bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of volunteer organizations in suicide prevention
Authors: Andriessen Karl
Published: February 2021

Contemporary suicide prevention emerged, to a large extent, as a result of groundwork conducted by volunteers. This chapter focuses on the involvement of volunteers in suicide prevention organizations throughout history and across the world, including the involvement of volunteers in suicide bereavement support. The characteristics of volunteers and volunteer organizations are presented. The question regarding the effectiveness of volunteer organizations is discussed (e.g. the available evidence regarding the positive effects of telephone crisis lines, online help, and community volunteer organizations). However, further research is needed given the shortage of studies. The chapter concludes with a plea for increased cooperation between volunteer and professional organizations, and integration of volunteer involvement in national suicide prevention policies, in order to provide optimal care to the people in need.
Involuntary hospitalization
Authors: Ryan Christopher James , Bartels Jane
Published: February 2021

The chapter outlines a series of arguments designed to answer possibly the most important ethical question in psychiatry: under what circumstances, if any, is it ethically justifiable to treat people with clinical features of mental illness, despite their objection? We argue that involuntary inpatient treatment is ethically justified, but only in circumstances where: the objection to treatment was made without decision-making capacity; there is no reason to believe that the person would have objected had he or she been competent; the treatment will protect the person from serious harms (when balancing these with any harms associated with the treatment); and involuntary treatment represents the avenue for protection least restrictive of the person’s freedom. Having established a model for ethically justified involuntary inpatient psychiatric treatment, we examine how it can be applied to two real-world cases.
Neuroethics
Authors: Northoff Georg
Published: February 2021

Neuroethics, located at the interface of conceptual and empirical dimensions, carries major implications for psychiatry, such as the neuroscientific basis of ethical concepts as moral agency. Drawing on data in neuroscience, this chapter highlights issues central to psychiatric ethics. First, it addresses a reductionistic model of the brain, often conceived as purely neuronal, and then it discusses empirical data suggesting that the brain’s activity is strongly aligned to its respective social (e.g., relation to others) and ecological (e.g., relation to the environment and nature) contexts; this implies a relational rather than reductionist model. Second, it suggests that self (e.g., the experience or sense of a self) and personhood (e.g., the person as existent independent of experience) must also be understood in such a social and ecological and, therefore, relational and spatio-temporal sense. Ethical concepts like agency, therefore, cannot be limited solely to the person and brain, but must rather be understood in a relational and neuro-ecological/social way. Third, it discusses deep brain stimulation as a treatment that promotes enhancement. In sum, this chapter presents findings in neuroscience that carry major implications for our view of brain, mental features, psychiatric disorders, and ethical issues like agency, responsibility, and enhancement.
Consultation-liaison psychiatry
Authors: Levin Tomer T. , Ryan Christopher J.
Published: February 2021

Ethics in consultation-liaison (C-L) psychiatry involves the intersection of medical illness and psychiatry. Because it is now clear that psychiatric illnesses and substance use also worsen medical outcomes, the field has broadened to a population level, overlapping with primary care. This brings distributive justice to the fore, as large-scale psychiatric screening requires adequate resources to treat identified populations. Ethical challenges masquerading as psychiatric problems or psychiatric issues masquerading as ethical dilemmas are common. Boundary issues, confidentiality, privacy, multiple loyalties in C-L settings, autonomy, decision-making capacity, and end-of-life conflict are frequent areas of ethical concern for the C-L psychiatrist.
Pulmonary arterial hypertension
Authors: Chakravarty Eliza
Published: February 2021

