bluuebunny/crossref_metadata_2025 huggingface dataset:
Endoscope-assisted Partial Cochlectomy for Intracochlear Schwannoma With Simultaneous Cochlear Implantation: A Case Report
Authors: Ma Andrew K. , Patel Nirmal
Published: January 2020

Introduction:

Intralabyrinthine schwannomas are a small subset of vestibular schwannomas which originate within the labyrinthine structures. Management typically consists of watch-and-wait strategies given that surgical intervention will sacrifice hearing. Endoscopic resection of primary intracochlear schwannoma with simultaneous cochlear implantation for a patient with progressive hearing loss and debilitating tinnitus is described.

Patient:

A 56-year-old male presenting with asymmetric left sensorineural hearing loss (SNHL) was diagnosed with intracochlear schwannoma on MRI.

Intervention:

Surgery was indicated due to tumor growth on serial imaging, worsening SNHL, and severe tinnitus. Partial cochlectomy was performed via transcanal endoscopic approach. Cochlear implantation via mastoidectomy and posterior tympanotomy was simultaneously performed with a CI512 Contour Advanced implant (Cochlear, Sydney, Australia).

Main Outcome Measures:

Post partial cochlectomy speech performance.

Results:

Preoperative audiometry showed left profound SNHL with 20% speech recognition score despite maximal amplification. Speech perception testing 5 months postoperatively demonstrated good unilateral discrimination when testing the implanted ear alone (BKB sentences 66%, CUNY sentences 79%), open-set comprehension, and excellent binaural performance.

Conclusion:

The endoscope offers an additional viable approach to the otic capsule for the removal of intracochlear schwannoma and good audiologic outcomes can be achieved with simultaneous cochlear implantation even after partial cochlectomy.
An Exploratory Examination of Client Perspectives on a Positive Memory Technique for PTSD
Authors: Caldas Stephanie V. , Jin Ling , Dolan Megan , Dranger Paula , Contractor Ateka A.
Published: January 2020

Posttraumatic stress disorder (PTSD) treatments primarily address traumatic memories, despite PTSD's association with both traumatic and positive memory difficulties. Addressing this gap, we explored the perspectives of trauma-exposed individuals with mental health treatment experience on therapeutically addressing positive memories. A treatment-seeking sample from a community mental health center (n
1 = 60) and a community sample from Amazon's Mechanical Turk (n
2 = 123) were queried on the acceptability, feasibility, and delivery/components of a pilot positive memory technique. Results indicated interest or willingness in therapeutically discussing positive memories; most endorsed benefits were improved mood, positive thoughts, and self-esteem. Few barriers were identified (e.g., lack of evidence) compared with feasibility factors (ease/usefulness, improved satisfaction/tolerability, and engagement in PTSD treatment). Preferred treatment components included identifying/discussing positive memories, eliciting associated positive affect, and writing about the positive memory as homework. Results provide formative support for the development and integration of a positive memory technique into PTSD treatments.
Designing Tomorrow
Authors: Beglinger Joan Ellis
Published: January 2020

A highly visible transition occurred earlier this year with the retirement of Pam Thompson, MS, RN, CENP, FAAN, from her role as CEO of the American Organization of Nurse Executives. Ms Thompson was always an advocate of promoting the voice of nursing. This month, the spotlight will shine on a team of nurse leaders who found their voice, got involved, and led the conversation. We will trace their journey as they analyzed their situation, applied the evidence, and used their seat at the table.
A Multidisciplinary Initiative to Increase Inpatient Discharges Before Noon
Authors: Kane Marlena , Weinacker Ann , Arthofer Rudolph , Seay-Morrison Timothy , Elfman Wesley , Ramirez Mark , Ahuja Neera , Pickham David , Hereford James , Welton Mark
Published: January 2020

OBJECTIVE:

The aim of this study is to evaluate the effect of 2 hospital-wide interventions on achieving a discharge-before-noon rate of 40%.

BACKGROUND:

A multidisciplinary team led by administrative and physician leadership developed a plan to diminish capacity constraints by minimizing late afternoon hospital discharges using 2 patient flow management techniques.

METHODS:

The study was a preintervention/postintervention retrospective analysis observing all inpatients discharged across 19 inpatient units in a 484-bed, academic teaching hospital measuring calendar month discharge-before-noon percentage, patient satisfaction, and readmission rates. Patient satisfaction and readmission rates were used as baseline metrics.

RESULTS:

The discharge-before-noon percentage increased from 14% in the 11-month preintervention period to an average of 24% over the 11-month postintervention period, whereas patient satisfaction scores and readmission rates remained stable.

CONCLUSIONS:

Implementation of the 2 interventions successfully increased the percentage of discharges before noon yet did not achieve the goal of 40%. Patient satisfaction and readmission rates were not negatively impacted by the program.
A Community Hospital’s Evaluation of Alarm Management Safety Factors
Authors: Kurnat-Thoma Emma , Shah Kayuri
Published: January 2020

BACKGROUND:

The Joint Commission’s 2014 National Patient Safety Goals required hospitals to evaluate alarm safety in 2014–2015 and implement alarm safety policies.

OBJECTIVE:

The aim of this study was to assess common alarm management safety factors in our 187-bed community hospital.

