vision during the act of teaching through the use of mobile eye-tracking. This novel approach poses the question: how do these two “professional visions” differ? Visual attention represented by gaze was used as a proxy to studying professional vision (specifically its noticing component). To achieve this, eye-tracking as a data collection method was used. We worked with three teachers and employed eye-tracking glasses to record teacher eye movements during teaching (4 lessons per teacher; labelled as IN mode). After each lesson, we selected short clips from the lesson recorded by a static camera aimed at pupils and showed them to the same teacher (i.e., providing a similar setting as traditional studies on professional vision) while recording eye movements and gaze behavior data through a screen-based eye-tracker (labelled as ON mode). The two modes differ and due to these differences, comparison is difficult. However, by overlaying them and describing them in detail we want to highlight the exact variance observed. A comparison between IN vs ON condition in terms of dwell time on the same students in either condition was made using both quantitative (correlation) and qualitative (timeline comparison) methods. The findings suggest that the greatest differences in attention given to individual pupils occur when a pupil who was interacted with during the situation is missing from the view in the video recording. Even though individual differences are present in the patterns of gaze in IN and ON modes, the teachers in our sample consistently monitored more pupils more often in the ON mode than in the IN mode. On the other hand, the IN mode was mostly characterized by focused gaze on the pupil that the teacher interacted with in the moment with few side glances. The results aim to open a discussion about our understanding of professional vision in different contexts and about how current research may need to expand its outlook.
Computational Design of an Integrated CMOS Readout Circuit for Sensing With Organic Field-Effect Transistors
Authors: Taheri H. Esmaeili , Ocheje Michael U. , St. Onge P. Blake J. , Rondeau-Gagné Simon , Mirhassani Mitra
Published: September 2021

Organic field-effect transistors (OFETs) are at the forefront of next generation electronics. This class of devices is particularly promising due to the possibility of fabrication on mechanically compliant and conformable substrates, and potential manufacturing at large scale through solution deposition techniques. However, their integration in circuits, especially using stretchable materials, is still challenging. In this work, the design and implementation of a novel structure for an integrated CMOS readout circuitry is presented and its fundamentals of operation are provided. Critical for sensing applications, the readout circuitry described is highly linear. Moreover, as several sources of mismatch and error are present in CMOS and OFET devices, a calibration technique is used to cancel out all the mismatches, thus delivering a reliable output. The readout circuit is verified in TSMC 0.18 μm CMOS technology. The maximum total power consumption in the proposed readout circuit is less than 571 μW, while fully loaded calibration circuit consumes a power less than 153 μW, making it suitable for sensors applications. Based on previously reported high mobility and stretchable semiconducting polymers, this new design and readout circuitry is an important step toward a broader utilization of OFETs and the design of stretchable sensors.
Phenotypic and Genetic Heterogeneity in a Thai Glucokinase MODY Family Reveals the Complexity of Young-Onset Diabetes
Authors: Thewjitcharoen Yotsapon , Wanothayaroj Ekgaluck , Krittiyawong Sirinate , Nakasatien Soontaree , Tsoi Tsz Fung , Lim Cadmon K. P. , Chan Juliana C. N. , Himathongkam Thep
Published: September 2021

Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY) is characterized by asymptomatic, non-progressive and fasting hyperglycemia, albeit not without phenotypic variability. We used next generation sequencing (NGS) to screen for 34 MODY genes in a non-obese person with familial young-onset diabetes followed by screening in 24 family members within three generations with varying presentations of young-onset diabetes and sensorineural hearing loss. The index patient was found to carry a paternally-inherited heterozygous missense variant (c.716 A>G) of GCK in exon 7 with amino acid change (Q239R). This variant was associated with phenotypic heterogeneity ranging from normal glucose tolerance to diabetes with complications amongst the siblings which might be modified by obesity and chronic hepatitis B infection. Two paternally-inherited variants of SLC29A3 encoding a nucleoside transporter protein and Apo-A1 genes also co-segregated with glucose and lipid traits. Co-occurrence of diabetes and deafness in maternal aunts led to discovery of WFS1 (Wolfram syndrome type 1) as a cause of non-syndromic deafness in multiple members of the maternal pedigree. Our findings highlight the complex causes of familial young-onset diabetes and the need of a multidisciplinary approach to interpret the clinical relevance of discoveries made by NGS in this era of genomic medicine.
Short and Long-Term Effects of Growth Hormone in Children and Adolescents With GH Deficiency
Authors: Ranke Michael B.
Published: September 2021

