bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoscopic submucosal dissection of papillary adenocarcinoma of stomach; protocol for a systematic review and meta-analysis
Authors: Bang Chang Seok , Choi Jae Ho , Lee Jae Jun , Baik Gwang Ho
Published: December 2018

Background:

Endoscopic submucosal dissection (ESD) is a primary treatment for the early gastric cancer (EGC) who has a negligible risk of lymph node metastasis. Papillary adenocarcinoma (PAC) of stomach is a rare histologic variant of gastric cancer and categorized into EGC with differentiated-histology. However, aggressive features such as higher rate of lymphovascular invasion (LVI) or submucosal invasion have been reported, whereas comparable lymph node metastasis (LNM) rate to the lesions meeting the current ESD criteria also has been reported. This study aimed to evaluate the feasibility of ESD for EGC with PAC.

Methods:

We will search the core databases (MEDLINE (through PubMed), the Cochrane Library, and Embase) from their inception to December 2018 by 2 independent evaluators. The P.I.C.O. is as follows; Patients: who have EGC with PAC, Intervention: ESD or surgery, Comparison: none, Outcome: at least one among the rate of complete resection, curative resection, en bloc resection, recurrence, procedure-related adverse event, LVI or LNM that enabled an evaluation of the feasibility of ESD. All types of study design with full text will be sought and included. The risk of bias will be assessed using the ROBINS-I tool. Descriptive data synthesis is planned, and quantitative synthesis will be used if the included studies are sufficiently homogenous. Publication bias will be assessed with quantitative analyses if more than 10 articles are enrolled.

Results:

The results will provide evidence for efficacy and safety of ESD for EGC with PAC.

Conclusion:

This study will provide evidence of ESD for EGC with PAC.
Associated risk factors for psychological distress in patients with gastric epithelial neoplasm undergoing endoscopic submucosal dissection
Authors: Lee San , Oh Seung-Taek , Lee Hyeok , Lee Jae Seung , Pak Haeyong , Choi Won-Jung , Jeon Han Ho
Published: December 2018

This study aimed to evaluate the psychological distress and associated risk factors for distress among patients with gastric epithelial neoplasm undergoing endoscopic submucosal dissection (ESD).

A total of 91 patients treated with ESD for gastric epithelial neoplasm between May 2015 and June 2016 were prospectively enrolled. Sociodemographic factors, psychological distress, anxiety, depression, stress, and associated risk factors for psychological distress were evaluated the day before ESD.

Twenty-six (28.6%) patients were identified as patients with psychological distress. The psychological distress group had a higher female ratio and more depression and anxiety symptoms than the non-distress group. Distress was also related to stress level. A multivariate analysis showed that unmarried status (odds ratio [OR], 4.94; 95% confidence interval [CI], 1.13–21.56, P = .034), anxiety (OR, 1.24; 95% CI, 1.12–1.39, P <.001), and stress (OR, 1.06; 95% CI, 1.01–1.12, P = .011) were associated with psychological distress.

An unmarried status and a high level of anxiety and stress were associated with more psychological distress in patients undergoing gastric ESD. It could be helpful to screen and proactively monitor patients with such conditions before performing gastric ESD.
Ultrasound risk evaluation of thyroid nodules that are “unspecified” in the 2015 American Thyroid Association management guidelines
Authors: Gao Luying , Xi Xuehua , Wang Juanjuan , Yang Xiao , Wang Ying , Zhu Shenling , Lai Xingjian , Zhang Xiaoyan , Zhao Ruina , Zhang Bo
Published: December 2018

This study sought to assess the malignant risks of “unspecified” thyroid nodules; that is, nodules that were not of a type described in the 2015 American Thyroid Association (ATA) guidelines.

We retrospectively reviewed medical records and ultrasound (US) data for 1808 consecutive patients with 2614 thyroid nodules who underwent thyroidectomy between January 2015 and December 2015. Nodules with US features that did not satisfy the criteria for any risk category in the 2015 ATA guidelines were defined as “unspecified” nodules. These thyroid nodules were retrospectively assessed using the Thyroid Imaging, Reporting and Data System proposed by Kwak (Kwak-TIRADS) and the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR-TIRADS).

There were 70 “unspecified” nodules (2.7%, 70/2614), and 18.6% (13/70) of these nodules were malignant. The percentages of nodules with Kwak-TIRADS grades 4a, 4b and 4c were 53.3%, 40.0%, and 6.7%, respectively. The percentages of nodules with ACR-TIRADS grades TR2, TR3, TR4, and TR5 were 5.7%, 2.9%, 70.0%, and 21.4%, respectively. Among the “unspecified” nodules, there were significantly more nodules in Kwak-TIRADS categories 4b and 4c in the malignant pathology group than in the benign pathology group (P <.01).

Our results imply that “unspecified” thyroid nodules based on the ATA guidelines could partly be evaluated using the Kwak-TIRADS and that the ATA guidelines could incorporate more accurate malignant risk stratification.
Transradial vs transfemoral access in patients with hepatic malignancy and undergoing hepatic interventions
Authors: Chen Yuan-Yuan , Liu Pan , Wu Yu-Shen , Lin Huapeng , Chen Xiaopin
Published: December 2018

Background:

The aim of this study was to compare transradial access (TRA) approach with transfemoral access (TFA) approach in patients undergoing hepatic interventions.