METHODS:

Two weeks’ worth of IV pump report data was evaluated to characterize 33 IV pump alarm types. Hospital and IV pump noise was measured, and an alarm management nurse survey was conducted.

RESULTS:

There were 8731 total IV pump alarms/alerts (24-hour mean, 623.6) across 6 units. The 2-minute idle alarm accounted for 32.4% of all total IV alarms/alerts, suggestive of high levels of nurse multitasking and nurse work interruptions. IV pump volumes contributed to overall hospital noise. Survey data identified patient units and alarm safety practices needing additional support.

CONCLUSIONS:

Characterization of IV pump alarms/alerts is an emerging area of scientific inquiry. Findings indicate the need for organizations to evaluate alarm burden and alarm management safety practices to reduce alarm fatigue risks.
Advancing Patient-Centered Communication Content for Prelicensure Nursing Students Using StudentSPEACS
Authors: Tate Judith Ann , Newtz Christa , Ali Awais , Happ Mary Beth
Published: January 2020

Background

Many patients live with communication disorders that present significant challenges during interactions with health care providers across settings. Yet, nurses receive little to no training in how to communicate with communication impaired patients.

Purpose

The purpose of this study was to determine the feasibility and acceptability of delivering the Study of Patient-Nurse Effectiveness With Assistive Communication Strategies (StudentSPEACS) program to prelicensure nursing students and to describe student clinical applications of this content in the year following the communication training.

Methods

We used mixed methods to describe student perceptions of StudentSPEACS content and application of content in clinical encounters.

Results

Junior nursing students (n = 86, 53.75%) responded to the survey. Students rated content as very valuable and rated their overall ability to communicate with patients after the training program as average. Students provided 48 clinical case application exemplars.

Conclusions

The StudentSPEACS program can help prelicensure nursing students acquire and practice communication skills with patients who have communication impairments.
Restrictions on Nursing Students' Electronic Health Information Access
Authors: Hansbrough Wendy , Dunker Kimberly Silver , Ross Jennifer Gunberg , Ostendorf Marilyn
Published: January 2020

Background

Restrictions on students' use of electronic health information have been anecdotally reported as a threat to clinical learning, development of informatics competency, and adherence to personal health information privacy laws. However, evidence on which informatics education and policy strategies can be designed is lacking.

Purpose

This study describes the scope of nursing students' access to and use of electronic health information systems as reported by clinical instructors.

Methods

Clinical faculty (n = 193) in prelicensure programs from 25 states completed the online survey.

Results

Students are often restricted in retrieving patient health information, charting assessment data and delivered care, and using medication administration systems. Students alternatively use faculty or staff nurses' system security access.

Conclusions

Results suggest the need for critical review of nursing curriculum related to informatics competency and clinical site health records access policies.
Pre-exposure Prophylaxis Awareness and Use Among Cisgender Men Who Have Sex With Men and Use Methamphetamine in 3 Western US Cities
Authors: McMahan Vanessa M. , Moreno Courtney , Al-Tayyib Alia , Menza Timothy W. , Orellana Edwin Roberto , Bhattarai Amisha , Stekler Joanne D. , Glick Sara N.
Published: January 2020

Background

In the United States, cisgender men who have sex with men (MSM) who use methamphetamine are at substantial risk for HIV and can benefit from pre-exposure prophylaxis (PrEP).

Methods

We used data from the National HIV Behavioral Surveillance 2017 survey from Seattle, WA; Portland, OR; and Denver, CO, to estimate PrEP awareness and use in the past 12 months among MSM who use methamphetamine. We then compared these estimates with participants who do not use methamphetamine but meet other criteria for PrEP use (i.e., condomless anal sex or a bacterial sexually transmitted infection). We explored reasons for not using PrEP and challenges using PrEP.

Results

Of the 1602 MSM who participated in the 2017 National HIV Behavioral Surveillance survey in Seattle, WA; Portland, OR; and Denver, CO, 881 met the inclusion criteria for this study, of whom 88 (10%) reported methamphetamine use in the past 12 months. Most (95%) participants had heard of PrEP, and 35% had used it in the past 12 months. Pre-exposure prophylaxis awareness was lower among MSM who used methamphetamine (P = 0.01), but use was not different (P = 0.26). Among those who had not used PrEP, the most common reason for not using it was not thinking one's HIV risk was high enough (51%). Men who have sex with men who used methamphetamine were more likely to report that they were not sure PrEP would prevent them from getting HIV (38% vs. 19%, P = 0.002).

Conclusions

These results highlight the need for continued efforts to educate and promote PrEP uptake among MSM, particularly those who use methamphetamine.
Anticoagulant chemoprophylaxis in patients with traumatic brain injuries: A systematic review
Authors: Spano Paul J. , Shaikh Saamia , Boneva Dessy , Hai Shaikh , McKenney Mark , Elkbuli Adel
Published: January 2020

BACKGROUND

Traumatic brain injury (TBI) continues to be a deadly injury. Universally accepted guidelines regarding the use of venous thromboembolism (VTE) chemoprophylaxis in trauma patients presenting with TBI have not been established. The purpose of this review was to identify and review the current literature and present the evidence for anticoagulant chemoprophylaxis regimens in patients with TBI.

METHODS

A search of five databases including PubMed, Web of Science, Google Scholar, JAMA Network, and Cochrane Journals was conducted for studies evaluating the safety and efficacy of venous thromboembolism prophylaxis regimens according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria were used for quality of evidence assessment.

