bluuebunny/crossref_metadata_2025 huggingface dataset:
How to calculate the ASDAS based on C-reactive protein without individual questions from the BASDAI: the BASDAI-based ASDAS formula
Authors: Aranda-Valera I Concepcion , Garrido-Castro Juan L , Ladehesa-Pineda Lourdes , Vazquez-Mellado Janitzia , Zarco Pedro , Juanola Xavier , Gonzalez-Navas Cristina , Font-Ugalde Pilar , Castro-Villegas M Carmen
Published: September 2019

Objectives

To develop a new equation to calculate the Ankylosing Spondylitis Disease Activity Score based on CRP (ASDAS-CRP) using only the BASDAI total score and CRP.

Methods

Axial SpA (axSpA) patients from the Cordoba Spondyloarthritis Registry cohort were recruited as a derivation cohort, while a retrospective sample from the Spanish Rheumatology Society National Registry of Spondyloarthropathies and Ibero American Spondyloarhtritis Registry registers was used as a validation cohort. We built a new equation based only on the BASDAI and CRP, defining a new formula: the BASDAI-based ASDAS (BASDAS). Linear regression analysis was used to determine the coefficients of the equation in the derivation cohort and it was subsequently validated in the validation cohort.

Results

A total of 52 axSpA patients in the derivation cohort and 3359 patients in the validation cohort were included. In the derivation cohort, the mean BASDAS [2.24 (s.d. 0.90)] was very similar to the ASDAS-CRP [2.23 (s.d. 0.95)], with a very strong correlation (r = 0.96, P < 0.001). In the validation cohort, the mean BASDAS was 3.31 (s.d. 1.37) and the ASDAS-CRP was 3.19 (s.d. 1.27), which also had a very strong correlation (r = 0.95, P < 0.001). Intraclass correlation coefficients were excellent in both cohorts (0.963 and 0.947, respectively).

Conclusion

The BASDAS performs similarly to the ASDAS-CRP and can be calculated with only the BASDAI total score and CRP, allowing evaluation of disease activity in retrospective studies where the individual items of the BASDAI are not available.
IN VIVO BIODOSIMETRY OF PORCINE T-LYMPHOCYTE SUBSETS AND NK CELLS
Authors: Andrejsová Lenka , Šinkorová Zuzana , Šinkora Jiří , Tichý Aleš , Filipová Alžběta , Němcová Markéta , Šinkora Marek
Published: September 2019

The aim of the present study was to evaluate the biodosimetric potential of peripheral blood lymphocytes, particularly of T-cell subsets (null and T helper) and natural killer cells (NK), upon exposure to gamma irradiation (60Co) in vivo. For this purpose, the change in relative numbers of NK cells and T-lymphocyte subsets, as well as in the H2AX phosphorylation rate, were evaluated as potential early markers of the lymphocytic response to irradiation in vivo. These experiments were performed on a Large White Pig model. As a result, significant but not dose-dependent changes in the proportion of lymphocyte subpopulations (NK cells, null and T helper cells) were found after exposure to ionising radiation in vivo. On the other hand, circulating NK cells showed relatively higher radioresistance capacity when compared to the T-lymphocyte subsets; however, gamma-H2AX expression showed no significant difference between the evaluated lymphocyte subsets.
Automatic detection of microsleep episodes with feature-based machine learning
Authors: Skorucak Jelena , Hertig-Godeschalk Anneke , Schreier David R , Malafeev Alexander , Mathis Johannes , Achermann Peter
Published: September 2019

Study Objectives

Microsleep episodes (MSEs) are brief episodes of sleep, mostly defined to be shorter than 15 s. In the electroencephalogram (EEG), MSEs are mainly characterized by a slowing in frequency. The identification of early signs of sleepiness and sleep (e.g. MSEs) is of considerable clinical and practical relevance. Under laboratory conditions, the maintenance of wakefulness test (MWT) is often used for assessing vigilance.

Methods

We analyzed MWT recordings of 76 patients referred to the Sleep-Wake-Epilepsy-Center. MSEs were scored by experts defined by the occurrence of theta dominance on ≥1 occipital derivation lasting 1–15 s, whereas the eyes were at least 80% closed. We calculated spectrograms using an autoregressive model of order 16 of 1 s epochs moved in 200 ms steps in order to visualize oscillatory activity and derived seven features per derivation: power in delta, theta, alpha and beta bands, ratio theta/(alpha + beta), quantified eye movements, and median frequency. Three algorithms were used for MSE classification: support vector machine (SVM), random forest (RF), and an artificial neural network (long short-term memory [LSTM] network). Data of 53 patients were used for the training of the classifiers, and 23 for testing.

Results

MSEs were identified with a high performance (sensitivity, specificity, precision, accuracy, and Cohen’s kappa coefficient). Training revealed that delta power and the ratio theta/(alpha + beta) were most relevant features for the RF classifier and eye movements for the LSTM network.

