bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluorescein Angiography Indications: Changes after Optical Coherence Tomography and Antiangiogenics
Authors: Labrador-Velandia Sonia C. , Sanabria María R.
Published: April 2018

SIGNIFICANCE

The present study provides quantitative data regarding the change of indications of fluorescein angiography in a tertiary hospital. Exhaustively compiled data over more than 10 years concerning all the angiographic studies including diagnosis, first-visit/follow-up, possible relation with antiangiogenics approval, and optic coherence tomography (OCT) are presented.

PURPOSE

The aim of this study was to determine the frequency and indications of fluorescein angiography before and after OCT and anti–vascular endothelial growth factor (anti-VEGF) treatment implantation.

METHODS

This was a retrospective and descriptive study of all fluorescein angiographies performed in a tertiary hospital between 2005 and 2016. Demographic data, diagnosis, follow-up, and type of angiograms were analyzed in relation with the implantation of time domain OCT (2006), spectral domain OCT (SD-OCT) (2013), and anti-VEGF (2007).

RESULTS

Of 3263 angiograms (2342 patients) analyzed, 72% were baseline angiograms, and 28% were follow-up angiograms. After anti-VEGF initiation, the number of angiograms per year increased progressively with peaks that matched with the approval of anti-VEGF for wet age-related macular degeneration (2007) (164.2%), macular edema secondary to retinal vein occlusions (2010) (102.2%), and diabetic macular edema (2011) (123.8%). After using SD-OCT, fluorescein angiographies decreased up to 57%.

CONCLUSIONS

Anti-VEGF introduction led to an increase in the indication of angiograms, which did not vary significantly after time domain OCT. Nevertheless, since SD-OCT became available, the indication of fluorescein angiography has halved in the hospital of reference.
Urothelial Carcinoma In Situ of the Bladder With Glandular Differentiation
Authors: Yang Zhiming , Epstein Jonathan I.
Published: April 2018

Urothelial carcinoma in situ (CIS) of the bladder with glandular differentiation (CIS-GL) is rare with some showing an association with small cell carcinoma. There is a paucity of data on whether CIS-GL diagnosed in the absence of invasive carcinoma is associated with an increased risk of developing small cell carcinoma of the bladder. Twenty-seven cases of CIS-GL were identified from the consult files of one of the authors from 2008 to 2015 without prior or coexisting invasive carcinoma at the time of diagnosis. Sixty-five additional cases were identified with concurrent CIS-GL and invasive carcinoma to assess the nature of the association. Of the 27 cases with only CIS-GL without invasive carcinoma at the time of diagnosis, follow-up time ranged from 11 to 91 months (mean, 41.1 mo). Of 24/27 cases with follow-up information: 13 (54.2%) had no evidence of disease at last follow-up, typically treated with induction and maintenance Bacillus Calmette-Guerin; 3 (12.5%) patients underwent radical cystectomy due to disease progression; 2 (8.3%) patients had recurrent CIS, and 1 (4.2%) had recurrent noninvasive low-grade papillary urothelial carcinoma (UC) (these patients underwent transurethral resection of the bladder and Bacillus Calmette-Guerin treatment); 2 (8.3%) patients died of metastatic UC; and 3 (12.5%) died of other or unknown causes. Of note, none of these 24 patients developed small cell carcinoma. Of the 65 cases with concurrent CIS-GL and invasive carcinoma, the invasive carcinoma was: pure UC in 29/65 (45%); invasive UC with GL in 13/65 (20%); coexisting small cell carcinoma and invasive UC in 8/65 (12%); plasmacytoid UC in 7/65 (11%); sarcomatoid UC in 3/65 (5%); micropapillary UC in 2/65 (3%); squamous in 2/65 (3%); and signet ring with colloid features in 1/65 (1%). Patients with CIS-GL without invasive carcinoma are at significant risk for cancer progression and in a minority of cases at risk for death from bladder carcinoma, similar to usual CIS. Typically, subsequent invasive carcinoma is UC rather than adenocarcinoma. Similarly, the largest fraction of concurrent invasive carcinoma and CIS-GL is UC. However, this study for the first time demonstrates the wide spectrum of other UC variants that coexist with CIS-GL, including a sizeable minority of cases with invasive UC with GL. Although there is a disproportionately high fraction of CIS-GL with coexisting small cell carcinoma, small cell carcinoma does not seem to develop at high frequency following the diagnosis and treatment of CIS-GL.
Landiolol Hydrochloride Rapidly Controls Junctional Ectopic Tachycardia After Pediatric Heart Surgery
Authors: Yoneyama Fumiya , Tokunaga Chiho , Kato Hideyuki , Nakajima Tomomi , Mathis Bryan J. , Sakamoto Hiroaki , Hiramatsu Yuji
Published: April 2018

Objectives:

Junctional ectopic tachycardia is a supraventricular tachyarrhythmia with atrioventricular dissociation that causes life-threatening postsurgical conditions in pediatric heart patients. This study evaluates the efficacy of landiolol hydrochloride for managing junctional ectopic tachycardia.

Design:

A single-center retrospective study.

Setting:

PICU at the university hospital.