RESULTS

Seventeen studies were included in this review: 1 randomized controlled trial, 2 prospective observational studies, 10 retrospective reviews, and 5 systematic reviews. Most studies demonstrated that early chemoprophylactic administration is associated with a decreased incidence of VTE in patients with TBI without an increase in intracranial bleed.

CONCLUSION

For patients with TBI resulting in intracranial hemorrhages, administration of VTE chemoprophylaxis is warranted for those patients with stable repeat computed tomography scans. Early chemoprophylaxis, at 24 to 72 hours is associated with reduced VTE incidence without a corresponding increase or exacerbation of intracranial hemorrhage in patients with TBI who have a stable repeat head computed tomography scan. More studies are needed to establish guidelines for the safety and efficacy of VTE prophylaxis protocols in adult patients with TBI.

LEVEL OF EVIDENCE

Systematic review, level III.
Molecular and genomic characterization of a novel equine molluscum contagiosum-like virus
Authors: Ehmann Rosina , Brandes K. , Antwerpen M. , Walter M. , v. Schlippenbach K. , Stegmaier E. , Essbauer S. , Bugert J. , Teifke J. P. , Meyer H.
Published: January 2020

Cases of pox-like lesions in horses and donkeys have been associated with poxviruses belonging to different genera of the family Poxviridae. These include the orthopoxviruses vaccinia virus (VACV), horsepoxvirus (HPXV) and cowpoxvirus (CPXV), as well as a potentially novel parapoxvirus and molluscum contagiosum virus (MOCV). However, with the exception of VACV, HPXV and CPXV, the genomic characterization of the causative agents remains largely elusive with only single short genome fragments available. Here we present the first full-length genome sequence of an equine molluscum contagiosum-like virus (EMCLV) directly determined from skin biopsies of a horse with generalized papular dermatitis. Histopathological analysis of the lesions revealed severe epidermal hyperplasia with numerous eosinophilic inclusion bodies within keratinocytes. Virions were detected in the lesions in embedded tissue by transmission electron microscopy. The genome sequence determined by next- and third-generation sequencing comprises 166 843 nt with inverted terminal repeats (ITRs) of 3473 nt. Overall, 20 of the predicted 159 ORFs have no equivalents in other poxviruses. Intriguingly, two of these ORFs were identified to encode homologues of mammalian proteins involved in immune signalling pathways, namely secreted and transmembrane protein 1 (SECTM1) and insulin growth factor-like family receptor 1 (IGFLR1), that were not described in any virus family so far. Phylogenetic analysis with all relevant representatives of the Poxviridae suggests that EMCLV should be nominated as a new species within the genus Molluscipoxvirus.
Physicochemical quality characteristics of Corni Fructus depending on the picking periods
Authors: Kim Su-Hui , Kang Chang-Jae , Seong Gi-Un , Chung Shin-Kyo
Published: January 2020

To determine the proper picking period for Corni Fructus, the seed removal degree, free sugar contents, antioxidant capacities, and Hunter's color values were investigated at intervals of 15 days from 236 days after full bloom (DAFB) to 327 DAFB. The seed removal degree maximized at 280 DAFB (p<0.05), at this point the moisture contents were 197.40% (db) and 66.00% (wb). The seed removal degrees were also investigated during hot air drying, and the best seed removal degree was obtained at moisture contents of 191.90% (db) and 65.74% (wb), similar to those observed at 280 DAFB. Fructose and glucose were detected, and their contents decreased slowly after 280 DAFB. Total phenolic contents (TPC), and DPPH radical scavening activity both decreased over the picking periods, but total anthocyanin contents (TAC) decreased after 280 DAFB. The redness, and yellowness of Corni Fructus powders, determined by using Hunter's colorimeter, decreased after 280 DAFB, but lightness decreased over the picking periods. Studies of the physicochemical quality characteristics revealed that the proper picking period of Corni Fructus should be 280 DAFB.
Quality characteristics of Tenebrio molitor L. ingested yuzu supplemented feed
Authors: Park Sang-Jun , Na Ji-Hoon , Lee Chul-Gyo , Jeong Jae-Hee , Kim Cheol-Min , Han Hong-Bi , Kim Bok-Seon , Park Chang-Hee , Huh Chang-Ki
Published: January 2020

In this study, we examined the quality of Tenebrio molitor L. that ingested yuzu supplemented feed at four feed compositions: C120 (120 g Chinese cabbage), C80+Y40 (80 g Chinese cabbage+40 g yuzu peel), C40+Y80 (40 g Chinese cabbage+80 g yuzu peel) and Y120 (120 g yuzu peel). Tenebrio molitor L. was fed for 90 d at a rate according to age, after which the moisture, crude protein, crude fat, and crude ash contents of the samples were determined to be 0.49-0.50%, 52.58-53.90%, 30.76-32.34%, and 3.32-3.45%, respectively. Color values, namely yellowness (b) and redness (a), were observed to decrease with increasing yuzu ingestion, and the C80+Y40 sample exhibited the highest lightness (L=36.28). The K and Mg contents were observed to increase with increasing yuzu content, and Pb and As were not detected in any Tenebrio molitor L. sample that ingested the yuzu supplemented feed. The free amino acid (serine and alanine) contents also increased with increasing yuzu content, while the histidine and arginine contents were observed to decrease with increasing yuzu ingestion. Naringin and hesperidin were detected at 1.77 mg% and 1.63 mg% in sample Y120, respectively, while trace amounts were detected in samples C80+Y40 and C40+Y80, but none were detected in the control. The total polyphenol and flavonoid contents increased with increasing level of yuzu ingestion, and were highest in sample Y120 (123.11 mg% and 5.69 mg%, respectively).
Analysis of retinol, β-carotene, vitamin E, and cholesterol contents in steamed and braised dishes of the Korean diet
Authors: Moon Hyun-Gyu , Islam Md. Atiqual , Chun Jiyeon
Published: January 2020