Conclusions

The automatic detection of MSEs was successful for our EEG-based definition of MSEs, with good performance of all algorithms applied.
How NPs can help expand telehealth services
Authors: Rincon Teresa A.
Published: September 2019

Consumers of healthcare services are demanding more convenient and accessible options to care. Technologic advancements can support this demand, but telehealth knowledge is lacking. This article will describe the current state of telehealth and examine the role that NPs can play in furthering its adoption.
Congress2018 poster winners
Authors: Muza Christie , Flinn Kathleen Hogan , Parrott Lori Ann , Schronk Crista
Published: September 2019

The following articles represent the first-place and runner-up winnersfrom the NMCongress2018 poster contest. Both posters were presented and recognized at last year's conference. Congratulations to our winners!
Recommendations for Systemic Antimicrobial Therapy in Fracture-Related Infection: A Consensus From an International Expert Group
Authors: Depypere Melissa , Kuehl Richard , Metsemakers Willem-Jan , Senneville Eric , McNally Martin A. , Obremskey William T. , Zimmerli Werner , Atkins Bridget L. , Trampuz Andrej ,   on behalf of the Fracture-Related Infection (FRI) Consensus Group
Published: September 2019

Fracture-related infection (FRI) is a major complication in musculoskeletal trauma and one of the leading causes of morbidity. Standardization of general treatment strategies for FRI has been poor. One of the reasons is the heterogeneity in this patient population, including various anatomical locations, multiple fracture patterns, different degrees of soft-tissue injury, and different patient conditions. This variability makes treatment complex and hard to standardize. As these infections are biofilm-related, surgery remains the cornerstone of treatment, and this entails multiple key aspects (eg, fracture fixation, tissue sampling, debridement, and soft-tissue management). Another important aspect, which is sometimes less familiar to the orthopaedic trauma surgeon, is systemic antimicrobial therapy. The aim of this article is to summarize the available evidence and provide recommendations for systemic antimicrobial therapy with respect to FRI, based on the most recent literature combined with expert opinion.

Level of Evidence:

Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.
Positive effect of metformin treatment in colorectal cancer patients with type 2 diabetes: national cohort study
Authors: Dulskas Audrius , Patasius Ausvydas , Linkeviciute-Ulinskiene Donata , Zabuliene Lina , Urbonas Vincas , Smailyte Giedre
Published: September 2019

We aimed to estimate colorectal cancer risk in patients with type 2 diabetes mellitus (T2DM) using metformin. Patients with colorectal cancer and diabetes from 2000 to 2012 were identified form Lithuanian Cancer Registry and the National Health Insurance Fund database. Standardized incidence ratios (SIRs) for colorectal cancers as a ratio of observed number of cancer cases in people with diabetes to the expected number of cancer cases in the underlying general population was calculated. We analysed 111 109 patients with diabetes. Overall, 1213 colorectal cancers were observed versus 954.91 expected within a period of observation entailing an SIR of 1.27 [95% confidence interval (CI): 1.20–1.34]. Significantly higher risk of colorectal cancer was found both in male and female patients with diabetes in all age groups. Higher risk was found for both colon and rectum cancers 1.36 (95% CI: 1.27–1.46) and 1.11 (95% CI: 1.01–1.22), respectively. There were no differences in risk over time since initial diabetes diagnosis. Never-users of metformin had twice higher risk of colorectal cancer compared to general population (SIR: 2.14, 95% CI: 1.95–2.35). Among metformin users, risk was lover (SIR: 1.47, 95% CI: 1.36–1.58) and colorectal cancer risk decreased with increasing cumulative dose of metformin (P < 0.001). Patients with T2DM had increased risk of colorectal cancer compared with the general Lithuanian population. Decreasing colorectal cancer risk with increasing cumulative dose of metformin indicates that metformin may be a protective agent for colorectal cancer development.
Analysis of Periorbital Soft Tissue in Thyroid Eye Disease
Authors: Mimura Masashi , Yang Patrick T. , Ko Audrey C. , Korn Bobby S. , Kikkawa Don O.
Published: September 2019

Superior and inferior periorbital fat is enlarged in thyroid eye disease with the superior periorbital fat expansion correlating with orbital fat expansion.

Purpose:

To investigate periorbital tissue enlargement in thyroid eye disease (TED) by 3-dimensional CT volumetric analysis.

Methods:

Twenty-four adult subjects, 16 with TED and 8 controls, were studied. Three-dimensional volumetric calculations were performed on CT imaging of the orbit and face, focusing on the retroorbicularis oculi fat, suborbicularis oculi fat, facial muscles in periorbital region, orbital fat, extraocular muscles, and orbital volume. Analysis was performed using JMP version 12 software. Each measure was compared between the TED and control groups using Wilcoxon rank sum test. Correlations were investigated between periorbital and orbital tissue using the Spearman’s correlation coefficient method.

Results:

A statistically significant increase in volume was measured in TED patients in the superior and inferior periorbital fat tissue (p = 0.0044, p = 0.047), including the retroorbicularis oculi fat (p = 0.0011), suborbicularis oculi fat (p = 0.0093), and a decrease in facial muscle of superior periorbital region (p = 0.035). Strong positive correlation was noted between the muscles of superior and inferior periorbital region (r

s
= 0.65; p = 0.0006), and between the suborbicularis oculi fat and retroorbicularis oculi fat (r

s
= 0.50; p = 0.013). No correlation was observed between orbital and periorbital tissue, except between the orbital fat and the inferior periorbital fat tissue (p = 0.047).