Methods:

We conducted a comprehensive search of the PubMed, Embase, and the Cochrane Library database to identify relevant available articles. Patients’ preference, success rate, intra- and postoperative outcomes were analyzed. The risk difference (RD), relative risk (RR), and weighted mean difference (WMD) values were reported with 95% confidence intervals (CIs). We used RevMan 5.3 to perform the pooled analyses.

Results:

Nine cohort studies were included. A total of 1096 procedures were performed in 877 patients. Of those, 545 procedures (49.7%) were performed by TRA, and 551 procedures (50.3%) were performed by TFA. Patients were significantly prefer the TRA (86.5%) to the TFA (13.5%) (RD = 0.88, P < .00001). The procedure time in TRA groups was longer (WMD = 3.36, 95% CI 1.24–5.47, P = .002). But there were no significant difference in terms of success rate, fluoroscopy time, radiation dosage, contrast volume, and postoperative vascular complications.

Conclusion:

For patients suffer from primary or secondary hepatic malignancy and undergoing hepatic interventions, the present meta-analysis demonstrated that patients prefer the TRA approach to the TFA approach. But the procedure time is longer in TRA group.
Gd-EOB-DTPA dynamic contrast-enhanced magnetic resonance imaging is more effective than enhanced 64-slice CT for the detection of small lesions in patients with hepatocellular carcinoma
Authors: Li Jiangfa , Li Xiaoqing , Weng Jun , Lei Liping , Gong Jianhua , Wang Junyi , Li Zhenghang , Zhang Longmiao , He Songqing
Published: December 2018

This study aimed to compare the sensitivity and accuracy for the detection of small lesions in patients with hepatocellular carcinoma (HCC) using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 64-slice computed tomography (CT) enhanced scanning, and to evaluate the necessity to perform MRI in patients diagnosed with HCC by CT.

The clinical data from 209 patients with HCC diagnosed prior to surgery in the Affiliated Hospital of Guilin Medical University, China were retrospectively analyzed. The 64-slice dynamic contrast-enhanced multi-detector CT (MDCT) and 3.0 T Gd-EOB-DTPA DCE MRI procedures were successively carried out on all patients who were enrolled in a self-controlled study including detection and diagnosis of HCC lesions by MRI and CT, respectively.

A total of 243 lesions were detected and both imaging methods could accurately detect lesions of diameter >2 cm. For lesions <2 cm, MRI detected 47, while CT detected 25 lesions indicating that the detection rate of MRI was 88% higher than that of CT. In addition, MRI detected lesions in 15 cases (7.81% in the total of 209 cases) that were not diagnosed by CT. Among these cases, 2 patients were diagnosed to have no lesion by CT.

Gd-EOB-DTPA DCE-MRI performed as a routine check prior to surgery in HCC patients can improve the detection of small HCC lesions.
Could larger diameter of 4th generation ceramic bearing increase the rate of squeaking after THA?
Authors: Luo Yuan , Sun Xue-Feng , Chen Jin , Cui Wei , Wang Tao
Published: December 2018

The present study aimed to evaluate the clinical outcomes and bearing-specific complications in a single center of 135 delta ceramic-on-ceramic (COC) total hip arthroplasties (THAs) and explore the occurrence rate of squeaking in 4th generation COC THAs and collate the risk factors for squeaking.

We retrospectively analyzed consecutive cohorts of 127 patients (135 hips) who had primary THA with delta COC bearings in our hospital between April 2010 and April 2012. Preoperative Harris hip score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and University of California Los Angeles (UCLA) activity score were evaluated preoperatively and postoperatively. We also evaluated ceramic fracture, squeak, mid-term results, and survival.

In our study, the final patient final follow-up date was July 31, 2016. The mean preoperative HHS improved from 39.5 to 93.1 points. Mean preoperative UCLA score was 3.2 points, improving to 8.2 points. The mean preoperative total WOMAC score was 55.5 points and the mean total WOMAC score was 13.3 points at the final follow-up. The Kaplan–Meier survival plot of revision for any reason as the end point was 98.5% and survival with ceramic fracture as the end point was 99.2% at a mean of 70 months’ follow-up. One post-operative ceramic liner rim fracture occurred at 50 months after surgery. Thirteen of the 135 hips produced a squeaking sound. There were no significant differences in gender (P = .56), age (P = .20), body mass index (BMI) (P = .11), diagnosis (P = .46), cup inclination (P = .36), or cup anteversion (P = 1.0) between the squeaking and non-squeaking groups. However, the incidence of squeaking in the 36 mm COC femoral head bearings was higher than in the 28 mm size (13.6% vs 2.1%, P = .033).