Steamed and braised dishes (SBDs) are staples of the Korean diet; therefore, knowledge of their nutritional contents is important for public health. To investigate the nutritional value of these foods, 25 different SBDs prepared following standard recipes were analyzed for retinol, β-carotene, vitamin E, and cholesterol contents using saponification coupled with GC and HPLC. To ensure the reliability of the data, the analytical methods were validated. The method showed acceptable precision (repeatability 0.9-1.3% RSD and reproducibility 1.1-5.9% RSD) and accuracy (95.6-101.1% recovery). The concentrations of the fat-soluble components in the SBDs varied widely depending on the constituent ingredients; cholesterol, retinol, β-carotene, and vitamin E concentrations were 0.0-246.7 mg/100 g, 0-155.1 μg/100 g, 0-1203.2 μg/100 g, and 0.09-1.85 mg α-tocopherol (T) equivalent/100 g, respectively. The highest retinol and β-carotene concentrations were observed in steamed egg with milk and braised egg, respectively, while neither was detected in braised mushroom or lotus root. SBDs prepared with egg showed the highest contents of cholesterol, vitamin A and E. The α-T form of vitamin E was detected in all SBDs and was predominant in most dishes, followed by γ-T. γ-Tocotrienol was a lesser ubiquitous form of vitamin E and detected only in Kkwarigochu-jjim and Eomuk-jorim. This work can help to provide nutritional guidance regarding the typical diet of the Korean population.
Quality characteristics of Baekseolgi made with Pu＇er tea extracts and agar powder
Authors: Seo Ji-Hyung
Published: January 2020

To evaluate whether pu´er tea extracts and agar powder could be of benefit in the processing of Baekseolgi, 5 kinds of Baekseolgi were prepared using agar along with various concentrations (i.e., 1, 2, and 3%) of pu´er tea extracts. The pH and moisture contents were found to be 6.07-6.12 and 41.49-42.08% in the prepared PAB (Ⅰ), PAB (Ⅱ), and PAB (Ⅲ) Baekseolgi samples, respectively. In addition, a decrease in the L value and increases in the a and b values were found upon increasing the amount of pu´er tea extract employed. In terms of the texture evaluation, the control Baekseolgi sample (Con(Ⅱ)) supplemented with only agar showed a significantly lower cohesiveness and an increased hardness, while an increased cohesiveness and a reduced hardness were observed upon the addition of pu´er tea extracts. Furthermore, for the three Baekseolgi samples, the polyphenol contents ranged from 2.62 to 7.18 mg GAE/g, while DPPH radical scavenging activities of 21.27, 29.85, and 40.32% were recorded for PAB (Ⅰ), PAB (Ⅱ), and PAB (Ⅲ), respectively. In terms of the sensory evaluation, a higher level of pu´er tea extracts resulted in a poorer taste. More specifically, PAB (Ⅲ), supplemented with agar and 3% pu´er tea extracts, exhibited the lowest acceptability over the three samples. It was therefore considered that the addition of 1-2% pu´er tea extracts is optimal to improve the antioxidant properties of Baekseolgi without having a detrimental effect on the product quality.
Polygenic modelling of treatment effect heterogeneity
Authors: Xu Zhi Ming , Burgess Stephen
Published: January 2020

Mendelian randomization is the use of genetic variants to assess the effect of intervening on a risk factor using observational data. We consider the scenario in which there is a pharmacomimetic (that is, treatment-mimicking) genetic variant that can be used as a proxy for a particular pharmacological treatment that changes the level of the risk factor. If the association of the pharmacomimetic genetic variant with the risk factor is stronger in one subgroup of the population, then we may expect the effect of the treatment to be stronger in that subgroup. We test for gene–gene interactions in the associations of variants with a modifiable risk factor, where one genetic variant is treated as pharmacomimetic and the other as an effect modifier, to find genetic sub-groups of the population with different predicted response to treatment. If individual genetic variants that are strong effect modifiers cannot be found, moderating variants can be combined using a random forest of interaction trees method into a polygenic response score, analogous to a polygenic risk score for risk prediction. We illustrate the application of the method to investigate effect heterogeneity in the effect of statins on low-density lipoprotein cholesterol.
Population-based stroke surveillance using Big Data: epidemiological trends in admissions and mortality in Australia
Authors: Gattellari Melina , Goumas Chris , Jalaludin Bin , Worthington John M.
Published: January 2020

Background

Epidemiological trends for major causes of death and disability, such as stroke, may be monitored using administrative data to guide public health initiatives and service delivery.