Conclusions:

Facial fat in the periorbital region is enlarged in TED, with the superior component correlating with orbital fat tissue expansion. These findings may assist in the clinical evaluation and management of disfigurement in TED patients.
Short-Term Efficacy and Safety of Tolvaptan in Patients with Left Ventricular Assist Devices
Authors: Fujino Takeo , Imamura Teruhiko , Nguyen Ann , Chung Ben , Raikhelkar Jayant , Rodgers Daniel , Nitta Daisuke , Smith Bryan , Sarswat Nitasha , Kalantari Sara , Narang Nikhil , LaBuhn Colleen , Jeevanandam Valluvan , Kim Gene , Sayer Gabriel , Uriel Nir
Published: September 2019

Tolvaptan is an effective therapy for heart failure patients with symptomatic congestion and hyponatremia. The efficacy of its use in patients with continuous-flow left ventricular assist devices (LVADs) is unknown. The aim of this study was to assess the clinical efficacy and safety of tolvaptan in LVAD patients. We retrospectively reviewed medical records of patients who underwent LVAD implantation between January 2014 and August 2018. Among 217 consecutive LVAD patients, tolvaptan was used in 20 patients. Mean age was 46 ± 14 years old and 14 patients were males. The duration of tolvaptan therapy was 4 (interquartile range 1–8) days. Urine volume significantly increased from 2,623 ± 1,109 ml/day before tolvaptan to 4,308 ± 1,432 ml/day during tolvaptan therapy (p < 0.001). Serum sodium increased from 127 ± 3 to 133 ± 3 mEq/L at the end of tolvaptan therapy (p < 0.001). No patients developed hypernatremia (serum sodium >150 mEq/L). The 90-day overall survival following tolvaptan therapy was 89% in both the tolvaptan group and a propensity score-matched non-tolvaptan group (p = 0.918). Survival free of heart failure readmissions was also comparable between the groups (p = 0.751). In conclusion, short-term use of tolvaptan following LVAD implantation is a safe and effective therapy to augment diuresis and improve hyponatremia.
In-vivo imaging of methionine metabolism in patients with suspected malignant pleural mesothelioma
Authors: Lopci Egesta , Novellis Pierluigi , Testori Alberto , Rahal Daoud , Voulaz Emanuele , Bottoni Edoardo , Ferraroli Giorgio Maria , Crepaldi Alessandro , Ceresoli Giovanni Luca , Perrino Matteo , Castello Angelo , Alloisio Marco , Veronesi Giulia , Zucali Paolo Andrea
Published: September 2019

Objectives

In-vivo characterization of malignant pleural mesothelioma (MPM) with 11C-methionine PET/computed tomography (MET PET).

Methods

Between September 2014 and February 2016, 30 consecutive patients with clinical suspicion of MPM were prospectively recruited. The study was approved and registered at www.clinicaltrials.gov (NCT02519049). Patients were evaluated at baseline with MET PET (experimental) and fluorine-18 fluorodeoxyglucose PET/computed tomography (FDG PET) (standard). Principal parameters analyzed were SUVmax, SUVmean, metabolic tumor volume (MTV), and metabolic tumor burden (MTB  = MTV ×SUVmean). The reference standard for diagnostic performance was based on histology.

Results

The presence of malignancy was confirmed in 29/30 patients: 23 (76.6%) with MPM (20 epithelioid, two biphasic, and one sarcomatoid), five (16.6%) with adenocarcinoma of the lung, and one (3.3%) with an undifferentiated carcinoma. In one case, diagnosis was benign pleural inflammation. All tumors showed increased uptake of 11C-methionine: median SUVmax, SUVmean, MTV, and MTB were, respectively, 5.70 [95% confidence interval (CI): 4.51–6.79], 3.15 (95% CI: 2.71–3.40), 33.85 (95% CI: 14.08–66.64), and 105.25 (95% CI: 41.77–215.25). Pathology data revealed MTV and MTB to be significantly higher in nonepithelioid histology (P < 0.05). The other parameters showed a homogeneous distribution across the tumor types. Overall, MET PET identified 49 lymph nodes, compared with 34 nodes on FDG PET, demonstrating a sensitivity of 91% (95% CI: 80–96%), a positive predictive value of 92% (95% CI: 82– 97%), and an accuracy of 85% (P = 0.0042).

Conclusions

MET PET is able to characterize MPM lesions regardless of histology. This technique shows higher sensitivity than FDG PET for the identification of secondary lymph nodes.
18F-Flourodeoxy glucose PET–computed tomography in testicular carcinoma: diagnostic and prognostic value
Authors: Soydal Cigdem , Araz Mine , Urun Yuksel , Gulpinar Basak , Nak Demet , Ozkan Elgin , Kucuk Nuriye Ozlem
Published: September 2019

Aim

This study aims to assess the diagnostic role of 18F-FDG PET/computed tomography in primary staging and restaging of testicular cancer in comparison with contrast-enhanced diagnostic thoracic-abdominopelvic computed tomography.

Material and method

Thirty-two consecutive male patients with testicular carcinoma (median age: 29, min–max: 17–65) who were referred to the nuclear medicine department for 18F-FDG PET/computed tomography were retrospectively included in the study. Patients were evaluated based on the 18F-FDG PET/computed tomography indications and germ cell tumor subtypes.

Results

On patient-based analysis, overall sensitivity, specificity, PPV, NPV and accuracy of 18F-FDG PET/computed tomography were 71%, 100%, 100%, 30% and 75%. On lesion-based analysis, for evaluation of lymph node metastasis they were 76%, 100%, 100%, 57% and 81%, and for detection of distant metastasis 85%, 100%, 100%, 90% and 93%, respectively. Median SUVmax for seminomas were calculated as 14.2 and for nonseminomas 7.8 (P = 0.62) Mean time to progression and overall survival were calculated as 76.6 ± 10.7 and 111 ± 7.5 months, respectively. Mean overall survival and time to progression for PET-positive and negative groups was not found significant (P = 0.69 and P = 0.81). The only significant factor in predict overall survival was the presence of distant organ metastases in PET/computed tomography (124.6 ± 5.2 vs. 78.7 ± 14.0 months, P = 0.02).