Patients:

Of 561 pediatric patients who underwent open-heart surgery between 2006 and 2017, 10 patients developed sustained junctional ectopic tachycardia and were selected for landiolol treatment.

Interventions:

None.

Measurements and Main Results:

Landiolol decreased mean heart rate significantly from 206.1 ± 14.5 to 158.0 ± 8.6 beats/min within 2 hours after administration (p < 0.01). Mean time to achieve 20% heart rate reduction was 2.1 ± 0.5 hours. Systolic blood pressure between pre and post landiolol administration did not change significantly (72.6 ± 5.9 to 79.7 ± 6.2 mm Hg). Once junctional heart rate was sufficiently suppressed, atrioventricular sequential pacing was introduced to stabilize hemodynamics. Nine of 10 cases (90%) had atrioventricular sequential pacing to maintain appropriate heart rate and restore atrioventricular synchronicity under suppressed junctional heart rate. Subsequently, eight of 10 cases (80%) were converted to regular sinus rhythm within 24 hours after starting landiolol administration. The average time to achieve sinus rhythm conversion was 7.9 ± 3.4 hours.

Conclusions:

Landiolol rapidly suppresses junctional heart rate in junctional ectopic tachycardia after pediatric heart surgery without significant blood pressure compromises. Subsequent atrioventricular sequential pacing was effective at restoring atrioventricular synchronicity and stabilizing hemodynamics. Combining junctional rate control with landiolol and atrioventricular sequential pacing is therefore suggested as a promising option for prompt management of postoperative junctional ectopic tachycardia.
Toward Live Virtual Constructive Simulations in Healthcare Learning
Authors: Padilla Jose J. , Diallo Saikou Y. , Armstrong Robert K.
Published: April 2018

Summary Statement

This article explores the combination of live, virtual, and constructive (LVC) simulations in healthcare. Live, virtual, and constructive simulations have long existed in the military, but their consideration (and deployment) in medical and healthcare domains is relatively new. We conducted a review on LVC— its current application in the military domain —and highlight an approach, challenges, and present suggestions for its implementation in healthcare learning. Furthermore, based on the state of the art in simulation in healthcare, we suggest that a combination of two simulation types (LV, VC, LC) at the time may be a simpler approach to the community at large.
Artificial intelligence can predict daily trauma volume and average acuity
Authors: Stonko David P. , Dennis Bradley M. , Betzold Richard D. , Peetz Allan B. , Gunter Oliver L. , Guillamondegui Oscar D.
Published: April 2018

BACKGROUND

The goal of this study was to integrate temporal and weather data in order to create an artificial neural network (ANN) to predict trauma volume, the number of emergent operative cases, and average daily acuity at a Level I trauma center.

METHODS

Trauma admission data from Trauma Registry of the American College of Surgeons and weather data from the National Oceanic and Atmospheric Administration was collected for all adult trauma patients from July 2013-June 2016. The ANN was constructed using temporal (time, day of week), and weather factors (daily high, active precipitation) to predict four points of daily trauma activity: number of traumas, number of penetrating traumas, average Injury Severity Score (ISS), and number of immediate operative cases per day. We trained a two-layer feed-forward network with 10 sigmoid hidden neurons via the Levenberg-Marquardt back propagation algorithm, and performed k-fold cross validation and accuracy calculations on 100 randomly generated partitions.

RESULTS

Ten thousand six hundred twelve patients over 1,096 days were identified. The ANN accurately predicted the daily trauma distribution in terms of number of traumas, number of penetrating traumas, number of OR cases, and average daily ISS (combined training correlation coefficientr= 0.9018 ± 0.002; validationr= 0.8899 ± 0.005; testingr= 0.8940 ± 0.006).

CONCLUSION

We were able to successfully predict trauma and emergent operative volume, and acuity using an ANN by integrating local weather and trauma admission data from a Level I center. As an example, for June 30, 2016, it predicted 9.93 traumas (actual: 10), and a mean ISS of 15.99 (actual: 13.12). This may prove useful for predicting trauma needs across the system and hospital administration when allocating limited resources.

LEVEL OF EVIDENCE

Prognostic/epidemiological, level III.
“It's Not the Asperger's That Causes the Anxiety, It's the Communication”
Authors: Walsh Irene P. , Delmar Patricia , Jagoe Caroline
Published: April 2018

This article focuses on a narrative account of a therapeutic journey experienced by 2 of the authors: an individual (P.D.) with a diagnosis in adulthood of autism spectrum disorder (ASD) and a speech–language pathologist/researcher (I.W.). Instead of adopting a traditional expert clinician treating an impaired patient stance in a highly formalized clinical setting, with concomitant role expectations of power and perceived inequality, a cultural–clinical borderland was coconstructed. The figurative notion ofborderlandin this context is used to describe a physical and psychological space characterized by a more flexible, informal, and authentically shared therapeutic relationship, influenced by a merging of cultures. The cultures at play in this context were an ASD and non-ASD culture and the culture and practice of speech–language pathology. Accounts of social communication experiences, challenges, and anxieties focused on personal reflections, when misunderstandings and miscommunications surfaced from perceived cultural differences. Instead of reinforcing experiences of otherness and difference—which may be an inadvertent by-product of impairment-focused therapy—a positive trajectory of hope and recovery emerged from these interactions when they were placed within a person-centered context.
Evolution of Deceased Organ Donation Activity Versus Efficiency Over a 15-year Period: An International Comparison
Authors: Weiss Julius , Elmer Andreas , Mahíllo Beatriz , Domínguez-Gil Beatriz , Avsec Danica , Nanni Costa Alessandro , Haase-Kromwijk Bernadette J.J.M. , Laouabdia Karim , Immer Franz F.
Published: April 2018