Methods

We calculated admissions rates for ischaemic stroke, intracerebral haemorrhage or subarachnoid haemorrhage between January 1, 2005 and December 31st, 2013 and rates of 30-day mortality and 365-day mortality in 30-day survivors to December 31st 2014 for patients aged 15 years or older from New South Wales, Australia (population 7.99 million). Annual Average Percentage Change in rates was estimated using negative binomial regression.

Results

Of 81,703 eligible admissions, 64,047 (78.4%) were ischaemic strokes and 13,302 (16.3%) and 4,778 (5.8%) were intracerebral and subarachnoid haemorrhages, respectively. Intracerebral haemorrhage admissions significantly declined by an average of 2.2% annually (95% Confidence Interval=-3.5% to −0.9%) (p<0.001). Thirty-day mortality rates significantly declined for ischaemic stroke (Average Percentage Change −2.9%, 95% Confidence Interval=-5.2% to −1.0%) (p=0.004) and subarachnoid haemorrhage (Average Percentage Change=-2.6%, 95% Confidence Interval=-4.8% to −0.2%) (p=0.04). Mortality at 365-days amongst 30-day survivors of ischaemic stroke and intracerebral haemorrhage was stable over time and increased in 30-day survivors of subarachnoid haemorrhage (Annual Percentage Change 6.2%, 95% Confidence Interval=-0.1% to 12.8%), although the increase was not statistically significant (p=0.05).

Conclusion

Improved prevention may have underpinned declining intracerebral haemorrhage rates while gains in survival suggest that innovations in stroke care are being successfully translated. Longer-term mortality in patients surviving the acute period is unchanged and may be increasing for subarachnoid haemorrhage warranting investment in post-discharge care and secondary prevention.
Assessment of Machine Learning Algorithms for Prediction of Breast Cancer Malignancy Based on Mammogram Numeric Data
Authors: Habib Peter T. , Alsamman Alsamman M. , Hassnein Sameh E. , Shereif Ghada A. , Hamwieh Aladdin
Published: January 2020

in 2019, estimated New Cases 268.600, Breast cancer has one of the most common cancers and is one of the world’s leading causes of death for women. Classification and data mining is an efficient way to classify information. Particularly in the medical field where prediction techniques are commonly used for early detection and effective treatment in diagnosis and research.These paper tests models for the mammogram analysis of breast cancer information from 23 of the more widely used machine learning algorithms such as Decision Tree, Random forest, K-nearest neighbors and support vector machine. The spontaneously splits results are distributed from a replicated 10-fold cross-validation method. The accuracy calculated by Regression Metrics such as Mean Absolute Error, Mean Squared Error, R2 Score and Clustering Metrics such as Adjusted Rand Index, Homogeneity, V-measure.accuracy has been checked F-Measure, AUC, and Cross-Validation. Thus, proper identification of patients with breast cancer would create care opportunities, for example, the supervision and the implementation of intervention plans could benefit the quality of long-term care. Experimental results reveal that the maximum precision 100%with the lowest error rate is obtained with Ada-boost Classifier.
Bimodal distribution and set point HBV DNA viral loads in chronic infection: retrospective analysis of cohorts from the UK and South Africa
Authors: Downs Louise O , Vawda Sabeehah , Bester Phillip Armand , Lythgoe Katrina A , Wang Tingyan , McNaughton Anna L , Smith David A , Maponga Tongai , Freeman Oliver , Várnai Kinga A , Davies Jim , Woods Kerrie , Fraser Christophe , Barnes Eleanor , Goedhals Dominique , Matthews Philippa C
Published: January 2020

Hepatitis B virus (HBV) DNA viral loads (VL) show wide variation between individuals with chronic hepatitis B (CHB) infection, and are used to determine treatment eligibility. There are few refined descriptions of VL distribution in CHB, and limited understanding of the biology that underpins these patterns. We set out to describe the VL distribution in independent cohorts from the UK and South Africa, to identify associated host characteristics, and to compare with VL in HIV-1 and hepatitis C (HCV) infection. We show the presence of a set-point in chronic HBV infection and report significant differences in the viral load distribution of HBV when compared to HIV and HCV.
DDIEM: Drug Database for Inborn Errors of Metabolism
Authors: Abdelhakim Marwa , McMurray Eunice , Syed Ali Raza , Kafkas Senay , Kamau Allan Anthony , Schofield Paul N , Hoehndorf Robert
Published: January 2020

Background

Inborn errors of metabolism (IEM) represent a subclass of rare inherited diseases caused by a wide range of defects in metabolic enzymes or their regulation. Of over a thousand characterized IEMs, only about half are understood at the molecular level, and overall the development of treatment and management strategies has proved challenging. An overview of the changing landscape of therapeutic approaches is helpful in assessing strategic patterns in the approach to therapy, but the information is scattered throughout the literature and public data resources.

Results

We gathered data on therapeutic strategies for 299 diseases into the Drug Database for Inborn Errors of Metabolism (DDIEM). Therapeutic approaches, including both successful and ineffective treatments, were manually classified by their mechanisms of action using a new ontology.