Conclusion

In this single-center experience with a limited number of patients, 18F-FDG PET/computed tomography appears to have a value of staging and restaging for both seminomatous and non-seminomatous GCTs.
Awareness of Hemophagocytic Lymphohistiocytosis as an Unusual Cause of Liver Failure in the Neonatal Period
Authors: Najib Khadijehsadat , Moghtaderi Mozhgan , Bordbar Mohammadreza , Monabati Ahmad
Published: September 2019

Background:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome that predominantly affects infants from birth to 18 months of age, characterized by fever and multiorgan failure. Liver injury has been rarely reported as a presenting sign in the neonatal period. This study reports a case with HLH in the neonatal period who presented with acute liver failure.

Case Presentation:

Herein, a 3-day-old female newborn was admitted with cytopenia, increased liver enzymes, hypofibrinogenemia, and markedly elevated serum ferritin. Hemophagocytosis of bone marrow biopsy confirmed the diagnosis of HLH. The newborn was treated with HLH-2004 protocol, but she finally died from multiorgan failure.

Conclusion:

Growing awareness of HLH as a cause of liver failure in the neonatal period can be associated with early treatment and reduces mortality in this group of patients.
Impact of a Quality Improvement Initiative to Optimize the Discharge Process of Pediatric Gastroenterology Patients at an Academic Children’s Hospital
Authors: Moo-Young Joseph A. , Sylvester Francisco A. , Dancel Ria D. , Galin Sheryl , Troxler Heidi , Bradford Kathleen K.
Published: September 2019

Introduction:

Discharge is an important and complex process that can be optimized to reduce inpatient healthcare inefficiency and waste. This study aimed to increase the percentage of patients discharged before 1 pm by 20% from an academic inpatient pediatric gastroenterology service (IPGS), over 6 months.

Methods:

We conducted a preintervention and postintervention study of patients discharged from IPGS. Patients discharged from January to June 2016, and those following our intervention from June to December 2016, were studied. Interventions included (1) implementation of the electronic medical record medical and logistical discharge criteria checklists for the 4 most common IPGS discharge diagnoses, (2) standardization of the rounds process to prioritize discharge, (3) education of nursing staff and families about the role they played in discharge. Process, outcome, and balancing measures were analyzed.

Results:

Three hundred fifty-five total discharges were studied. Between the preintervention and postintervention groups, there were no significant improvements in discharge order time, physical discharge time, discharge response time, or discharges before 1 pm. The balancing measure of 30-day readmission was unaffected. However, length of stay (LOS) index, calculated as the ratio of actual to expected LOS, improved; when translated into days, LOS declined by 1 day, with potential associated savings of $373,000.

Conclusions:

Interventions to improve discharge timeliness on IPGS service demonstrated mixed effectiveness. Only LOS index improved. Further iterative quality improvement interventions are needed to continue optimizing discharge timeliness and change the culture of pediatric discharge on inpatient subspecialty services in academic children’s hospitals.
Swinging Eyelid Approach to Zygomaticomaxillary Complex Fracture
Authors: Miyazaki Hidetaka , Okuda Katsuya , Ueno Kazuki , Wada Yoshitaka , Kumegawa Shinji , Uemura Kazuhisa , Sakata Yasuhiro , Asamura Shinichi
Published: September 2019

A surgical approach to zygomaticomaxillary complex (ZMC) fracture has not been standardized. The authors reviewed 15 cases of ZMC fractures treated with the swinging eyelid approach and evaluated the effectiveness of the technique by an observational study of Japanese patients. Results were assessed from authentic and functional perspectives: the presence of entropion/ectropion, external canthal malposition and chemosis of the conjunctiva. After a minimum follow-up of 10 months, no patients had lower eyelid ectropion, entropion or retraction. Wounds appeared inconspicuous, and a lateral canthal shape was preserved. No post-operative chemosis of the conjunctiva was observed. Each case was evaluated based on patient satisfaction about their aesthetic outcomes. Patient self-assessment is classified into 4 groups (excellent, good, fair, and unsatisfactory). Thirteen patients were assessed to have an “excellent” outcome, and 2 patients were assessed to have a “good” outcome. No patients had “fair” or “unsatisfactory” outcomes. Avoidance of scarring is a goal of every craniofacial surgeon. The swinging eyelid approach to ZMC fractures offers a simple alternative to the conventional technique. It is versatile and provides sufficient exposure to surgical fields with less visible scar because skin incision is made along the natural crease line, “the crow's feet.”
The Role of Ultrasound in the Diagnosis of Pediatric Nasal Fractures
Authors: Navaratnam Ragavan , Davis Tessa
Published: September 2019

Background:

Nasal fractures are the most commonly encountered facial fracture in children presenting to emergency departments. Though plain radiographs have long been used to aid the diagnosis of fractures, its limited diagnostic accuracy has led to the increasing use of ultrasound. Ultrasound offers a cheap, safe, and readily available imaging modality. Evidence in the adult population has shown ultrasound to be far more accurate in identifying nasal fractures. The efficacy of ultrasound in the pediatric setting though remains uncertain.

Methods:

A systematic review of the Pubmed and EmBase databases was undertaken. The search terms (nose OR nasal) AND (fracture) AND (ultrasound OR ultrasonography OR sonography) and associated MeSH terms were searched. The search was limited to those <18 years of age.

Results:

Following review and exclusion, 3 papers met the inclusion criteria. All 3 studies showed ultrasound was able to detect nasal fractures in children. Two studies showed that ultrasound diagnosed fractures with a greater accuracy than plain radiographs. One study used ultrasound alone and reported a sensitivity of 75% and specificity as 92.3%.