The 4th generation COC bearing performed well and provides an encouraging rate of survival with no osteolysis or loosening. However, we found that a squeaking sound associated with use of the delta ceramic occurred at a rate of 9.6%, with the larger-diameter heads having significantly higher incidence.
Improving Aseptic Technique During the Treatment of Pediatric Septic Shock
Authors: Spangler Hillary , Piehl Mark , Lane Andrew , Robertson Galen
Published: December 2018

Rapid fluid resuscitation is used to treat pediatric septic shock. However, achieving fluid delivery goals while maintaining aseptic technique can be challenging. Two methods of fluid resuscitation—the commonly used push-pull technique (PPT) and a new fluid infusion technique using the LifeFlow device (410 Medical, Inc; Durham, NC)—were compared in a simulated patient model. PPT was associated with multiple aseptic technique violations related to contamination of the syringe barrel. This study confirms the risk of PPT-associated syringe contamination and suggests that this risk could be mitigated with the use of a protected syringe system, such as LifeFlow.
Conceptual Model for Predicting Academic Success in Prelicensure Nursing Programs Through Expanded Cognitive Aptitude Assessment
Authors: Twidwell Julie , Sanner-Stiehr Ericka , Allen Kimberly , Records Kathie , Hsueh Kuei-Hsiang
Published: December 2018

Background

Attrition from prelicensure nursing programs is a serious issue with implications for students, nursing programs, and the nursing workforce. Academic failure due to insufficient cognitive aptitude often contributes to this problematic attrition rate. Thus, cognitive aptitude could be included in admission criteria, as a predictor of academic success and a strategy to minimize attrition.

Problem

Currently, admissions practices are often incomplete and lack standardization for measuring cognitive aptitude.

Approach

The Nursing Cognitive Aptitude Model (NCAM) presented in this article is an innovative conceptual model to guide educators in expanding current admissions processes.

Conclusion

The NCAM model depicts the cognitive domains involved in student academic success including current scholastic knowledge, previous academic performance, and critical-thinking ability. Together, these three domains predict student academic success and are a useful reference for the admissions process.
An Analysis of Female Plastic Surgery Authorship: Where Are We Today?
Authors: Andry Danielle , Moliver Clayton , Phillips Linda G.
Published: December 2018

Background:

Authorship in a peer-reviewed journal is highly regarded in both the academic and private sectors of plastic surgery. Recently, several articles have cited an increased contribution from women in the plastic surgery literature; however, none to date has analyzed the demographic trends of these female authors. The purpose of this study was to conduct an analysis of female authors in three well-known plastic surgery journals.

Methods:

Articles published in Plastic and Reconstructive Surgery, Annals of Plastic Surgery, and Aesthetic Surgery Journal between January of 2015 and December of 2015 were reviewed. Supplemental journal, review, and CME articles were excluded. First, second, and last authors from the United States were reviewed and stratified by a number of categories, including sex, geographic location, and title.

Results:

Two-thousand fifty authors were reviewed. Of these, 20 percent of first authors, 24 percent of second authors, and 15 percent of last authors were women. Female representation was fairly equal among the journals, and 39 percent of women authors were international. Overall, 16 percent of fully trained plastic surgeon authors and 25 percent of resident authors were women, as compared to 15 percent female fully trained plastic surgeons and 36.2 percent female residents represented in the overall community.

Conclusions:

Faculty are on par with national percentages of women plastic surgeons; however, women residents have lower representation in the literature than in the community as a whole. Residents and faculty must promote productivity of the younger generation of women plastic surgeons to continue increasing contributions of women to the specialty.
Risk Factors for Preoperative Developmental Delay in Patients with Nonsyndromic Sagittal Craniosynostosis
Authors: Imahiyerobo Thomas A. , Johns Alexis L. , Christian Eisha A. , Sanchez-Lara Pedro A. , Krieger Mark D. , McComb J. Gordon , Urata Mark M.
Published: December 2018

Background:

Some patients with isolated sagittal craniosynostosis have demonstrated mild neurodevelopmental delays. This study examined potential preoperative risk factors for developmental delay.

Methods:

Patients completed preoperative Bayley Scales of Infant and Toddler Development, Third Edition, and medical records were reviewed. Multivariate analyses of covariance and correlations were calculated.

Results:

Participants (n = 77) were predominantly male (77.9 percent) and were aged 2 to 12 months (mean, 5.1 ± 2.3 months). Patients were classified with no delays [n = 63 (82 percent)] or delays [n = 14 (18 percent)] in one or more developmental area(s). There were no group sociodemographic differences. Prenatally, patients with delays versus no delays had lower mean gestational age in weeks (36.9 ± 2.8 weeks versus 39.1 ± 1.7 weeks; p = 0.001) with higher rates of gestational diabetes (36 percent versus 5 percent; p = 0.006) and premature rupture of membranes (14 percent versus 2 percent; p = 0.026). At birth, patients with delays had lower mean birth weight (2982 ± 714 g versus 3374 ± 544 g; p = 0.053), higher rates of respiratory distress (29 percent versus 5 percent; p = 0.005), additional medical diagnoses (57 percent versus 13 percent; p = 0.001), and longer mean neonatal intensive care unit stays (1.4 ± 1.8 weeks versus 0.2 ± 0.9 week; p = 0.002). Variables differing by group had moderate correlations.

Conclusions:

Patients with nonsyndromic sagittal craniosynostosis that had delays in development had lower gestational age and birth weight, with more prenatal and birth complications. These factors can help identify patients who might be at risk for delay and need close monitoring.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Evaluating an Interdisciplinary EEG Initiative on In-Training Examination EEG-Related Item Scores for Anesthesiology Residents
Authors: Fahy Brenda G. , Vasilopoulos Terrie , Bensalem-Owen Meriem , Chau Destiny F.
Published: December 2018

Purpose:

Clinical neurophysiology is an evolving area of medicine with clinical applications in intensive care unit and intraoperative settings, where EEG is used. An interdisciplinary module was implemented over 7 years in one institution to strengthen anesthesiology residents' EEG education. This study researched the module's outcome by evaluating participants' specific performance on EEG-related questions (keywords) through independent testing, i.e., the in-training examinations (ITEs).