Conclusions

We present a manually curated, ontologically formalized knowledgebase of drugs, therapeutic procedures, and mitigated phenotypes. DDIEM is freely available through a web interface and for download athttp://ddiem.phenomebrowser.net.
Portable Automated Rapid Testing (PART) for auditory assessment: Validation in a young adult normal-hearing population
Authors: de Larrea-Mancera E. Sebastian Lelo , Stavropoulos Trevor , Hoover Eric C. , Eddins David A. , Gallun Frederick J. , Seitz Aaron R.
Published: January 2020

This study aims to determine the degree to which Portable Automated Rapid Testing (PART), a freely-available program running on a tablet computer, is capable of reproducing standard laboratory results. Undergraduate students were assigned to one of three within-subject conditions that examined repeatability of performance on a battery of psychoacoustical tests of temporal fine structure processing, spectro-temporal amplitude modulation, and targets in competition. The Repeatability condition examined test/retest with the same system, the Headphones condition examined the effects of varying headphones (passive and active noise-attenuating), and the Noise condition examined repeatability in the presence of recorded cafeteria noise. In general, performance on the test battery showed high repeatability, even across manipulated conditions, and was similar to that reported in the literature. These data serve as validation that suprathreshold psychoacoustical tests can be made accessible to run on consumer-grade hardware and performed in less controlled settings. This dataset also provides a distribution of thresholds that can be used as a normative baseline against which auditory dysfunction can be identified in future work.
Phosphoglycerol-type wall- and lipoteichoic acids are enantiomeric polymers differentially cleaved by the stereospecific glycerophosphodiesterase GlpQ
Authors: Walter Axel , Unsleber Sandra , Rismondo Jeanine , Jorge Ana Maria , Peschel Andreas , Gründling Angelika , Mayer Christoph
Published: January 2020

The cell envelope of Gram-positive bacteria generally comprises two types of polyanionic polymers, either linked to peptidoglycan, wall teichoic acids (WTA), or to membrane glycolipids, lipoteichoic acids (LTA). In some bacteria, includingBacillus subtilisstrain 168, WTA and LTA both are glycerolphosphate polymers, yet are synthesized by different pathways and have distinct, although not entirely understood morphogenetic functions during cell elongation and division. We show here that the exo-lyticsn-glycerol-3-phosphodiesterase GlpQ can discriminate betweenB. subtilisWTA and LTA polymers. GlpQ completely degrades WTA, lacking modifications at the glycerol residues, by sequentially removing glycerolphosphates from the free end of the polymer up to the peptidoglycan linker. In contrast, GlpQ is unable to cleave unmodified LTA. LTA can only be hydrolyzed by GlpQ when the polymer is partially pre-cleaved, thereby allowing GlpQ to get access to the end of the polymer that is usually protected by a connection to the lipid anchor. This indicates that WTA and LTA are enantiomeric polymers: WTA is made ofsn-glycerol-3-phosphate and LTA is made ofsn-glycerol-1-phosphate. Differences in stereochemistry between WTA and LTA were assumed based on differences in biosynthesis precursors and chemical degradation products, but so far had not been demonstrated directly by differential, enantioselective cleavage of isolated polymers. The discriminative stereochemistry impacts the dissimilar physiological and immunogenic properties of WTA and LTA and enables independent degradation of the polymers, while appearing in the same location; e.g. under phosphate limitation,B. subtilis168 specifically hydrolyzes WTA and synthesizes phosphate-free teichuronic acids in exchange.
Nα-acetylation of EsxA is required for mycobacterial cytosolic translocation and virulence
Authors: Aguilera Javier , Karki Chitra B. , Li Lin , Vazquez-Reyes Salvador , Zhang Qi , Arico Chenoa D. , Ouellet Hugues , Sun Jianjun
Published: January 2020

Mycobacterium tuberculosisvirulence factors, EsxA and EsxB, are secreted as a heterodimer (EsxA:B) and play an essential role in mycobacterial phagosomal escape and cytosolic translocation. Current studies support a model that EsxA must dissociate from its chaperon EsxB at low pH in order for EsxA to interact with host membranes. However, the mechanism of the heterodimer separation is not clear. In the present study, we have obtained evidence that the Nα-acetylation of Thr2 on EsxA, a post-translational modification that is present in mycobacteria, but absent inE. coli, is required for the heterodimer separation. The point mutations at Thr2 without Nα-acetylation inhibited the heterodimer separation and hence prevented EsxA from interacting with the membranes, which resulted in attenuated mycobacterial cytosolic translocation and virulence. Molecular dynamic simulation showed that at low pH the Nα-acetylated Thr2 made direct and frequent “bind-and-release” contacts with EsxB, which generates a dragging force to pull EsxB away from EsxA.
Species tree disequilibrium positively misleads models of gene family evolution
Authors: Lauterbur M. Elise , Heder Sarah , Yohe Laurel R. , Dávalos Liliana M.
Published: January 2020