Conclusion:

With the limited evidence to date in the pediatric population, ultrasound appears to offer a more accurate radiological investigation in nasal fractures. It could be considered diagnostically superior to plain radiographs and reduces radiation exposure in children. Further work is required to better determine its true utility and improve its diagnostic accuracy.
Long-term Apomorphine Infusion Users Versus Short-term Users: An International Dual-center Analysis of the Reasons for Discontinuing Therapy
Authors: Bhidayasiri Roongroj , Phokaewvarangkul Onanong , Boonpang Kamolwan , Boonmongkol Thanatat , Thongchuem Yuwadee , Kantachadvanich Nitinan , García Ruiz Pedro J.
Published: September 2019

Objectives

A retrospective analysis at 2 specialist centers was undertaken to determine the long-term efficacy of subcutaneous apomorphine infusion (APO), rates and reasons for discontinuation, and factors that might contribute to discontinuation.

Methods

Demographics, clinical outcomes data, and reasons for discontinuation were collected for patients treated with APO at Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Bangkok, Thailand (n = 36) and Fundacion Jimemez Diaz Universidad Autonoma de Madrid, Spain (n = 16).

Results

There were 19 (52.7%) patients in the Thai cohort and 10 (62.5%) patients in the Spanish cohort who discontinued treatment within around 6 months of initiation, most commonly due to skin nodules (Thai cohort) and perceived lack of efficacy (Spanish cohort). Those who continued APO tended to stay on treatment. In both cohorts, APO resulted in significant reductions in Unified Parkinson's Disease Rating Scale 3 motor scores, daily OFF time, and levodopa-equivalent dose in patients who subsequently stopped therapy, suggesting APO is clinically effective even when “lack of efficacy” is stated as a reason for discontinuing. Daily OFF hours after APO therapy was found to be a significant predictive factor for APO discontinuation with an odds ratio of 5.952 (P = 0.040). The cutoff point that determined APO discontinuation was calculated to be 1.75 or more OFF hours (sensitivity, 84.6%; specificity, 63.2%).

Conclusions

Apomorphine infusion is a minimally invasive therapy and therefore very easy to discontinue if difficulties arise. This fact might explain the high dropout rate of this technique. Successful long-term adherence to APO therapy requires a multidisciplinary health care team approach including regular patient follow-up and assessment and prompt resolution of queries and concerns.
Intravital dynamic and correlative imaging reveals diffusion-dominated canalicular and flow-augmented ductular bile flux
Authors: Vartak Nachiket , Guenther Georgia , Joly Florian , Damle-Vartak Amruta , Wibbelt Gudrun , Fickel Jörns , Jörs Simone , Begher-Tibbe Brigitte , Friebel Adrian , Wansing Kasimir , Ghallab Ahmed , Rosselin Marie , Boissier Noemie , Vignon-Clementel Irene , Hedberg Christian , Geisler Fabian , Hofer Heribert , Jansen Peter , Hoehme Stefan , Drasdo Dirk , Hengstler Jan G.
Published: September 2019

Small-molecule flux in tissue-microdomains is essential for organ function, but knowledge of this process is scant due to the lack of suitable methods. We developed two independent techniques that allow the quantification of advection (flow) and diffusion in individual bile canaliculi and in interlobular bile ducts of intact livers in living mice, namely Fluorescence Loss After Photoactivation (FLAP) and Intravital Arbitrary Region Image Correlation Spectroscopy (IVARICS). The results challenge the prevailing ‘mechano-osmotic’ theory of canalicular bile flow. After active transport across hepatocyte membranes bile acids are transported in the canaliculi primarily by diffusion. Only in the interlobular ducts, diffusion is augmented by regulatable advection. Photoactivation of fluorescein bis-(5-carboxymethoxy-2-nitrobenzyl)-ether (CMNB-caged fluorescein) in entire lobules demonstrated the establishment of diffusive gradients in the bile canalicular network and the sink function of interlobular ducts. In contrast to the bile canalicular network, vectorial transport was detected and quantified in the mesh of interlobular bile ducts. In conclusion, the liver consists of a diffusion dominated canalicular domain, where hepatocytes secrete small molecules and generate a concentration gradient and a flow-augmented ductular domain, where regulated water influx creates unidirectional advection that augments the diffusive flux.

One Sentence Summary/Keywords

Bile flux proceeds by diffusion in canaliculi, augmented by advection in ducts.
Removing reference bias and improving indel calling in ancient DNA data analysis by mapping to a sequence variation graph
Authors: Martiniano Rui , Garrison Erik , Jones Eppie R. , Manica Andrea , Durbin Richard
Published: September 2019

Background

During the last decade, the analysis of ancient DNA (aDNA) sequence has become a powerful tool for the study of past human populations. However, the degraded nature of aDNA means that aDNA molecules are short and frequently mutated by post-mortem chemical modifications. These features decrease read mapping accuracy and increase reference bias, in which reads containing non-reference alleles are less likely to be mapped than those containing reference alleles. Recently, alternative approaches for read mapping and genetic variation analysis have been developed that replace the linear reference by a variation graph which includes known alternative variants at each genetic locus. Here, we evaluate the use of variation graph software vg to avoid reference bias for ancient DNA and compare our approach to existing methods.