Background

The donation rate (DR) per million population is not ideal for an efficiency comparison of national deceased organ donation programs. The DR does not account for variabilities in the potential for deceased donation which mainly depends on fatalities from causes leading to brain death. In this study, the donation activity was put into relation to the mortality from selected causes. Based on that metric, this study assesses the efficiency of different donation programs.

Methods

This is a retrospective analysis of 2001 to 2015 deceased organ donation and mortality registry data. Included are 27 Council of Europe countries, as well as the United States. A donor conversion index (DCI) was calculated for assessing donation program efficiency over time and in international comparisons.

Results

According to the DCI and of the countries included in the study, Spain, France, and the United States had the most efficient donation programs in 2015. Even though mortality from the selected causes decreased in most countries during the study period, differences in international comparisons persist. This indicates that the potential for deceased organ donation and its conversion into actual donation is far from being similar internationally.

Conclusions

Compared with the DR, the DCI takes into account the potential for deceased organ donation, and therefore is a more accurate metric of performance. National donation programs could optimize performance by identifying the areas where most potential is lost, and by implementing measures to tackle these issues.
Heavy Alcohol Use Among Deceased Donors Does Not Impact Recipient Outcomes After Liver Transplantation
Authors: Arora Sumant S. , Chahal Khushdeep S. , Axley Page , Eckhoff Devin E. , Kuo Yong-Fang , Satapathy Sanjaya K. , Wiesner Russell , Singal Ashwani K.
Published: April 2018

Background

Data on liver transplant (LT) outcomes using deceased donors with heavy drinking (HD) (>2 drinks per day) are scanty.

Methods

Using the United Network for Organ Sharing database (2002-2014), we examined outcomes after LT in adults comparing deceased HD donors with non-HD (ND) donors.

Results

Of 56 182 first LTs performed in the United States for 10 common indications using deceased donors, 47 882 with available information on alcohol use were analyzed. Of these 47 882 LT recipients, 7298 (15%) were from HD donors, with similar proportion over time (2002-2014, Armitage trend test P = 0.75) and for recipient liver disease etiology (χ2
P = 0.42). Proportion of liver organ used for LT was lower for HD donors compared with ND donors (63% vs 78%; P < 0.001). Five-year outcomes on first LT comparing 7166 HD donors and 21 498 ND donors matched based on propensity score were similar for liver graft (73.7% vs 73.7%, log rank P = 0.98) and patient survival (77.6% vs 77.0%, P = 0.36). On Cox regression analysis, history of HD in deceased donors did not affect liver graft 1.02 (0.97-1.08) or patient survival 1.03 (0.97-1.09).

Conclusions

Among LT recipients using select liver grafts, history of HD in deceased donors does not impact outcomes after LT.
State of the Art: Role of the Dendritic Cell in Induction of Allograft Tolerance
Authors: Rosen Sarah J. , Harris Paul E. , Hardy Mark A.
Published: April 2018

Despite decades of research, the induction and maintenance of long-term allograft tolerance without immunosuppression remains an elusive goal in the field of solid organ and cell transplantation. Immunosuppressive medications frequently prevent or minimize acute cellular rejection but have failed to halt antidonor antibody production and chronic organ rejection. Past efforts aimed at promoting lasting allograft tolerance have focused primarily on peripheral T-cell depletion, augmentation of regulatory T cells, or induction via simultaneous hematopoietic stem cell transplantation and facilitation of donor chimerism. So far, none of these methods have led to consistently safe, feasible and long lasting donor organ acceptance. Over the course of the past 4 decades, the study of a unique population of antigen-presenting cells known as dendritic cells has shown promise for breaking new ground in achieving indefinite allograft survival without immunosuppression and its associated adverse effects. In this review, we discuss the discovery and early investigations of dendritic cells and chronicle some of the key studies demonstrating their role in transplantation, particularly in indirect allorecognition, the immunologic pathway thought to drive chronic rejection and perhaps tolerance induction.
Outcomes After Cardiac Transplant for Wild Type Transthyretin Amyloidosis
Authors: Rosenbaum Andrew N. , AbouEzzeddine Omar F. , Grogan Martha , Dispenzieri Angela , Kushwaha Sudhir , Clavell Alfredo , Daly Richard C. , Edwards Brooks S.
Published: April 2018

Background

The true prevalence of heart failure due to wild type transthyretin amyloidosis (ATTRwt) is likely underestimated. There is a paucity of data with regard to the management of ATTRwt-related advanced heart failure and the natural history of extracardiac ATTRwt.

Methods

We conducted a retrospective cohort study of patients undergoing cardiac transplant (HTx) for ATTRwt at a single institution. Comprehensive clinical data, including baseline hemodynamic and echocardiographic characteristics, and posttransplant outcomes, were obtained.