Gene duplication is a key source of evolutionary innovation, and multigene families evolve in a birth-death process, continuously duplicating and pseudogenizing through time. To empirically test hypotheses about adaptive expansion and contraction of multigene families across species, models infer gene gain and loss in light of speciation events and these inferred gene family expansions may lead to interpretations of adaptations in particular lineages. While the relative abundance of a gene subfamily in the subgenome may reflect its functional importance, tests based on this expectation can be confounded by the complex relationship between the birth-death process of gene subfamily evolution and the species phylogeny. Using simulations, we confirmed tree heterogeneity as a confounding factor in inferring multi-gene adaptation, causing spurious associations between shifts in birth-death rate and lineages with higher branching rates. We then used theolfactory receptor(OR) repertoire, the largest gene family in the mammalian genome, of different bat species with divergent diets to test whether expansions in olfactory receptors are associated with shifts to frugivorous diets. After accounting for tree heterogeneity, we robustly inferred that certainORsubfamilies exhibited expansions associated with dietary shifts to frugivory. Taken together, these results suggest ecological correlates of individualORgene subfamilies can be identified, setting the stage for detailed inquiry into within-subfamily functional differences.
A cortical wiring space links cellular architecture, functional dynamics and hierarchies in humans
Authors: Paquola Casey , Seidlitz Jakob , Benkarim Oualid , Royer Jessica , Klimes Petr , Bethlehem Richard A. I. , Larivière Sara , Vos de Wael Reinder , Hall Jeffery A. , Frauscher Birgit , Smallwood Jonathan , Bernhardt Boris C.
Published: January 2020

Abstract

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico-cortical wiring established by post mortem anatomical studies and capitalizes on cutting-edge neuroimaging and machine learning. The new model expands the currently prevailing diffusion MRI tractography approach by incorporation of additional features of cortical microstructure and cortico-cortical proximity. Studying several datasets, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior-posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics across a broad range contexts (based on resting-state fMRI, task-based fMRI, and human intracranial EEG coherence). Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.
Insights into smouldering MS brain pathology with multimodal diffusion tensor and PET imaging
Authors: Bezukladova Svetlana , Tuisku Jouni , Matilainen Markus , Vuorimaa Anna , Nylund Marjo , Smith Sarah , Sucksdorff Marcus , Mohammadian Mehrbod , Saunavaara Virva , Laaksonen Sini , Rokka Johanna , Rinne Juha , Rissanen Eero , Airas Laura
Published: January 2020

Objective: To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter damage in multiple sclerosis (MS) brain, and to examine their association with clinical disability.
Methods: 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO-binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the whole normal appearing white matter (NAWM) and segmented NAWM regions appearing normal in conventional MRI. 55 MS patients and 15 healthy controls were examined.
Results: Microstructural damage was observed in the NAWM of MS brain. DTI parameters of MS patients were significantly altered in the NAWM, when compared to an age- and sex-matched healthy control group: mean FA was decreased, and MD, AD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p<0.05 for all correlations; p<0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with expanded disability status scale (EDSS).
Conclusions: Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI imaging allows in vivo evaluation of widespread MS pathology not visible using conventional MRI.
Free Energy Landscape and Conformational Kinetics of Hoogsteen Base-Pairing in DNA vs RNA
Authors: Ray D. , Andricioaei I.
Published: January 2020

Genetic information is encoded in the DNA double helix which, in its physiological milieu, is characterized by the iconical Watson-Crick nucleobase pairing. Recent NMR relaxation experiments revealed the transient presence of an alternative, Hoogsteen base pairing pattern in naked DNA duplexes and estimated its relative stability and lifetime. In contrast, HG transitions in RNA were not observed. Understanding Hoogsteen (HG) base pairing is important because the underlying "breathing" can modulate significantly DNA/RNA recognition by proteins. However, a detailed mechanistic insight into the transition pathways and kinetics is still missing. We performed enhanced sampling simulation (with combined metadynamics and adaptive force bias method) and Markov State modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both naked B-DNA and A-RNA duplexes. The Markov state model constructed from our unbiased MD simulation data revealed previously unknown complex extra-helical intermediates in this seemingly simple process of base pair conformation switching in B-DNA. Extending our calculation to A-RNA, for which HG base pair is not observed experimentally, resulted in relatively unstable single hydrogen bonded distorted Hoogsteen like base pair. Unlike B-DNA the transition pathway primarily involved base paired and intra-helical intermediates with transition timescales much higher than that of B-DNA. The seemingly obvious flip-over reaction coordinate, i.e., the glycosidic torsion angle is unable to resolve the intermediates; so a multidimensional picture, involving backbone dihedral angles and distance between atoms participating in hydrogen bonds, is required to gain insight into the molecular mechanism.

SIGNIFICANCE

Formation of unconventional Hoogsteen (HG) base pairing is an important problem in DNA biophysics owing to its key role in facilitating the binding of DNA repairing enzymes, proteins and drugs to damaged DNA. X-ray crystallography and NMR relaxation experiments revealed the presence of HG base pair in naked DNA duplex and protein-DNA complex but no HG base pair was observed in RNA. Molecular dynamics simulations could reproduce the experimental free energy cost of HG base pairing in DNA although a detailed mechanistic insight is still missing. We performed enhanced sampling simulation and Markov state modeling to obtain accurate free energy, kinetics and the intermediates in the transition pathway between WC and HG base pair for both B-DNA and A-RNA.
Ostrea edulisat shipwrecks in the Dutch North Sea
Authors: Coolen Joop W.P. , Dongen Udo Van , Driessen Floor M.F. , Wurz Erik , Bergsma Joost H. , Olie Renate A. , Deden Brenda , Bos Oscar G.
Published: January 2020