Results

We used vg to align simulated and real aDNA samples to a variation graph containing 1000 Genome Project variants, and compared these with the same data aligned with bwa to the human linear reference genome. We show that use of vg leads to a balanced allelic representation at polymorphic sites, effectively removing reference bias, and more sensitive variant detection in comparison with bwa, especially for insertions and deletions (indels). Alternative approaches that use relaxed bwa parameter settings or filter bwa alignments can also reduce bias, but can have lower sensitivity than vg, particularly for indels.

Conclusions

Our findings demonstrate that aligning aDNA sequences to variation graphs effectively mitigates the impact of reference bias when analysing aDNA, while retaining mapping sensitivity and allowing detection of variation, in particular indel variation, that was previously missed.
The Readiness Potential reflects the internal source of action, rather than decision uncertainty
Authors: Travers Eoin , Haggard Patrick
Published: September 2019

Voluntary actions are preceded by a Readiness Potential (RP), a slow EEG component generated in medial frontal cortical areas. The RP is classically thought to be specific to internally-driven decisions to act, and to reflect post-decision motor preparation. Recent work suggests instead that it may reflect noise or conflict during the decision itself, with internally-driven decisions tending to be more random, more conflictual and thus more uncertain than externally-driven actions. To contrast accounts based on endogenicity with accounts based on uncertainty, we recorded EEG in a task where participants decided to act or withhold action to accept or reject visually-presented gambles, and used multivariate methods to extract an RP-like component.. We found no difference in amplitude of this component between actions driven by strong versus weak evidence, suggesting that the RP may not reflect uncertainty. In contrast, the same RP-like component showed higher amplitudes prior to actions performed without any external evidence (guesses) than for actions performed in response to equivocal, conflicting evidence. This supports the view that the RP reflects the internal source of action, rather than decision uncertainty.

Significance Statement

The EEG Readiness Potential (RP) seen prior to self-initiated actions is often taken as a neural marker of volition (Shibasaki & Hallett, 2006). It has been argued that the RP may instead reflect conflict and uncertainty in the decisions leading up to these actions, raising questions about decades of previous findings. We directly tested these explanations by asking participants to decide whether to act or not in a gambling task, while manipulating both uncertainty and the source of the information (internal or external) guiding the decision. Only the source of information affected the presence of the RP. Therefore, the RP remains a marker of internally-generated voluntary action, not a marker of uncertainty.
Genetic and epigenetic characteristics associated with the rapid radiation of Aquilegia species
Authors: Wang Zhen-Hui , Lu Tianyuan , Li Ming-Rui , Ding Ning , Lan Li-Zhen , Gao Xiang , Xiong Ai-Sheng , Zhang Jian , Li Lin-Feng
Published: September 2019

Elucidating the genetic and epigenetic bases underlying species diversification is crucial to understanding the evolution and persistence of biodiversity. As a well-known horticultural plant grown worldwide, the genus Aquilegia (columbine) is also a model system in adaptive radiation research. In this study, we surveyed the genomes and DNA methylomes of ten representative Aquilegia species from the Asian, European and North American lineages. Our inferences of the phylogenies and population structure revealed clearly high genetic and DNA methylomic divergence across the three lineages. By multi-levelled genome-wide scanning, we identified candidate genes exhibiting lineage-specific genetic or epigenetic variation patterns that are signatures of inter-specific divergence. We demonstrated that these species diversification-associated genetic variations and epigenetic variabilities were partially independent but were both functionally related to various biological processes vital to adaptation, including stress tolerance, cell reproduction and DNA repair. Our study provides an exploratory overview of how the established genetic and epigenetic signatures are associated with the rapid radiation of Aquilegia species.
Pan-genome analysis identifies intersecting roles for Pseudomonas specialized metabolites in potato pathogen inhibition
Authors: Pacheco-Moreno Alba , Stefanato Francesca L. , Ford Jonathan J. , Trippel Christine , Uszkoreit Simon , Ferrafiat Laura , Grenga Lucia , Dickens Ruth , Kelly Nathan , Kingdon Alexander D. H. , Ambrosetti Liana , Nepogodiev Sergey A. , Findlay Kim C. , Cheema Jitender , Trick Martin , Chandra Govind , Tomalin Graham , Malone Jacob G. , Truman Andrew W.
Published: September 2019

Agricultural soil harbors a diverse microbiome that can form beneficial relationships with plants, including the inhibition of plant pathogens. Pseudomonas spp. are one of the most abundant bacterial genera in the soil and rhizosphere and play important roles in promoting plant health. However, the genetic determinants of this beneficial activity are only partially understood. Here, we genetically and phenotypically characterize the Pseudomonas fluorescens population in a commercial potato field, where we identify strong correlations between specialized metabolite biosynthesis and antagonism of the potato pathogens Streptomyces scabies and Phytophthora infestans. Genetic and chemical analyses identified hydrogen cyanide and cyclic lipopeptides as key specialized metabolites associated with S. scabies inhibition, which was supported by in planta biocontrol experiments. We show that a single potato field contains a hugely diverse and dynamic population of Pseudomonas bacteria, whose capacity to produce specialized metabolites is shaped both by plant colonization and defined environmental inputs.
Cachexia and fibrosis are costs of chronic IL-1R-mediated disease tolerance inT. gondiiinfection
Authors: Melchor Stephanie J. , Hatter Jessica A. , LaTorre Castillo Erika A. , Saunders Claire M. , Byrnes Kari A. , Sanders Imani , Abebayehu Daniel , Barker Thomas , Coutermarsh-Ott Sheryl , Ewald Sarah E.
Published: September 2019