Results

Seven patients with ATTRwt underwent HTx between 2007 and 2015. All patients were male with a mean age of 66 ± 9. Patients had a reduced ejection fraction (mean, 37 ± 14%) and elevated filling pressures pre-HTx (mean pulmonary capillary wedge pressure 22 ± 7 mm Hg) before HTx. Three-year survival was 100%; 1 patient died of pancreatic cancer 45 months post-HTx (1 death per 30.8 patient-years). Oxygen consumption (Δ +6.8 ± 4.9 mL·kg−1·min−1) and 6-minute walk distances (Δ +189 ± 60 m) improved. Symptomatic gastrointestinal involvement (n = 2) and peripheral nerve involvement (n = 4) by ATTRwt developed late.

Conclusions

This is the first report of a series of ATTRwt patients receiving HTx in which excellent outcomes are demonstrated. Although cardiac death is averted, systemic manifestations of ATTRwt may develop posttransplantation.
Role of MRCP in Diagnosing Biliary Anastomotic Strictures After Liver Transplantation: A Single Tertiary Care Center Experience
Authors: Akbar Ali , Tran Quynh T. , Nair Satheesh P. , Parikh Salil , Bilal Muhammad , Ismail Mohammed , Vanatta Jason M. , Eason James D. , Satapathy Sanjaya K.
Published: April 2018

Background

Biliary strictures (BS) are common complication after liver transplantation. We aimed to determine the accuracy of magnetic resonance cholagiopancreatography (MRCP) in diagnosing BS in liver transplant recipients (LTRs) when compared to direct cholangiographic methods (endoscopic resonance cholagiopancreatography [ERCP] and/or percutaneous transhepatic cholangiography [PTC]).

Methods

Retrospective chart review of 910 LTRs (July 2008 to April 2015) was performed, and a total of 39 patients with duct-to-duct anastomosis (22 males; 56.4%; mean age, 52.8 ± 8.3 years) were included who had an MRCP followed by either ERCP and/or PTC within 4 weeks. A cholangiographic narrowing (on ERCP and/or PTC) that required balloon dilation and/or stent placement was considered a BS and was considered clinically significant if the intervention resulted in at least 30% improvement of bilirubin within 2 weeks. Sensitivity, specificity, accuracy, positive predictive values and negative predictive values of MRCP in diagnosing BS were calculated.

Results

Magnetic resonance cholagiopancreatography showed anastomotic BS in 17 of 39 patients, and subsequent ERCP and/or PTC revealed a total of 25 BS (positive predictive value of 0.94). Nine BS on cholangiography (ERCP, 8; PTC, 1) were not detected on earlier MRCP (sensitivity, 0.64; 95% CI, 0.45-0.82); 2 were clinically significant BS and 6 of the remaining 7 had no improvement in their liver function test with biliary intervention. Thirteen LTRs had no BS on either modality (specificity, 0.93; 95% CI, 0.66-0.99). The negative predictive value of MRCP was 0.59 for cholangiographic BS. The overall accuracy of MRCP is 0.74 (exact 95% CI, 0.58-0.87). Inclusion of age, race, and alanine aminotransferase level improved the predictive value of MRCP (area under the curve = 0.94, 95% CI: 0.86-1.00).

Conclusions

Magnetic resonance cholagiopancreatography has high specificity but low sensitivity in diagnosing cholangiographic BS in LTRs, although the predictive value further improved with inclusion of age, race, and alanine aminotransferase. Clinical significance of BS in LTRs not identified on MRCP is questionable because ERCP with intervention did not improve their liver function tests in the vast majority.
Hybrid graphene–ceramic nanofibre network for spontaneous neural differentiation of stem cells
Authors: Kazantseva Jekaterina , Hussainova Irina , Ivanov Roman , Neuman Toomas , Gasik Michael
Published: April 2018

A challenge in regenerative medicine is governed by the need to have control over the fate of stem cells that is regulated by the physical and chemical microenvironment
in vitro
and
in vivo
. The differentiation of the stem cells into specific lineages is commonly guided by use of specific culture media. For the first time, we demonstrate that human mesenchymal stem cells are capable of turning spontaneously towards neurogenic lineage when seeded on graphene-augmented, highly anisotropic ceramic nanofibres without special differentiation media, contrary to commonly thought requirement of ‘soft’ substrates for the same purpose. Furthermore, pro-inflammatory gene expression is simultaneously suppressed, and expression of factors promoting focal adhesion and monocytes taxis is upregulated. This opens new possibilities of using local topo-mechanical cues of the ‘graphenized’ scaffold surfaces to guide stem cell proliferation and differentiation, which can be used in studies of neurological diseases and cell therapy.
The effect of graphene–poly(methyl methacrylate) fibres on microbial growth
Authors: Matharu Rupy Kaur , Porwal Harshit , Ciric Lena , Edirisinghe Mohan
Published: April 2018