During diving expeditions in July and September 2019 two live European flat oysters (Ostrea edulis) were observed by SCUBA divers. The first oyster was found lying amongst coarse shelly material in the scour hole around shipwreck #3251, 37 nautical miles north west of Texel (NL). The second oyster was found on the Gustav Nachtigal wreck, 6 nautical miles north of Schiermonnikoog (NL). Additional shipwrecks were also inspected for O. edulis individuals but no live specimens were observed, although on 9 out of 11 inspected locations empty, fossil O. edulis shells were found. The September dive on the #3251 shipwreck revealed the presence of several large empty flat oyster shells, some of which were attached to each other, with up to three individuals in a cluster. This implies that the area around the #3251 shipwreck was a suitable location for flat oysters in the past and that oyster larvae are still capable of reaching the location. The findings suggest that shipwrecks and their surroundings are promising locations for future O. edulis restoration projects.
Pleiotropy promotes male exaggerated weapon and its associated fighting behaviour in a water strider
Authors: Toubiana William , Armisén David , Amélie Decaras , Khila Abderrahman
Published: January 2020

Exaggerated sexually selected traits, often carried by males, are characterized by the evolution of hyperallometry, resulting in their disproportionate growth relative to the rest of the body1–3. While the evolution of allometry has attracted much attention for centuries, our understanding of the developmental genetic mechanisms underlying its emergence remains fragmented4,5. Here we show that the hyperallometric legs in the males of the water striderMicrovelia longipesare associated with a specific signature of gene expression during development. Using RNAi knockdown, we demonstrate that a broadly expressed growth factor, Bone Morphogenetic Protein 11 (BMP11, also known as Growth Differentiation Factor 11), regulates leg allometries through increasing the allometric coefficient and mean body size in males. In contrast, BMP11 RNAi reduced mean body size but did not affect slope in females. Furthermore, our data show that a tissue specific factor, Ultrabithorax (Ubx), increases intercept without affecting mean body size. This indicates a genetic correlation between mean body size and variation in allometric slope, but not intercept. Strikingly, males treated with BMP11 RNAi exhibited a severe reduction in fighting frequency compared to both controls and Ubx RNAi-treated males. Overall, we demonstrate a genetic correlation between male body size, the exaggerated weapon, and the intense fighting behaviour associated with it inM. longipes. Our results provide evidence for a role of pleiotropy in the evolution of allometric slope.
Nanopore Sequencing at Mars, Europa and Microgravity Conditions
Authors: Carr Christopher E. , Bryan Noelle C. , Saboda Kendall N. , Bhattaru Srinivasa A. , Ruvkun Gary , Zuber Maria T.
Published: January 2020

Nanopore sequencing, as represented by Oxford Nanopore Technologies’ MinION, is a promising technology forin situlife detection and for microbial monitoring including in support of human space exploration, due to its small size, low mass (∼100 g) and low power (∼1W). Now ubiquitous on Earth and previously demonstrated on the International Space Station (ISS), nanopore sequencing involves translocation of DNA through a biological nanopore on timescales of milliseconds per base. Nanopore sequencing is now being done in both controlled lab settings as well as in diverse environments that include ground, air and space vehicles. Future space missions may also utilize nanopore sequencing in reduced gravity environments, such as in the search for life on Mars (Earth-relative gravito-inertial acceleration (GIA)g= 0.378), or at icy moons such as Europa (g= 0.134) or Enceladus (g= 0.012). We confirm the ability to sequence at Mars as well as near Europa or Lunar (g= 0.166) and lowerglevels, demonstrate the functionality of updated chemistry and sequencing protocols under parabolic flight, and reveal consistent performance acrossglevel, during dynamic accelerations, and despite vibrations with significant power at translocation-relevant frequencies. Our work strengthens the use case for nanopore sequencing in dynamic environments on Earth and in space, including as part of the search for nucleic-acid based life beyond Earth.
Bayesian genomic models boost prediction accuracy for resistance againstStreptococcus agalactiaein Nile tilapia (Oreochromus nilioticus)
Authors: Joshi Rajesh , Skaaurd Anders , Alvarez Alejandro Tola , Moen Thomas , Ødegård Jørgen
Published: January 2020

Streptococcosis due to Streptococcus agalactiae is a major bacterial disease in Nile tilapia, and development of the resistant genetic strains can be a sustainable approach towards combating this problematic disease. Thus, a controlled disease trial was performed on 120 full-sib families to i) quantify and characterize the potential of genomic selection for S. agalactiae resistance in Nile tilapia and to ii) select the best genomic model and optimal SNP-chip for this trait.

In total, 40 fish per family (15 fish intraperitoneally injected and 25 fish as cohabitants) were selected for the challenge test and mortalities recorded every 3 hours, until no mortalities occurred for a period of 3 consecutive days. Genotypes (50,690 SNPs) and phenotypes (0 for dead and 1 for alive) for 2472 cohabitant fish were available. The pedigree-based analysis utilized a deep pedigree, going 17 generations back in time. Genetic parameters were obtained using various genomic selection models (GBLUP, BayesB, BayesC, BayesR and BayesS) and traditional pedigree-based model (PBLUP). The genomic models were further analyzed using 10 different subsets of SNP-densities for optimum marker density selection. Prediction accuracy and bias were evaluated using 5 replicates of 10-fold cross-validation.

Using an appropriate Bayesian genomic selection model and optimising it for SNP density increased prediction accuracy up to ∼71%, compared to a pedigree-based model. This result is encouraging for practical implementation of genomic selection for S. agalactiae resistance in Nile tilapia breeding programs.