Cachexia is an immune-metabolic disease of progressive muscle wasting that impairs patient survival and quality of life across a range of chronic diseases.T. gondiiis a protozoan parasite that causes lifelong infection in many warm-blooded organisms, including humans and mice. Here we show that mice infected withT. gondiidevelop robust, sustained cachexia and perivascular fibrosis in metabolic tissues. Consistent with an emerging role for the IL-1 axis in disease tolerance, we show that mice deficient in the Type 1 IL-1 receptor (IL-1R) have more severe acute muscle wasting, adipocyte and hepatocyte necrosis, independent of parasite burden. Unexpectedly, IL-1R-/-mice rapidly recover from acute disease, despite sustained parasite infection, and are protected from chronic cachexia as well as perivascular liver and muscle fibrosis. These data are consistent with a model where IL-1R signaling benefits cell survival and tissue integrity over short periods of inflammation, but sustained reliance on IL-1 mediated tolerance programs come at the cost of fibrosis and cachexia.

IL-1R signaling drives a disease tolerance program that protects mice from tissue pathology during acuteToxoplasma gondiiinfection. However, extended IL-1R signaling drives chronic cachexia and perivascular fibrosis in the liver and skeletal muscle.
Digitalizing heterologous gene expression in Gram-negative bacteria with a portable on/off module
Authors: Calles Belén , Goñi-Moreno Angel , de Lorenzo Víctor
Published: September 2019

While prokaryotic promoters controlled by signal-responding regulators typically display a range of input/output ratios when exposed to cognate inducers, virtually no naturally occurring cases are known to have an off state of zero transcription—as ideally needed for synthetic circuits. To overcome this problem we have modelled and implemented simple digitalizer module that completely suppresses the basal level of otherwise strong promoters in such a way that expression in the absence of induction is entirely impeded. The circuit involves the interplay of a translation-inhibitory sRNA with the translational coupling of the gene of interest to a repressor such as LacI. The digitalizer module was validated with the strong inducible promotersPm(induced by XylS in the presence of benzoate) andPalkB(induced by AlkS/dicyclopropylketone) and shown to perform effectively both inE. coliand the soil bacteriumPseudomonas putida.The distinct expression architecture allowed cloning and conditional expression of e.g. colicin E3, one molecule of which per cell suffices to kill the host bacterium. Revertants that escaped ColE3 killing were not found in hosts devoid of insertion sequences, suggesting that mobile elements are a major source of circuit inactivationin vivo.
Differential stromal reprogramming in benign and malignant naturally occurring canine mammary tumours identifies disease-promoting stromal components
Authors: Amini Parisa , Nassiri Sina , Malbon Alexandra , Markkanen Enni
Published: September 2019

The importance of cancer-associated stroma (CAS) for initiation and progression of cancer is well accepted. However, as stromal changes in benign forms of naturally occurring tumours are poorly understood, it remains unclear how CAS from benign and malignant tumours compare. Spontaneous canine mammary tumours are viewed as excellent models of human mammary carcinomas (mCA). We have recently reported highly conserved stromal reprogramming between canine and human mCA based on transcriptome analysis of laser-capture-microdissected FFPE specimen. To identify stromal changes between benign and malignant mammary tumours, we have analysed CAS and matched normal stroma from 13 canine mammary adenomas and compared them to 15 canine mCA. Our analyses revealed distinct stromal reprogramming even in small benign tumours. While similarities in stromal reprogramming exist, the CAS signature clearly distinguished adenomas from mCA, suggesting that it may reliably discriminate between benign and malignant tumours. We identified strongly discriminatory genes and found strong differential enrichment in several hallmark signalling pathways between benign and malignant CAS. The distinction between CAS from adenoma and mCA was further substantiated by differential abundance in cellular composition. Finally, to determine key players in CAS reprograming between adenomas and mCA, a network-based gene screening method identified modules of co-expressing genes with distinct expression profile in benign and malignant CAS, and revealed several hub genes as potential molecular drivers in CAS. Given the relevance of canine CAS as a model for the human disease, our approach identifies potential stromal drivers of tumour malignancy with implications for human mCA.

Summary statement

RNAsequencing-based analysis of stromal reprogramming between benign and malignant naturally occurring canine mammary tumours identifies potential molecular drivers in cancer-associated stroma that support tumour growth and malignancy.
Age-dependent neuroprotective effect of an SK3. channel agonist on excitotoxity to dopaminergic neurons in organotypic culture
Authors: Maldonado Oscar , Jenkins Alexandra , Belalcazar Helen M. , Hyman Katelynn M. , Cuervo Helena-Hernandez , Ladaga Giannina , Padilla Lucia , de Erausquin Gabriel A.
Published: September 2019