The syndrome of impaired GH secretion (GH deficiency) in childhood and adolescence had been identified at the end of the 19thcentury. Its non-acquired variant (naGHD) is, at childhood onset, a rare syndrome of multiple etiologies, predominantly characterized by severe and permanent growth failure culminating in short stature. It is still difficult to diagnose GHD and, in particular, to ascertain impaired GH secretion in comparison to levels in normally-growing children. The debate on what constitutes an optimal diagnostic process continues. Treatment of the GH deficitviareplacement with cadaveric pituitary human GH (pit-hGH) had first been demonstrated in 1958, and opened an era of therapeutic possibilities, albeit for a limited number of patients. In 1985, the era of recombinant hGH (r-hGH) began: unlimited supply meant that substantial long-term experience could be gained, with greater focus on efficacy, safety and costs. However, even today, the results of current treatment regimes indicate that there is still a substantial fraction of children who do not achieve adult height within the normal range. Renewed evaluation of height outcomes in childhood-onset naGHD is required for a better understanding of the underlying causes, whereby the role of various factors - diagnostics, treatment modalities, mode of treatment evaluation - during the important phases of child growth - infancy, childhood and puberty - are further explored.
Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors
Authors: März Juliane , Kurlbaum Max , Roche-Lancaster Oisin , Deutschbein Timo , Peitzsch Mirko , Prehn Cornelia , Weismann Dirk , Robledo Mercedes , Adamski Jerzy , Fassnacht Martin , Kunz Meik , Kroiss Matthias
Published: September 2021

Context

Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet.

Objective

Evaluation of quantitative metabolomics as a diagnostic tool for PPGL.

Design

Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study.

Patients

Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded.

Results

Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines.

By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling.

Conclusions

The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.
Comparison of 68Ga-DOTANOC and 18F-FDG PET-CT Scans in the Evaluation of Primary Tumors and Lymph Node Metastasis in Patients With Rectal Neuroendocrine Tumors
Authors: Zhou Zhihao , Wang Zhixiong , Zhang Bing , Wu Yanzhang , Li Guanghua , Wang Zhao
Published: September 2021

Background

Lymph node metastasis of rectal neuroendocrine tumors (RNETs) predicts poor prognosis. However, the assessment of lymph node metastasis remains a challenge. It has been reported that 68Ga-DOTANOC and 18F-FDG PET-CT scans could be employed in the work-up of rectal neuroendocrine tumors (RNETs). This study aimed to assess both tracers’ ability to identify primary tumors and lymph node (LN) metastasis in RNETs.

Methods

A total of 537 patients with RNETs were enrolled from January 2014 to January 2021. Both 68Ga-DOTANOC and 18F-FDG PET-CT scans were used to evaluate primary tumors and LN group metastasis. PET images were evaluated through visual and semiquantitative assessment. Receiver Operating Characteristics (ROC) curve analysis was used to investigate the performance of SUVmax of 68Ga-DOTANOC and 18F-FDG PET in predicting LN group metastasis.

Results

Fifty-two patients with preoperative 68Ga-DOTANOC with 18F-FDG PET-CT scans underwent endoscopic biopsy or dissection of the primary tumor, while 11 patients underwent rectal surgery together with regional LN dissection. For primary tumors, 68Ga-DOTANOC had a sensitivity of 89.58% and a positive predictive value (PPV) of 95.56% through visual assessment, while 18F-FDG PET-CT showed 77.08% sensitivity and 97.37% PPV. For the prediction of LN group metastasis, 68Ga-DOTANOC PET-CT had 77.78% sensitivity and 91.67% specificity, while 18F-FDG PET-CT had 38.89% sensitivity and 100% specificity according to visual assessment. The area under the ROC curves (AUC) for 68Ga-DOTANOC PET/CT was 0.852 (95%CI:0.723-0.981) with an optimal SUVmax cut-off value of 2.25, while the AUC for 18F-FDG PET were 0.664 (95%CI:0.415-0.799) with an optimal SUVmax cut-off value of 1.05.

Conclusions

This study showed that 68Ga-DOTANOC PET-CT was a promising tool for detecting LN metastasis in RNETs with high sensitivity and specificity in visual assessment and semiquantitative assessment, which was better than 18F-FDG PET-CT.
Web-Based Ultrasonic Nomogram Predicts Preoperative Central Lymph Node Metastasis of cN0 Papillary Thyroid Microcarcinoma
Authors: Huang Chunwang , Cong Shuzhen , Shang Shiyao , Wang Manli , Zheng Huan , Wu Suqing , An Xiuyan , Liang Zhaoqiu , Zhang Bo
Published: September 2021

Background

Many clinicians are facing the dilemma about whether they should apply the active surveillance (AS) strategy for managing Clinically Node-negative (cN0) PTMC patients in daily clinical practice. This research plans to construct a dynamic nomogram based on network, connected with ultrasound characteristics and clinical data, to predict the risk of central lymph node metastasis (CLNM) in cN0 PTMC patients before surgery.