A novel class of ultra-thin fibres, which affect microbial growth, were explored. The microbial properties of poly(methyl methacrylate) fibres containing 2, 4 and 8 wt% of graphene nanoplatelets (GNPs) were studied. GNPs were dispersed in a polymeric solution and processed using pressurized gyration. Electron microscopy was used to characterize GNP and fibre morphology. Scanning electron microscopy revealed the formation of beaded porous fibres. GNP concentration was found to dictate fibre morphology. As the GNP concentration increased, the average fibre diameter increased from 0.75 to 2.71 µm, while fibre porosity decreased. Gram-negative bacteriaEscherichia coliandPseudomonas aeruginosawere used to investigate the properties of 2, 4 and 8 wt% GNP-loaded fibres. GNP-loaded fibres (0 wt%) were used as the negative control. The fibres were incubated for 24 h with the bacteria; bacterial colony-forming units were enumerated by adopting the colony-counting method. The presence of 2 and 4 wt% GNP-loaded fibres promoted microbial growth, while 8 wt% GNP-loaded fibres showed antimicrobial activity. These results indicate that the minimum inhibitory concentration of GNPs required within a fibre is 8 wt%.
No evidence of functional co-adaptation between clustered microRNAs
Authors: Marco Antonio
Published: April 2018

A significant fraction of microRNA loci are organized in genomic clusters. The origin and evolutionary dynamics of these clusters have been extensively studied, although different authors have come to different conclusions. In a recent paper, it has been suggested that microRNAs in the same clusters evolve to target overlapping sets of genes. The authors interpret this as functional co- adaptation between clustered microRNAs. Here I reanalyze their results and I show that the observed overlap is mostly due to two factors: similarity between two seed sequences of a pair of clustered microRNAs, and the expected high number of common targets between pairs of microRNAs that have a large number of targets each. After correcting for these factors, I observed that clustered microRNAs from different microRNA families do not share more targets than expected by chance. During an exchange of correspondence and manuscripts, the authors of the original report acknowledged that the permutation methods they performed was not the method they described in their original paper. Here I show that the new permutation test proposed is biased and leads to systematic errors of the first kind, which will explain why the p-values reported were extremely (and unrealistically) low. I also discuss how to investigate the evolutionary dynamics of clustered microRNAs and their targets. In conclusion, there is no evidence of widespread functional co-adaptation between clustered microRNAs.
Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas
Authors: Rosario SR , Long MD , Affronti HC , Rowsam AM , Eng KH , Smiraglia DJ
Published: April 2018

Understanding the levels of metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Using transcriptomic data from 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we developed a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. This pathway dysregulation was confirmed in separate patient populations, further demonstrating the robustness of this approach. A bootstrapping simulation was then applied to assess whether these alterations were biologically meaningful, rather than expected by chance. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest in both common and rare disease sites. Utilizing a pathway mapping approach to understand patterns of metabolic flux, differential drug sensitivity, can accurately be predicted. Further, the identification of Master Metabolic Transcriptional Regulators, whose expression was highly correlated with pathway gene expression, explains why metabolic differences exist in different disease sites. We demonstrate these also have the ability to segregate patient populations and predict responders to different metabolism-targeted therapeutics.
Tigmint: Correcting Assembly Errors Using Linked Reads From Large Molecules
Authors: Jackman Shaun D , Coombe Lauren , Chu Justin , Warren Rene L , Vandervalk Benjamin P , Yeo Sarah , Xue Zhuyi , Mohamadi Hamid , Bohlmann Joerg , Jones Steven JM , Birol Inanc
Published: April 2018

Genome sequencing yields the sequence of many short snippets of DNA (reads) from a genome. Genome assembly attempts to reconstruct the original genome from which these reads were derived. This task is difficult due to gaps and errors in the sequencing data, repetitive sequence in the underlying genome, and heterozygosity, and assembly errors are common. These misassemblies may be identified by comparing the sequencing data to the assembly, and by looking for discrepancies between the two. Once identified, these misassemblies may be corrected, improving the quality of the assembly. Although tools exist to identify and correct misassemblies using Illumina pair-end and mate-pair sequencing, no such tool yet exists that makes use of the long distance information of the large molecules provided by linked reads, such as those offered by the 10x Genomics Chromium platform. We have developed the tool Tigmint for this purpose. To demonstrate the effectiveness of Tigmint, we corrected assemblies of a human genome using short reads assembled with ABySS 2.0 and other assemblers. Tigmint reduced the number of misassemblies identified by QUAST in the ABySS assembly by 216 (27%). While scaffolding with ARCS alone more than doubled the scaffold NGA50 of the assembly from 3 to 8 Mbp, the combination of Tigmint and ARCS improved the scaffold NGA50 of the assembly over five-fold to 16.4 Mbp. This notable improvement in contiguity highlights the utility of assembly correction in refining assemblies. We demonstrate its usefulness in correcting the assemblies of multiple tools, as well as in using Chromium reads to correct and scaffold assemblies of long single-molecule sequencing. The source code of Tigmint is available for download from https://github.com/bcgsc/tigmint, and is distributed under the GNU GPL v3.0 license.
DNA profiling reveals Neobenedenia girellae as the primary culprit in global fisheries and aquaculture
Authors: Brazenor Alexander K. , Bertozzi Terry , Miller Terrence L. , Whittington Ian D. , Hutson Kate S.
Published: April 2018