Methods:

Residency program ITE performance reports from 2002 to 2014 were searched for EEG keyword items. The ITE uses images for assessment. Analysis of variance was used to evaluate differences in the composite performance (mean percent correct on EEG-related keywords) of anesthesiology trainees from their clinical anesthesia year 1 (CA-1) to their clinical anesthesia year 3 (CA-3) who received the education module and compared with those who did not receive the training module, as well as compared with the national average for the corresponding training level.

Results:

Residents who received the education module (mean percent correct = 83.3%, 95% CI: 74.0–92.7) performed significantly better than residents within the same program who did not receive the module (P = 0.04; mean difference = 22.0%, 95% CI: 1.0–43.0), as well as national residents on the same keywords (P = 0.01; mean difference = 23.4%, 95% CI: 3.9–42.9). Differences between residents who did not receive the module and national residents (matched for same keywords) were not statistically significant (P = 0.983, mean difference = 5.2%, 95% CI: −17.3 to 27.7).

Conclusions:

The multidisciplinary education module was effective for the EEG-specific topics as measured by the national ITE examination performance that resulted in sustained learning over time.
PLZF limits enhancer activity during hematopoietic progenitor aging
Authors: Poplineau Mathilde , Vernerey Julien , Platet Nadine , N’guyen Lia , Hérault Léonard , Esposito Michela , Saurin Andrew J. , Guilouf Christel , Iwama Atsushi , Duprez Estelle
Published: December 2018

PLZF (promyelocytic leukemia zinc finger) is a transcription factor acting as a global regulator of hematopoietic commitment. PLZF displays an epigenetic specificity by recruiting chromatin-modifying factors but little is known about its role in remodeling chromatin of cells committed towards a given specific hematopoietic lineage. In murine myeloid progenitors, we decipher a new role for PLZF in restraining active genes and enhancers by targeting acetylated lysine 27 of Histone H3 (H3K27ac). Functional analyses reveal that active enhancers bound by PLZF are involved in biological processes related to metabolism and associated with hematopoietic aging. Comparing the epigenome of young and old myeloid progenitors, we reveal that H3K27ac variation at active enhancers is a hallmark of hematopoietic aging. Taken together, these data suggest that PLZF, associated with active enhancers, appears to restrain their activity as an epigenetic gatekeeper of hematopoietic aging.
Coordinated emergence of hippocampal replay and theta sequences during post-natal development
Authors: Muessig Laurenz , Lasek Michal , Varsavsky Isabella , Cacucci Francesca , Wills Thomas J
Published: December 2018

Hippocampal place cells encode an animal's current position in space during exploration. During subsequent sleep, hippocampal network activity recapitulates patterns observed during recent experience: place cells with overlapping spatial firing fields during locomotion show a greater tendency to co-fire ("reactivation") and temporally ordered and compressed sequences of place cell firing observed during wakefulness are reinstated ("replay"). Reactivation and replay are thought to be network mechanisms underlying memory consolidation. Compressed sequences of place cell firing also occur during exploration: during each cycle of the theta oscillation, the set of active place cells shifts from those signalling positions behind to those signalling positions ahead of an animal's current location. These "theta sequences" have been linked to spatial planning. Here we demonstrate that, before weaning (post-natal day 21, P21), offline place cell activity reflects predominantly stationary locations in recently visited environments. By contrast, sequential place cell firing, describing extended trajectories through space during exploration ("theta sequences") and subsequent sleep ("replay"), emerge gradually after weaning in a coordinated fashion, possibly due to a protracted decrease in the threshold for experience-driven plasticity. Hippocampus-dependent learning and memory emerge late in altricial mammals, appearing around weaning in rats and slowly maturing thereafter. In contrast, spatially localised firing can be observed at least one week earlier (albeit with reduced spatial tuning/stability). By examining the emergence of hippocampal reactivation, replay, and theta sequences during development, we show that the coordinated maturation of offline consolidation and online sequence generation parallels the late emergence of hippocampal memory in the rat.
The Unique Evolutionary Trajectory and Dynamic Conformations of DR and IR/DR- coexisting Plastomes of the Early Vascular Plant Selaginellaceae (Lycophyte)
Authors: Zhang Hong-Rui , Xiang Qiao-Ping , Zhang Xian-Chun
Published: December 2018

Both direct repeats (DR) and inverted repeats (IR) are documented in the published plastomes of four Selaginella species indicating the unusual and diverse plastome structure in the family Selaginellaceae. In this study, we newly sequenced complete plastomes of seven species from five main lineages of Selaginellaceae and also re-sequenced three species (S. tamariscina, S. uncinata and S. moellendorffii) to explore the evolutionary trajectory of Selaginellaceae plastomes. Our results showed that the plastomes of Selaginellaceae vary remarkably in size, gene contents, gene order and GC contents. Notably, both DR and IR structure existed in the plastomes of Selaginellaceae with DR structure being an early diverged character. The occurrence of DR structure was right after the Permian-Triassic (P-T) extinction (ca. 246 Ma) and remained in most subgenera of Selaginellaceae, whereas IR structure only reoccurred in the most derived subg. Heterostachys (ca. 23 Ma). The presence of a pair of large repeats psbK-trnQ, together with DR/IR region in S. bisulcata, S. pennata, S. uncinata, and S. hainanensis, could frequently mediate diverse homologous recombination and create approximately equal stoichiometric isomers (IR/DR-coexisting) and subgenomes. High proportion of repeats is presumably responsible for the dynamic IR/DR-coexisting plastomes, which possess a lower synonymous substitution rate (dS) compared with DR-possessing plastomes. We propose that the occurrence of DR structure, together with few repeats, is possibly selected to adapt to the environmental upheaval during the P-T crisis and the IR/DR-coexisting plastomes also reached an equilibrium in plastome organization through highly efficient homologous recombination to maintain stability.