Methods

A retrospective analysis of 659 patients with cN0 PTMC who had underwent thyroid surgery and central compartment neck dissection. Patients were randomly (2:1) divided into the development cohort (439 patients) and validation cohort (220 patients). The group least absolute shrinkage and selection operator (Group Lasso) regression method was used to select the ultrasonic features for CLNM prediction in the development cohort. These features and clinical data were screened by the multivariable regression analysis, and the CLNM prediction model and web-based calculator were established. Receiver operating characteristic, calibration curve, Clinical impact curve and decision curve analysis (DCA) were used to weigh the performance of the prediction model in the validation set.

Results

Multivariable regression analysis showed that age, tumor size, multifocality, the number of contact surface, and real-time elastography were risk factors that could predict CLNM. The area under the curve of the prediction model in the development and validation sets were 0.78 and 0.77, respectively, with good discrimination and calibration. A web-based dynamic calculator was built. DCA proved that the prediction model had excellent net benefits and clinical practicability.

Conclusions

The web-based dynamic nomogram incorporating US and clinical features was able to forecast the risk of preoperative CLNM in cN0 PTMC patients, and has good predictive performance. As a new observational indicator, NCS can provide additional predictive information.
Diagnostic Accuracy of Female Pelvic Ultrasonography in Differentiating Precocious Puberty From Premature Thelarche: A Systematic Review and Meta-analysis
Authors: Nguyen Nam Nhat , Huynh Linh Ba Phuong , Do Minh Duc , Yang Tien Yun , Tsai Meng-Che , Chen Yang-Ching
Published: September 2021

Background

The gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and may create an unpleasant experience for participants. Moreover, some overlaps may occur between PP and premature thelarche (PT) in the early stage of PP. Female pelvic ultrasonography may provide additional information to help differentiate PP from PT and subsequently initiate early treatment. In this study, we aimed to first directly compare pelvic ultrasonography parameters between PP and PT groups and secondly, investigate their diagnostic accuracy compared with the GnRH stimulation test.

Methods

A systematic search of the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed up to March 31, 2021. All types of studies, except for case reports and review articles, were included. The GnRH stimulation test was used to confirm PP diagnosis. Those whose organic conditions might cause PP were excluded. The mean, standard deviation, sensitivity, and specificity of each parameter were documented. Forest plots were constructed to display the estimated standardized mean differences (SMDs) from each included study and the overall calculations. A bivariate model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR).

Results

A total of 13 studies were included for analysis. The SMDs (95% confidence interval – CI) in ovarian volume, fundal-cervical ratio, uterine length, uterine cross-sectional area, and uterine volume between PP and PT groups were 1.12 (0.78–1.45; p < 0.01), 0.90 (0.07–1.73; p = 0.03), 1.38 (0.99–1.78; p < 0.01), 1.06 (0.61–1.50; p < 0.01), and 1.21 (0.84–1.58; p <0.01), respectively. A uterine length of 3.20 cm yielded a pooled sensitivity of 81.8% (95% CI 78.3%–84.9%), specificity of 82.0% (95% CI 61.0%–93.0%), PLR of 4.56 (95% CI 2.15–9.69), NLR of 0.26 (95% CI 0.17–0.39), and DOR of 19.62 (95% CI 6.45–59.68). The area under the summary receiver operating characteristics curve was 0.82.

Conclusion

Female pelvic ultrasonography may serve as a complementary tool to the GnRH stimulation test in differentiating PP from PT.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232427, ID: CRD42021232427.
Clinical Characteristics and Follow-Up of 19 Children With Hashimoto’s Thyroiditis Aged Below 3 Years: A Single-Center Retrospective Analysis
Authors: Tang Shi , Yang Min , Zhang Dan , Tong Ya-jie , Xin Ying
Published: September 2021

Aim

To analyze the clinical characteristics of Hashimoto’s thyroiditis (HT) in children below 3 years of age in order to improve the understanding of the disease, avoid misdiagnosis, and achieve early diagnosis and treatment.

Methods

The study retrospectively analyzed the clinical data of 19 patients diagnosed with HT in the first three years of life.