We evaluated the age-dependency of the neuroprotective effect of an small-conductance calcium activated potassium channel 3 (SK3) agonist, 1-EBIO, on AMPA excitoxicity to dopaminergic neurons (DN) in organotypic cultures. Most TH+ neurons were also SK3+. SK3+/TH-cells (DN+) were common at each developmental stage but more prominently at day in vitro (DIV) 8. Young DN+ neurons were small bipolar and fusiform, whereas mature ones were large and multipolar. Exposure of organotypic cultures to AMPA (100 μm, 16 h) had no effect on the survival of DN+ at DIV 8, but caused significant toxicity at DIV 15 (n=15, p=0.005) and DIV 22 (n=15, p<<0.001). These results indicate that susceptibility of DN to AMPA excitotoxicity is developmental stage-dependent in embryonic VM organotypic cultures. Immature DN+ (small, bipolar) were increased after AMPA (100 μm, 16 h) at DIV 8, at the expense of the number of differentiated (large, multipolar) DN+ (p=0.039). This effect was larger at DIV 15 (p<<<0.0001) and at DIV 22 (p<<<0.0001). At DIV 8, 30 μM 1-EBIO resulted in a large increase in DN+. At DIV 15, AMPA toxicity was prevented by exposure to 30 μM, but not 100 μM 1-EBIO. At DIV 22, excitotoxicity was unaffected by 30 μM 1-EBIO, and partially reduced by 100 μM 1-EBIO. The effects of the SK3. channel agonist 1-EBIO on the survival of SK3.-expressing dopaminergic neurons were concentrationdependent and influenced by neuronal developmental stage.
A single nucleotide polymorphism in the HOMER1 gene is associated with sleep latency and theta power in sleep electroencephalogram
Authors: Pedrazzoli Mario , Mazzotti Diego Robles , Ribeiro Amanda Oliveira , Mendes Juliana Viana , Bittencourt Lia Rita Azeredo , Tufik Sergio
Published: September 2019

Glutamate is the most excitatory neurotransmitter in the central nervous system and it is involved in the initiation and maintaining of waking and rapid-eye-movement (REM) sleep. Homer proteins act in the trafficking and/or clustering of metabotropic glutamate receptors, and polymorphisms in the HOMER1 gene have been associated with phenotypes related to glutamate signaling dysregulation. In this study, we report the association of a single nucleotide polymorphism (SNP) in the HOMER1 gene (rs3822568) with specific aspects of sleep in a sample of the Brazilian population. To accomplish this, 1,042 individuals were subjected to a full-night polysomnography, and a subset of 983 subjects had rs3822568 genotyping data available. When compared with the A allele carriers, GG genotyped individuals showed higher sleep latency, lower sleep efficiency, reduced number of arousals per hour, lower apnea-hypopnea index (AHI) and lower theta spectral power. In summary, the present findings suggest that the rs3822568 polymorphism in the HOMER1 gene is associated with sleep EEG profiles and might have an impact on sleep quality and sleep structure, with potential to explain inter-individual variation in sleep homeostasis.
Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression
Authors: Medrihan Lucian , Umschweif Gali , Sinha Anjana , Reed Shayna , Gindinova Katherina , Sinha Subhash C. , Greengard Paul , Sagi Yotam
Published: September 2019

Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high level of p11, a protein associated with depression and action of antidepressants. Here we show that either specific deletion of p11 (p11 cKO) or chemogenetic inhibition in dentate gyrus (DG) PV neurons leads to anxiety-like behavior and susceptibility to depression in mice. DG PV neurons from p11 cKO mice showed reduced level and function of Kv3.1, and consequentially reduced capacity of high-frequency firing and altered short-term plasticity at synapses on granule cells. Activation of Kv3.1 or overexpression of the channel attenuated the vulnerability to depressive behavior.
The burden of deleterious variants in a non-human primate biomedical model
Authors: Ramensky Vasily , Jasinska Anna J. , Deverasetty Sandeep , Svardal Hannes , Zelaya Ivette , Jorgensen Matthew J. , Kaplan Jay Ross , Cline J. Mark , Zharikova Anastasia , Service Susan K. , Wilson Richard K. , Coppola Giovanni , Freimer Nelson B. , Warren Wesley C.
Published: September 2019

Genome sequencing studies of nonhuman primate (NHP) pedigree and population samples are discovering variants on a large and rapidly growing scale. These studies are increasing the utility of several NHP species as model systems for human disease. In particular, by identifying homozygous protein truncating variants (hPTVs) in genes hypothesized to play a role in causing human diseases, it may be possible to elucidate mechanisms for the phenotypic impact of such variants through investigations that are infeasible in humans. The Caribbean vervet (Chlorocebus aethiops sabaeus) is uniquely valuable for this purpose, as the dramatic expansion of its population following severe bottlenecks has enabled PTVs that passed through the bottleneck to attain a relatively high frequency. Using whole genome sequence (WGS) data from 719 monkeys of the Vervet Research Colony (VRC) extended pedigree, we found 2,802 protein-truncating alleles in 1,747 protein-coding genes present in homozygous state in at least one monkey. Polymorphic sites for 923 SNV hPTVs were also observed in natural Caribbean populations from which the VRC descends. The vervet genome browser (VGB) includes information on these PTVs, together with a catalog of phenotypes and biological samples available for monkeys who carry them. We describe initial explorations of the possible impact of vervet PTVs on early infant mortality.
The use of mutants and inhibitors to study sterol biosynthesis in plants
Authors: Vriese Kjell De , Pollier Jacob , Goossens Alain , Beeckman Tom , Vanneste Steffen
Published: September 2019

Sterols are very well known for their important roles in membranes and signaling in eukaryotes. Plants stand out among eukaryotes by the large variety of sterols that they can produce, and employing them across a wide spectrum of physiological processes. Therefore, it is critical to understand the wiring of the biosynthetic pathways by which plants generate these distinct sterols, to allow manipulating them and dissect their precise physiological roles. Many enzymatic steps show a deep evolutionary conservation, while others are executed by completely different enzymes. Here, we review the complexity and variation of the biosynthetic routes of the most abundant phytosterols in the green lineage and how different enzymes in these pathways are conserved and diverged from humans,yeast and even bacteria. Based on their evolutionary conservation we discuss the use of human and yeast sterol biosynthesis inhibitors in plants, as an argument for the development of plant-tailored inhibitors of sterol biosynthesis.