Data deposition

All the plastomes were deposited in GenBank under accession numbers MG272483-MG272484, MH598531-MH598537 and MK156800.
Dynamics of Spaetzle morphogen shuttling in theDrosophilaembryo shapes pattern
Authors: Rahimi Neta , Averbukh Inna , Carmon Shari , Schejter Eyal D. , Barkai Naama , Shilo Ben-Zion
Published: December 2018

Establishment of morphogen gradients in the earlyDrosophilaembryo is challenged by a diffusible extracellular milieu, and rapid nuclear divisions that occur at the same time. To understand how a sharp gradient is formed within this dynamic environment, we followed the generation of graded nuclear Dorsal (Dl) protein, the hallmark of pattern formation along the dorso-ventral axis, in live embryos. We show that a sharp gradient is formed through extracellular, diffusion-based morphogen shuttling that progresses through several nuclear divisions. Perturbed shuttling inwntDmutant embryos results in a flat activation peak and aberrant gastrulation. Re-entry of Dl into the nuclei at each cycle refines the signaling output, by guiding graded accumulation of theT48transcript that drives patterned gastrulation. We conclude that diffusion-based ligand shuttling, coupled with dynamic readout, establishes a refined pattern within the diffusible environment of early embryos.
The division of amyloid fibrils – Systematic comparison of fibril fragmentation stability by linking theory with experiments
Authors: Beal David M. , Tournus Magali , Marchante Ricardo , Purton Tracey , Smith David P. , Tuite Mick F. , Doumic Marie , Xue Wei-Feng
Published: December 2018

The division of amyloid protein fibrils is required for the propagation of the amyloid state, and is an important contributor to their stability, pathogenicity and normal function. Here, we combine kinetic nano-scale imaging experiments with analysis of a mathematical model to resolve and compare the division stability of amyloid fibrils. Our theoretical results show that the division of any type of filament is uniquely described by a set of three characteristic properties, resulting in convergence to self-similar length distributions distinct to each fibril type and conditions applied. By applying these results to profile the dynamical stability towards breakage for four different amyloid types, we reveal particular differences in the division properties of disease-related amyloid formed from alpha-synuclein compared with non-disease associated model amyloid, the former showing lowered intrinsic stability towards breakage and increased likelihood of shedding smaller particles. Our results enable the comparison of protein filaments’ intrinsic dynamic stabilities, which are key to unravelling their toxic and infectious potentials.
An acute immune response underlies the benefit of cardiac adult stem cell therapy
Authors: Vagnozzi Ronald J. , Maillet Marjorie , Sargent Michelle A. , Khalil Hadi , Katrine Johansen Anne , Schwanekamp Jennifer A. , York Allen J. , Huang Vincent , Nahrendorf Matthias , Sadayappan Sakthivel , Molkentin Jeffery D.
Published: December 2018

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day1–3despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biologic effect4–6. The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischemic injury7–9. Here we examined the mechanistic basis for cell therapy in mice after ischemia/reperfusion (I/R) injury, and while heart function was enhanced, it was not associated with new cardiomyocyte production. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2+and CX3CR1+macrophages. Here we observed that intra-cardiac injection of 2 distinct types of progenitor cells, freeze/thaw-killed cells or a chemical inducer of the innate immune response similarly induced regional CCR2+and CX3CR1+macrophage accumulation and provided functional rejuvenation to the I/R-injured heart. Mechanistically, this selective macrophage response altered cardiac fibroblast activity and reduced border zone extracellular matrix (ECM) content and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound healing response that rejuvenates the mechanical properties of the infarcted area of the heart. Such results suggest a re-evaluation of strategies underlying cardiac cell therapy in current and planned human clinical trials.
S3norm: simultaneous normalization of sequencing depth and signal-to-noise ratio in epigenomic data
Authors: Xiang Guanjue , Keller Cheryl A. , Giardine Belinda , An Lin , Li Qunhua , Zhang Yu , Hardison Ross C.
Published: December 2018