Accurate identification of parasite species and strains is crucial to mitigate the risk of epidemics and emerging disease. Species of Neobenedenia are harmful monogenean ectoparasites that infect economically important bony fishes in aquaculture worldwide, however, the species boundaries between two of the most notorious taxa, N. melleni and N. girellae, has been a topic of contention for decades. Historically, identifications of Neobenedenia isolates have overwhelmingly been attributed to N. melleni, and it has been proposed that N. girellae is synonymous with N. melleni. We collected 33 Neobenedenia isolates from 22 host species spanning nine countries and amplified three genes including two nuclear (Histone 3 and 28S rDNA) and one mitochondrial (cytochrome b). Four major clades were identified using Maximum Likelihood and Bayesian inference analyses; clades A-D corresponding to N. girellae, N. melleni, N. longiprostata and N. pacifica respectively. All unidentified isolates and the majority of Neobenedenia sequences from GenBank fell into clade A. The results of this study indicate that N. girellae is a separate species to N. melleni, and that a large proportion of previous samples identified as N. melleni may be erroneous and a revision of identifications is needed.

The large diversity of host species that N. girellae is able to infect as determined in this study and the geographic range in which it is present (23.8426° S and 24.1426° N) makes it a globally cosmopolitan species and a threat to aquaculture industries around the world.
Testing the causal effects between subjective wellbeing and physical health using Mendelian randomisation
Authors: Wootton Robyn E , Lawn Rebecca B , Millard Louise A C , Davies Neil M , Taylor Amy E , Munafò Marcus R , Timpson Nicholas J , Davis Oliver S P , Smith George Davey , Haworth Claire M A
Published: April 2018

Objectives

To investigate whether the association between subjective wellbeing (subjective happiness and life satisfaction) and physical health is causal.

Design

We conducted two-sample bidirectional Mendelian randomisation between subjective wellbeing and six measures of physical health: coronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol and body mass index (BMI).

Participants

We used summary data from four large genome-wide association study consortia: CARDIoGRAMplusC4D for coronary artery disease and myocardial infarction; the Global Lipids Genetics Consortium for cholesterol measures; the Genetic Investigation of Anthropometric Traits consortium for BMI; and the Social Science Genetics Association Consortium for subjective wellbeing. A replication analysis was conducted using 337,112 individuals from the UK Biobank (54% female, mean age =56.87, SD=8.00 years at recruitment).

Main outcome measures

Coronary artery disease, myocardial infarction, total cholesterol, HDL cholesterol, LDL cholesterol, BMI and subjective wellbeing.

Results

There was evidence of a causal effect of BMI on subjective wellbeing such that each 1 kg/m2 increase in BMI caused a 0.045 (95%CI 0.006 to 0.084, p=0.023) SD reduction in subjective wellbeing. Replication analyses provided strong evidence of an effect of BMI on satisfaction with health (β=0.034 (95% CI: −0.042 to −0.026) unit decrease in health satisfaction per SD increase in BMI, p<2-16). There was no clear evidence of a causal effect between subjective wellbeing and the other physical health measures in either direction.

Conclusions

Our results suggest that a higher BMI lowers subjective wellbeing. Our replication analysis confirmed this finding, suggesting the effect in middle-age is driven by satisfaction with health. BMI is a modifiable determinant and therefore, our study provides further motivation to tackle the obesity epidemic because of the knock-on effects of higher BMI on subjective wellbeing.
Animacy and real world size shape object representations in the human medial temporal lobes
Authors: Blumenthal Anna , Stojanoski Bobby , Martin Chris , Cusack Rhodri , Köhler Stefan
Published: April 2018

Identifying what an object is, and whether an object has been encountered before, is a crucial aspect of human behavior. Despite this importance, we do not have a complete understanding of the neural basis of these abilities. Investigations into the neural organization of human object representations have revealed category specific organization in the ventral visual stream in perceptual tasks. Interestingly, these categories fall within broader domains of organization, with distinctions between animate, inanimate large, and inanimate small objects. While there is some evidence for category specific effects in the medial temporal lobe (MTL), it is currently unclear whether domain level organization is also present across these structures. To this end, we used fMRI with a continuous recognition memory task. Stimuli were images of objects from several different categories, which were either animate or inanimate, or large or small within the inanimate domain. We employed representational similarity analysis (RSA) to test the hypothesis that object-evoked responses in MTL structures during recognition-memory judgments also show evidence for domain-level organization along both dimensions. Our data support this hypothesis. Specifically, object representations were shaped by either animacy, real-world size, or both, in perirhinal and parahippocampal cortex, as well as the hippocampus. While sensitivity to these dimensions differed when structures when probed individually, hinting at interesting links to functional differentiation, similarities in organization across MTL structures were more prominent overall. These results argue for continuity in the organization of object representations in the ventral visual stream and the MTL.
Reward-related regions form a preferentially coupled system at rest
Authors: Huckins Jeremy F. , Adeyemo Babatunde , Miezin Fran M. , Power Jonathan D. , Gordon Evan M. , Laumann Timothy O. , Heatherton Todd F. , Petersen Steven E. , Kelley William M.
Published: April 2018