Results

The patients (12 female, 7 male) had an average age of 26.1 ± 8.2 months (range 10–36 months). At presentation, one patient had euthyroidism, ten had hypothyroidism, seven had subclinical hypothyroidism, and one had hyperthyroidism. The most common reasons for doctor’s visits were thyroid enlargement (21.1%), global developmental delay (21.1%), and routine thyroid function tests in patients with type 1 diabetes (26.3%). Sixteen patients provided follow-up data, and the mean follow-up time was 23.31 ± 16.44 months (range 1–48 months). In the hypothyroidism group, one patient stopped levothyroxine (LT4) treatment after 2 months; the remaining patients had been treated with LT4 since their diagnosis. In the subclinical hypothyroidism group, one patient whose thyroid function returned to normal after 1 month of being diagnosed was not treated. The remaining patients received LT4 treatment at their diagnosis or during follow-up. The patient with hyperthyroidism was treated with methimazole after diagnosis, but treatment was discontinued 11 months later and LT4 was initiated 26 months after diagnosis. One in four patients with global developmental delay approached normal mental development after LT4 treatment. Four in six patients with short stature achieved height catch-up.

Conclusion

At their initial HT diagnosis, most of the children showed hypothyroidism or subclinical hypothyroidism. Children with global developmental delay require continual screening, even if the thyroid function is normal after birth, to determine whether they have HT-induced hypothyroidism. Thyroxine replacement could partially relieve the clinical manifestations of hypothyroidism and early diagnosis and treatment are essential for improving patient prognosis.
Hypoxia in Solid Tumors: How Low Oxygenation Impacts the “Six Rs” of Radiotherapy
Authors: Rakotomalala Andria , Escande Alexandre , Furlan Alessandro , Meignan Samuel , Lartigau Eric
Published: September 2021

Radiotherapy is an important component of cancer treatment, with approximately 50% of all cancer patients receiving radiation therapy during their course of illness. Nevertheless, solid tumors frequently exhibit hypoxic areas, which can hinder therapies efficacy, especially radiotherapy one. Indeed, hypoxia impacts the six parameters governing the radiotherapy response, called the « six Rs of radiation biology » (for Radiosensitivity, Repair, Repopulation, Redistribution, Reoxygenation, and Reactivation of anti-tumor immune response), by inducing pleiotropic cellular adaptions, such as cell metabolism rewiring, epigenetic landscape remodeling, and cell death weakening, with significant clinical repercussions. In this review, according to the six Rs, we detail how hypoxia, and associated mechanisms and pathways, impact the radiotherapy response of solid tumors and the resulting clinical implications. We finally illustrate it in hypoxic endocrine cancers through a focus on anaplastic thyroid carcinomas.
Negative Effects of the Neonicotinoid Clothianidin on Foraging Behavior and Antennal Sensitivity in Two Common Pollinator Species, Osmia bicornis and Bombus terrestris
Authors: Straub Florian , Orih Ihotu Joy , Kimmich Judith , Ayasse Manfred
Published: September 2021

Insect species richness and abundance has declined rapidly over the last few decades. Various stressors, such as the conversion of natural habitats, climate change, land-use intensification, agrochemicals and pathogens, are thought to be major factors in this decline. We treated female bees of two common pollinator species in Europe, Osmia bicornis and Bombus terrestris, with a field-realistic dose of the neonicotinoid clothianidin. We tested its effects on the foraging behavior of O. bicornis under semi-natural conditions and on the antennal sensitivity of both bee species to common floral volatiles by using electroantennography. Clothianidin negatively affected the foraging behavior in O. bicornis by decreasing the number of flowers visited per foraging flight and by increasing the time per flower visit and the searching time between two flowers. It also decreased the antennal sensitivity to 2-phenylethanol in the two bee species. Thus, clothianidin is clearly a threat for bees via its effects on their foraging behavior and antennal sensitivity and is hence probably detrimental for pollination and the reproductive success of bees.
Antecedent Drought Condition Affects Responses of Plant Physiology and Growth to Drought and Post-drought Recovery
Authors: Li Ximeng , Bao Jingting , Wang Jin , Blackman Chris , Tissue David
Published: September 2021