Quantitative comparison of epigenomic data across multiple cell types or experimental conditions is a promising way to understand the biological functions of epigenetic modifications. However, differences in sequencing depth and signal-to-noise ratios in the data from different experiments can hinder our ability to identify real biological variation from raw epigenomic data. Proper normalization is required prior to data analysis to gain meaningful insights. Most existing methods for data normalization standardize signals by rescaling either background regions or peak regions, assuming that the same scale factor is applicable to both background and peak regions. While such methods adjust for differences in sequencing depths, they do not address differences in the signal-to-noise ratios across different experiments. We developed a new data normalization method, called S3norm, that normalizes the sequencing depths and signal-to-noise ratios across different data sets simultaneously by a monotonic nonlinear transformation. We show empirically that the epigenomic data normalized by our method, compared to existing methods, can better capture real biological variation, such as impact on gene expression regulation.
Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer
Authors: Musa Julian , Cidre-Aranaz Florencia , Aynaud Marie-Ming , Orth Martin F. , Mirabeau Olivier , Varon Mor , Grossetête Sandrine , Surdez Didier , Ohmura Shunya , Gerke Julia S. , Marchetto Aruna , Dallmayer Marlene , Baldauf Michaela C. , Gartlgruber Moritz , Westermann Frank , Stein Stefanie , Hölting Tilman L. B. , Knott Maximilian M. L. , Sannino Giuseppina , Li Jing , Romero-Pérez Laura , Hartmann Wolfgang , Dirksen Uta , Gymrek Melissa , Anderson Nathaniel D. , Shlien Adam , Rotblat Barak , Kirchner Thomas , Delattre Olivier , Grünewald Thomas G. P.
Published: December 2018

INTRODUCTORY PARAGRAPH

Deciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma (EwS) feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome.

Here we demonstrate in the EwS model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response.

We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Analysis of paired germline and tumor whole-genome sequencing data revealed that regulatory variability at this locus is inherited via the germline. CRISPR-mediated interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased cell proliferation, cell survival and tumorigenicity of EwS cells. Combined RNA- and ChIP-seq analyses as well as functional experiments and clinical data identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments, high MYBL2 levels sensitized EwS cells for inhibition of its activating cyclin dependent kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.

Collectively, our findings establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.
Analysis of 100 high coverage genomes from a pedigreed captive baboon colony
Authors: Robinson Jacqueline , Birnbaum Shifra , Newman Deborah E. , Chan Jeannie , Glenn Jeremy P. , Cox Laura A. , Wall Jeffrey D.
Published: December 2018

Baboons (genus Papio) are broadly studied in the wild and in captivity. They are widely used as a non-human primate model for biomedical studies, and the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute has maintained a large captive baboon colony for more than 50 years. Unlike other model organisms though, the genomic resources for baboons are severely lacking. This has hindered the progress of studies using baboons as a model for basic biology or human disease. Here, we describe a dataset of 100 high-coverage whole-genome sequences obtained from the mixed colony of olive (P. anubis) and yellow (P. cynocephalus) baboons housed at the SNPRC. These data provide a comprehensive catalog of common genetic variation in baboons, as well as a fine-scale genetic map. We show how the data can be used to learn about ancestry and admixture, and to correct errors in the colony records. Finally, we investigated the consequences of inbreeding within the SNPRC colony and found clear evidence for increased rates of juvenile mortality and increased homozygosity of putatively deleterious alleles in inbred individuals.
Clinical diagnosis of TIA or stroke and prognosis in patients with neurological symptoms: a rapid access clinic cohort
Authors: Whiteley William N , Graham Catriona , Bailey David , Hart Simon , Hutchison Aidan , Sandercock Peter , Doubal Fergus , Sudlow Cathie , Farrall Andrew , Wardlaw Joanna , Dennis Martin
Published: December 2018

Background

The long-term risk of stroke or MI in patients with minor neurological symptoms who are not clinically diagnosed with transient ischaemic attack (TIA) or minor stroke is uncertain.

Methods

We used data from a rapid access clinic for patients with suspected TIA or minor stroke and follow-up from four overlapping data sources for a diagnosis of ischaemic or haemorrhagic stroke, myocardial infarction, major haemorrhage and death. We identified patients with and without a clinical diagnosis of TIA or minor stroke. We estimated hazard ratios of stroke, MI and death in early and late time periods.

Results

5,997 patients were seen from 2004–2013, who were diagnosed TIA or minor stroke (n=3604, 60%) or with other diagnoses (n=2392, 40%). By 5 years the proportion of patients who had a subsequent ischaemic stroke or MI, in patients with a clinical diagnosis of minor stroke or TIA was 19% [95% confidence interval (CI): 17–20%], and in patients with other diagnoses was 10% (95%CI: 8–15%). Patients with clinical diagnosis of TIA or minor stroke had three times the hazard of stroke or MI compared to patients with other diagnoses (HR 2.83 95%CI:2.13–3.76, adjusted age and sex) by 90 days post-event; however from 90 days to end of follow up, this difference was attenuated (HR 1.52, 95%CI:1.25–1.86). Older patients and those who had a history of vascular disease had a high risk of stroke or MI, whether or not they were diagnosed with minor stroke or TIA.