Neuroimaging studies have implicated a set of striatal and orbitofrontal cortex (OFC) regions that are commonly activated during reward processing tasks. Resting-state functional connectivity (RSFC) studies have demonstrated that the human brain is organized into several functional systems that show strong temporal coherence even in the absence of goal-directed tasks. Here we use seed-based and graph-theory RSFC approaches to characterize the systems-level organization of putative reward regions of at rest. Peaks of connectivity from seed-based RSFC patterns for the nucleus accumbens (NAcc, anatomically defined) and orbitofrontal cortex (OFC, functionally defined) were used to identify candidate reward regions which were merged with a previously used set of regions (Power et al., 2011). Graph-theory was then used to determine system-level membership for all regions. Several regions previously implicated in reward-processing (NAcc, lateral and medial OFC, and ventromedial prefrontal cortex) comprised a distinct, preferentially coupled system. This RSFC system is stable across a range of connectivity thresholds and shares strong overlap with meta-analyses of task-based reward studies. This reward system shares between-system connectivity with systems implicated in cognitive control and self-regulation, including the fronto-parietal, cingulo-opercular, and default systems. Further, differences may exist in the pathways through which control systems interact with key regions of this reward system. Whereas NAcc regions of the reward system are functionally connected to cingulo-opercular and default systems, OFC regions of the reward system show stronger connectivity with the fronto-parietal system. We propose that future work may be able to interrogate group or individual differences in connectivity profiles using the regions delineated in the current work to explore potential relationships to appetitive behaviors, self-regulation failure, and addiction.
Extraordinary genome instability and widespread chromosome rearrangements during vegetative growth
Authors: Möller Mareike , Habig Michael , Freitag Michael , Stukenbrock Eva H.
Published: April 2018

The haploid genome of the pathogenic fungusZymoseptoria triticiis contained on “core” and “accessory” chromosomes. While 13 core chromosomes are found in all strains, as many as eight accessory chromosomes show presence/absence variation and rearrangements among field isolates. We investigated chromosome stability using experimental evolution, karyotyping and genome sequencing. We report extremely high and variable rates of accessory chromosome loss during mitotic propagationin vitroandin planta. Spontaneous chromosome loss was observed in 2 to >50 % of cells during four weeks of incubation. Similar rates of chromosome loss in the closely relatedZ. ardabiliaesuggest that this extreme chromosome dynamic is a conserved phenomenon in the genus. Elevating the incubation temperature greatly increases instability of accessory and even core chromosomes, causing severe rearrangements involving telomere fusion and chromosome breakage. Chromosome losses do not impact the fitness ofZ. tritici in vitro, but some lead to increased virulence suggesting an adaptive role of this extraordinary chromosome instability.
RefSeq database growth influences the accuracy of k-mer-based species identification
Authors: Nasko Daniel J. , Koren Sergey , Phillippy Adam M. , Treangen Todd J.
Published: April 2018

Accurate species-level taxonomic classification and profiling of complex microbial communities remains a challenge due to homologous regions shared among closely related species and a sparse representation of non-human associated microbes in the database. Although the database undoubtedly has a strong influence on the sensitivity of taxonomic classifiers and profilers, to date, no study has carefully explored this topic on historical RefSeq releases and explored its impact on accuracy. In this study, we examined the influence of the database, over time, on k-mer based sequence classification and profiling. We present three major findings: (i) database growth over time resulted in more classified reads, but fewer species-level classifications and more species-level misclassifications; (ii) Bayesian re-estimation of abundance helped to recover species-level classifications when the exact target strain was present; and (iii) Bayesian reestimation struggled when the database lacked the target strain, resulting in a notable decrease in accuracy. In summary, our findings suggest that the growth of RefSeq over time has strongly influenced the accuracy of k-mer based classification and profiling methods, resulting in different classification results depending on the particular database used. These results suggest a need for new algorithms specially adapted for large genome collections and better measures of classification uncertainty.
Reverse transcription-PCR using a Primer Set Targeting the 3D Region Detects Foot-and-Mouth Disease Virus with High Sensitivity
Authors: Nishi Tatsuya , Kanno Toru , Shimada Nobuaki , Morioka Kazuki , Yamakawa Makoto , Fukai Katsuhiko
Published: April 2018

Because foot-and-mouth disease (FMD) has the potential to spread extensively, methods used for its diagnosis must be rapid and accurate. Therefore, reverse transcription-PCR (RT-PCR) plays an important diagnostic role. Here we designed the primer set FM8/9 to amplify 644 bases of the conserved 3D region of all seven serotypes of FMD virus (FMDV). We compared the performance of RT-PCR assays using FM8/9 with that using the primer set 1F/R targeting the 5’-UTR described in the manual of the World Organization for Animal Health. The detection limits of the RT-PCR assays were determined for 14 strains representing all serotypes. Compared with the sensitivities of the RT-PCR assay using 1F/R, those using FM8/9 were 101-to 104-fold higher for eight strains. To assess the validity of the methods for analyzing clinical samples, sera and saliva samples from pigs and cows infected with FMDV were collected daily and analyzed using the two PCR assays. The FM8/9 assay detected FMDV from all infected pigs and cows for longer times compared with the 1F/R assay, therefore revealing higher sensitivity for the clinical samples. Our results suggest that the FM8/9 RT-PCR assay is highly sensitive and is therefore suitable for the diagnosis of FMD.
Interferon lambda 4 impacts broadly on hepatitis C virus diversity
Authors: Ansari M Azim , Aranday-Cortes Elihu , Ip Camilla LC , Filipe Ana da Silva , Hin Lau Siu , Bamford Connor G G , Bonsall David , Trebes Amy , Piazza Paolo , Sreenu Vattipally , Cowton Vanessa M ,   STOP-HCV Consortium, Hudson Emma , Bowden Rory , Patel Arvind H , Foster Graham R , Irving William L , Agarwal Kosh , Thomson Emma C , Simmonds Peter , Klenerman Paul , Holmes Chris , Barnes Eleanor , Spencer Chris CA , McLauchlan John , Pedergnana Vincent
Published: April 2018