Antecedent environmental conditions may have a substantial impact on plant response to drought and recovery dynamics. Saplings of Eucalyptus camaldulensis were exposed to a range of long-term water deficit pre-treatments (antecedent conditions) designed to reduce carbon assimilation to approximately 50 (A50) and 10% (A10) of maximum photosynthesis of well-watered plants (A100). Thereafter, water was withheld from all plants to generate three different levels of water stress before re-watering. Our objective was to assess the role of antecedent water limitations in plant physiology and growth recovery from mild to severe drought stress. Antecedent water limitations led to increased soluble sugar content and depletion of starch in leaves of A50 and A10 trees, but there was no significant change in total non-structural carbohydrate concentration (NSC; soluble sugar and starch), relative to A100 plants. Following re-watering, A50 and A10 trees exhibited faster recovery of physiological processes (e.g., photosynthesis and stomatal conductance) than A100 plants. Nonetheless, trees exposed to the greatest water stress (−5.0 MPa) were slowest to fully recover photosynthesis (Amax) and stomatal conductance (gs). Moreover, post-drought recovery of photosynthesis was primarily limited by gs, but was facilitated by biochemistry (Vcmax and Jmax). During recovery, slow regrowth rates in A50 and A10 trees may result from insufficient carbon reserves as well as impaired hydraulic transport induced by the antecedent water limitations, which was dependent on the intensity of drought stress. Therefore, our findings suggest that antecedent water stress conditions, as well as drought severity, are important determinants of physiological recovery following drought release.
Identification of a Ferroptosis Gene Set That Mediates the Prognosis of Squamous Cell Carcinoma of the Head and Neck
Authors: Li Chunyan , Wang Xuemin , Qin Rujia , Zhong Zhaoming , Sun Chuanzheng
Published: September 2021

Squamous cell carcinoma of the head and neck (HNSCC) is one of the six most common malignancies. HNSCC has both a high incidence and poor prognosis, and its prognostic factors remain unclear. Ferroptosis is a newly discovered form of programmed cell death that is iron-dependent. Increasing evidence indicates that targeting ferroptosis may present a new form of anti-tumor treatment. However, the prognostic value of ferroptosis-related genes (FRGs) in HNSCC is unclear. This study was designed to identify molecular markers associated with ferroptosis that influence prognosis in patients with HNSCC. We used HNSCC tumor and normal data from The Cancer Genome Atlas (TCGA) to identify prognosis-related FRGs. An FRG-based prognostic risk score was constructed, and its prognostic value for patients with HNSCC was evaluated using receiver operating characteristic curve (ROC) and nomogram analyses. The model was validated using the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis in patients with HNSCC revealed 11 FRGs that were significantly associated with overall survival (OS). We constructed a ferroptosis risk score model based on five genes and divided the patients into different risk groups based on its median value. Kaplan-Meier curve analysis showed that patients with a higher ferroptosis risk score had shorter OS (TCGA training set: P < 0.001, TCGA validation set: P < 0.05,GEO validation set: P < 0.001), and Gene Expression Profiling Interactive Analysis (GEPIA) further verified the relationships between these five genes and prognosis in patients with HNSCC. Multivariate Cox regression analysis showed that the risk score remained an independent predictor of OS after the exclusion of clinical confounders (HR > 1, P < 0.01). Significant differences in gene function enrichment analysis and immune cell infiltration status were identified between the two groups. The prognostic model can be used to predict the prognosis of patients with HNSCC. Moreover, the five FRGs may affect ferroptosis in HNSCC and thereby represent potential treatment targets. These results provide new directions for HNSCC treatment.
Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa
Authors: De Rosa Laura , Enzo Elena , Zardi Giulia , Bodemer Christine , Magnoni Cristina , Schneider Holm , De Luca Michele
Published: September 2021

Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene LAMB3 has been the first genetic skin disease successfully tackled by ex vivo gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of LAMB3-related JEB. Autologous clonogenic keratinocytes will be isolated from patients’ skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human LAMB3 cDNA and plated onto a fibrin support (144cm2). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with LAMB3 mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses.

Clinical Trial Registration: EudraCT Number: 2018-000261-36.
ggVennDiagram: An Intuitive, Easy-to-Use, and Highly Customizable R Package to Generate Venn Diagram
Authors: Gao Chun-Hui , Yu Guangchuang , Cai Peng
Published: September 2021

Venn diagrams are widely used diagrams to show the set relationships in biomedical studies. In this study, we developed ggVennDiagram, an R package that could automatically generate high-quality Venn diagrams with two to seven sets. The ggVennDiagram is built based on ggplot2, and it integrates the advantages of existing packages, such as venn, RVenn, VennDiagram, and sf. Satisfactory results can be obtained with minimal configurations. Furthermore, we designed comprehensive objects to store the entire data of the Venn diagram, which allowed free access to both intersection values and Venn plot sub-elements, such as set label/edge and region label/filling. Therefore, high customization of every Venn plot sub-element can be fulfilled without increasing the cost of learning when the user is familiar with ggplot2 methods. To date, ggVennDiagram has been cited in more than 10 publications, and its source code repository has been starred by more than 140 GitHub users, suggesting a great potential in applications. The package is an open-source software released under the GPL-3 license, and it is freely available through CRAN (https://cran.r-project.org/package=ggVennDiagram).