Conclusions

Careful attention to vascular risk factors in patients presenting with transient or minor neurological symptoms not thought to be due to stroke or TIA is justified, particularly those who are older or have a history of vascular disease.
A multi-scale sub-voxel perfusion model to estimate diffusive capillary wall conductivity in multiple sclerosis lesions from perfusion MRI data
Authors: Koch Timo , Flemisch Bernd , Helmig Rainer , Wiest Roland , Obrist Dominik
Published: December 2018

We propose a new mathematical model to infer capillary leakage coefficients from dynamic susceptibility contrast MRI data.
To this end, we derive an embedded mixed-dimension flow and transport model for brain tissue perfusion on a sub-voxel scale.
This model is used to obtain the contrast agent concentration distribution in a single MRI voxel during a perfusion MRI sequence.
We further present a magnetic resonance signal model for the considered sequence including a model for local susceptibility effects.
This allows modeling MR signal--time curves that can be compared to clinical MRI data.
The proposed model can be used as a forward model in the inverse modeling problem of inferring model parameters such as the diffusive capillary wall conductivity.
Acute multiple sclerosis lesions are associated with a breach in the integrity of the blood brain barrier. Applying the model to perfusion MR data
of a patient with acute multiple sclerosis lesions, we conclude that diffusive capillary wall conductivity is a good indicator for characterizing activity of lesions,
even if other patient-specific model parameters are not well-known.
Progress towards lymphatic filariasis elimination in Ghana from 2000-2016: analysis of microfilaria prevalence data from 430 communities
Authors: Biritwum Nana-Kwadwo , Frempong Kwadwo K. , Verver Suzanne , Odoom Samuel , Alomatu Bright , Asiedu Odame , Kontoroupis Periklis , Yeboah Abednego , Hervie Edward Tei , Marfo Benjamin , Boakye Daniel A. , de Vlas Sake J. , Gyapong John O. , Stolk Wilma A.
Published: December 2018

Background

Ghana started its national programme to eliminate lymphatic filariasis (LF) in 2000, with mass drug administration (MDA) with ivermectin and albendazole as main strategy. We review the progress towards elimination that was made by 2016 for all endemic districts of Ghana and analyze mf prevalence from sentinel and spot-check sites in endemic districts.

Methods

We reviewed district level data on the history of MDA and outcomes of transmission assessment surveys (TAS). We further collated and analyzed microfilaria (mf) prevalence data from sentinel and spot-check sites.

Results

MDA was initiated in 2001-2006 in all 98 endemic districts; by the end of 2016, 81 had stopped MDA after passing TAS and after an average of 11 rounds of treatment (range 8 – 14 rounds). The median reported coverage for the communities was 77-80%. Mf prevalence survey data were available for 430 communities from 78/98 endemic districts. Baseline mf prevalence data were available for 53 communities, with an average mf prevalence of 8.7% (0 - 45.7%). Repeated measurements were available for 78 communities, showing a steep decrease in mean mf prevalence in the first few years of MDA, followed by a gradual further decline. In the 2013 and 2014 surveys, 7 and 10 communities respectively were identified with mf prevalence still above 1% (maximum 5.6%). Two stopped MDA in 2015 and 2016 respectively, while the rest of the 15 communities above threshold are all within 13/17 districts where MDA is still ongoing.

Conclusions

The MDA programme of the Ghana Health Services has reduced mf prevalence in sentinel sites below the 1% threshold in 81/98 endemic districts in Ghana, yet 15 communities within 13 districts (MDA ongoing) had higher prevalence than this threshold during the surveys in 2013 and 2014. These districts may need to intensify interventions to achieve the WHO 2020 target.
Selective kinase inhibition shows that Bur1 (Cdk9) phosphorylates the Rpb1 linker in vivo
Authors: Chun Yujin , Suh Hyunsuk , Joo Yoo Jin , Batot Gaelle , Hill Christopher P. , Formosa Tim , Buratowski Stephen
Published: December 2018

Cyclin-dependent kinases play multiple roles in RNA polymerase II transcription. Cdk7/Kin28, Cdk9/Bur1, and Cdk12/Ctk1 phosphorylate the polymerase and other factors to drive the dynamic exchange of initiation and elongation complex components over the transcription cycle. We engineered strains of the yeast Saccharomyces cerevisiae for rapid, specific inactivation of individual kinases by addition of a covalent inhibitor. While effective, the sensitized kinases can display some idiosyncrasies, and inhibition can be surprisingly transient. As expected, inhibition of Cdk7/Kin28 blocked phosphorylation of the Rpb1 C-terminal domain heptad repeats at Serines 5 and 7, which are known target sites, but also at Serine 2. Consistent with our previous results using gene deletions, Cdk12/Ctk1 is the predominant kinase responsible for Serine 2 phosphorylation. Phosphorylation of the Rpb1 linker enhances binding of the Spt6 tSH2 domain, and here we show that Bur1/Cdk9 is the kinase responsible for this modification in vivo.
Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas
Authors: Scala F. , Kobak D. , Shan S. , Bernaerts Y. , Laturnus S. , Cadwell C.R. , Hartmanis L. , Froudarakis E. , Castro J. , Tan Z.H. , Papadopoulos S. , Patel S. , Sandberg R. , Berens P. , Jiang X. , Tolias A.S.
Published: December 2018

Layer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking neurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ neurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell-type specific circuit motifs, such as the Martinotti/pyramidal and non-Martinotti/stellate pairs, are optionally used across the cortex as building blocks to assemble cortical circuits.
Human, Nonhuman Primate, and Bat Cells Are Broadly Susceptible to Tibrovirus Particle Cell Entry
Authors: Cai Yingyun , Yu Shuiqing , Jangra Rohit , Postnikova Elena , Wada Jiro , Tesh Robert , Whelan Sean , Lauck Michael , Wiley Michael , Finch Courtney , Radoshitzky Sheli , O'Connor David , Palacios Gustavo , Chandran Kartik , Chiu Charles , Kuhn Jens
Published: December 2018