Type III interferons (IFN-λ) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-λ4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-λ4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-λ4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-λ4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.
Destabilization of Ran C-terminus promotes GTP loading and occurs in multiple Ran cancer mutations
Authors: Zhang Yuqing , Zhou Jinhan , Tan Yuping , Zhou Qiao , Tong Aiping , Shen Xiaofei , Jia Da , Sun Xiaodong , Sun Qingxiang
Published: April 2018

Ran (Ras-related nuclear protein) plays several important roles in nucleo-cytoplasmic transport, mitotic spindle formation, nuclear envelope/nuclear pore complex assembly, and other diverse functions in the cytoplasm, as well as in cellular transformation when activated. Unlike other Ras superfamily proteins, Ran contains an auto-inhibitory C-terminal tail, which packs against its G domain and bias Ran towards binding GDP over GTP. The biological importance of this C-terminal tail is not well understood. By disrupting the interaction between the C-terminus and the G domain, we were able to generate Ran mutants that are innately active and potently bind to RanBP1 (Ran Binding Protein 1), nuclear export factor CRM1 and nuclear import factor KPNB1. In contrast to previously reported activated Ran mutants, the C-terminus destabilized mutants are hydrolysis competent in cells, support nuclear transport, and do not form nuclear rim staining. Crystal structures show that one of these C-terminal mutations slightly changes its mode of binding to RanBP1. Finally, a high percentage of Ran C-terminus mutations from cancer patients were found to be destabilizing and hyperactivating, suggesting that Ran C-destabilization might be an unprecedented cellular transformation mechanism in affected cancers. This study also highlights a new drug design strategy towards treating patients with hyperactivated Ras proteins including K-Ras.
Changes in neuronal immunofluorescence in the C- versus N-terminal domains of hnRNP H following D1 dopamine receptor activation
Authors: Ruan Qiu T. , Yazdani Neema , Beierle Jacob A. , Hixson Kathryn M. , Hokenson Kristen E. , Apicco Daniel J. , Luttik Kimberly P. , Zheng Karen , Maziuk Brandon F. , Ash Peter E. A. , Szumlinski Karen K. , Russek Shelley J. , Wolozin Benjamin , Bryant Camron D.
Published: April 2018

RNA binding proteins are a diverse class of proteins that regulate all aspects of RNA metabolism. Accumulating studies indicate that heterogeneous nuclear ribonucleoproteins are associated with cellular adaptations in response to drugs of abuse. We recently mapped and validated heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1) as a quantitative trait gene underlying differential behavioral sensitivity to methamphetamine. The molecular mechanisms by which hnRNP H1 alters methamphetamine behaviors are unknown but could involve preand/or post-synaptic changes in protein localization and function. Methamphetamine initiates post-synaptic D1 dopamine receptor signaling indirectly by binding to pre-synaptic dopamine transporters and vesicular monoamine transporters of midbrain dopaminergic neurons which triggers revers e transport and accumulation of dopamine at the synapse. Here, we examined changes in neuronal localization of hnRNP H in primary rat cortical neurons that express dopamine receptors that can be modulated by the D1 or D2 dopamine receptor agonists SKF38393 and (-)-Quinpirole HCl, respectively. Basal immunostaining of hnRNP H was localized primarily to the nucleus. D1 dopamine receptor activation induced an increase in hnRNP H nuclear immunostaining as detected by immunocytochemistry with a C-domain directed antibody containing epitope near the glycine-rich domain but not with an N-domain specific antibody. Although there was no change in hnRNP H protein in the nucleus or cytoplasm, there was a decrease in Hnrnph1 transcript following D1 receptor stimulation. Taken together, these results suggest that D1 receptor activation increases availability of the hnRNP H C-terminal epitope, which could potentially reflect changes in protein-protein interactions. Thus, D1 receptor signaling could represent a key molecular post-synaptic event linking Hnrnph1 polymorphisms to drug-induced behavior.

Highlights

We investigated immunofluorescence and localization of hnRNP H following dopamine receptor activation in primary rat cortical neurons.

Activation of D1 dopamine receptor increased nuclear immunofluorescence of the C-terminal domain but not the N-terminal domain of hnRNP H with no change in either nuclear or cytoplasmic levels of hnRNP H protein.

D1 dopamine signaling could alter interaction of hnRNP H with other proteins.