In 2012, the genome of a novel rhabdovirus, Bas-Congo virus, was discovered in the acute-phase serum of a Congolese patient with presumed viral hemorrhagic fever. In the absence of a replicating virus isolate, fulfilling Koch's postulates to determine whether Bas-Congo virus is indeed a human virus and/or pathogen has been impossible. However, experiments with vesiculoviral particles pseudotyped with Bas-Congo glycoprotein suggested that Bas-Congo virus particles can enter cells from multiple animals, including humans. In 2015, genomes of two related viruses, Ekpoma virus 1 and Ekpoma virus 2, were detected in human sera in Nigeria. Isolates could not be obtained. Phylogenetic analyses led to the classification of Bas-Congo virus, Ekpoma virus 1, and Ekpoma virus 2 in the same genus, Tibrovirus, together with five biting midge-borne rhabdoviruses (i.e., Beatrice Hill virus, Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus) not known to infect humans. Using individual recombinant vesiculoviruses expressing the glycoproteins of all eight known tibroviruses and more than 75 cell lines representing different animal species, we demonstrate that the glycoproteins of all tibroviruses can mediate vesiculovirus particle entry into human, bat, nonhuman primate, cotton rat, boa constrictor, and Asian tiger mosquito cells. Using four of five isolated authentic tibroviruses (i.e., Bivens Arm virus, Coastal Plains virus, Sweetwater Branch virus, and Tibrogargan virus), our experiments indicate that many cell types may be partially resistant to tibrovirus replication after virion cell entry. Consequently, experimental data solely obtained from experiments using tibrovirus surrogate systems (e.g., vesiculoviral pseudotypes, recombinant vesiculoviruses) cannot be used to predict whether Bas-Congo virus, or any other tibrovirus, infects humans.
A machine-learning classifier trained with microRNA ratios to distinguish melanomas from nevi
Authors: Torres Rodrigo , Lang Ursula E , Hejna Miroslav , Shelton Samuel J , Joseph Nancy M , Shain Alan Hunter , Yeh Iwei , Wei Maria L , Oldham Michael C. , Bastian Boris C , Judson-Torres Robert L
Published: December 2018

The use of microRNAs as biomarkers has been proposed for many diseases including the diagnosis of melanoma. Although hundreds of microRNAs have been identified as differentially expressed in melanomas as compared to benign melanocytic lesions, limited consensus has been achieved across studies, constraining the effective use of these potentially useful markers. In this study we quantified microRNAs by next-generation sequencing from melanomas and their adjacent benign precursor nevi. We applied a machine learning-based pipeline to identify a microRNA signature that separated melanomas from nevi and was unaffected by confounding variables, such as patient age and tumor cell content. By employing the ratios of microRNAs that were either enriched or depleted in melanoma compared to nevi as a normalization strategy, the classifier performed similarly across multiple published microRNA datasets, obtained by microarray, small RNA sequencing, or RT-qPCR. Validation on separate cohorts of melanomas and nevi correctly classified lesions with 83% sensitivity and 71-83% specificity, independent of variation in tumor cell content of the sample or patient age.
Altered crosstalk of estradiol and progesterone with Myeloid‐derived suppressor cells and Th1/Th2 cytokines in early miscarriage is associated with early breakdown of maternal‐fetal tolerance
Authors: Verma Priyanka , Verma Rachna , Nair Rohini R. , Budhwar Snehil , Khanna Anuradha , Agrawal Nisha Rani , Sinha Ruchi , Birendra Ruchi , Rajender Singh , Singh Kiran
Published: December 2018

Problem

Decline in myeloid‐derived suppressor cells (MDSCs) and Th2 cytokines levels lead to early miscarriage (EM) but how the hormonal milieu of the body regulates MDSCs and Th1/Th2 cytokine balance is still a matter of investigation.

Method of study

Peripheral blood and decidua samples were collected from 20 EM patients, and 20 healthy pregnant women opted for elective abortion. MDSCs and G‐MDSCs levels were analyzed in peripheral blood mononuclear cells, and Th1/Th2 cytokines levels were determined in serum via flow cytometry. Estrogen (E2), Progesterone (P4), and Testosterone levels were measured via ELISA. Further, proliferation and apoptosis in decidual samples were checked via immunoblot/immunohistochemistry of estrogen receptor ‐α (ER‐α), STAT‐3/pSTAT‐3, and caspase‐3, respectively.

Results

Our results clearly indicate that in EM patients; decline in E2 and P4 significantly correlates with decline in MDSCs, particularly with subtype granulocytic MDSCs (G‐MDSCs) and skewness of the Th1/Th2 cytokines balance toward Th1 response. Downregulation of ER‐ α and increased caspase‐3 expression in endometrium decidua signifies poor endometrial receptivity in EM. STAT‐3 activation regulates proliferation, differentiation and suppressive potency of MDSCs. In decidua of EM, significantly lower expression of pSTAT‐3 indicates that these processes pertaining to MDSCs are compromised.

Conclusion

Altogether, this unfavorable systemic milieu may drive toward early breakdown of maternal‐fetal tolerance in EM. Therefore, regulated crosstalk of E2, P4 with MDSCs and balanced Th1/Th2 cytokines is prerequisite for successful pregnancy.