Pulmonary arterial hypertension (PAH) is a recognized manifestation of connective tissue diseases, particularly systemic lupus erythematosus and systemic sclerosis. It is associated with high rates of morbidity and mortality in general, and these risks increase substantially during pregnancy and delivery. Women with systemic sclerosis who wish to conceive should have an evaluation for PAH prior to pregnancy. Women with known PAH should be counselled about the high risks to maternal health associated with pregnancy, and permanent or long acting reversible contraception strongly recommended. Women who strongly desire pregnancy despite the risks should be supported and aggressive monitoring and management of PAH and congestive heart failure undertaken with vasodilators. Endothelin receptor antagonists and oral anticoagulants should be avoided due to risks of teratogenicity. Women with progressive or abrupt dyspnea should be evaluated for the development of venous thromboembolism (VTE) or PAH, and treated accordingly. o
Ankylosing spondylitis in pregnancy
Authors: Østensen Monika
Published: February 2021

Ankylosing spondylitis (AS), now called axial spondyloarthritis (axSpA) shows no tendency to improve spontaneously during pregnancy but remains stable or active. An aggravation of symptoms occurs often around mid-gestation. Treatment with medications is needed in many pregnant patients and has to be modified according to stage of pregnancy. Vaginal delivery is possible in most women with axSpA, however, disease-related and iatrogenic reasons or patient preferences increase the rate of surgical delivery. AS typically affects individuals in the 3rd decade of life and is in its radiographic form predominant in men with a male to female ratio of 2–3:1 whereas the non-radiographic form has an equal gender distribution.
Longitudinal change in fine motor skills after brain radiotherapy and in vivo imaging biomarkers associated with decline
Authors: Salans Mia , Tibbs Michelle D , Karunamuni Roshan , Yip Anthony , Huynh-Le Minh-Phuong , Macari Anna Christina , Reyes Anny , Tringale Kathryn , McDonald Carrie R , Hattangadi-Gluth Jona A
Published: February 2021

Background

We explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs).

Methods

On a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons.

Results

Higher RT dose was associated with right paracentral cortical thinning (β = −2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (β = 38.7 points/(month × µm2/ms), P = .004) and right (β = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = −8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = −0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = −17.3 points/(month × mm), P = .02). Left (β = −0.87 points/(month × cm3), P = .001) and right (β = −0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (β = −19.8 points/(month × cm3), P = .02), and right pallidum (β = −10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (β = −1.02 points/month, P = .03) were associated with worse PNDH performance.

Conclusions

Biomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.
Developing a Professionalism and Harassment Policy for Organized Neurosurgery
Authors: Air Ellen L , Orrico Katie O , Benzil Deborah L , Scarrow Alan M , Bean James R , Mazzola Catherine A , Liau Linda M , Rutka James T , Muraszko Karin M
Published: February 2021

Annual conferences, educational courses, and other meetings draw a diverse community of individuals, yet also create a unique environment without the traditional guard rails. Unlike events held at one's home institution, clear rules and jurisdiction have not been universally established. To promote the open exchange of ideas, as well as an environment conducive to professional growth of all participants, the leading neurosurgical professional organizations joined forces to delineate the expectations for anyone who participates in sponsored events. The One Neurosurgery Summit Taskforce on Professionalism and Harassment developed a foundational policy that establishes common expectations for behavior and a unified roadmap for the prompt response to untoward events. We hope that publishing this policy will inspire other medical organizations to establish their own meeting and conference policies. More importantly, we wish to bring greater attention to everyone's responsibility for ensuring a safe and respectful space for education, scientific debate, and networking during organized events.
Efficacy and comorbidities of hypofractionated and single-dose radiosurgery for vestibular schwannomas: a systematic review and meta-analysis
Authors: Tosi Umberto , Guadix Sergio , An Anjile , Wright Drew , Christos Paul J , Pannullo Susan , Brandmaier Andrew , Knisely Jonathan P S , Stieg Philip E , Ramakrishna Rohan
Published: February 2021

Background

Vestibular schwannomas (VS) are tumors of the cerebellopontine angle with significant morbidity, causing hearing loss, tinnitus, and trigeminal and facial nerve compromise. An effective alternative to microsurgical resection is stereotactic radiosurgery (SRS), which can be delivered in either single-fraction (SRS) or hypofractionated stereotactic radiotherapy (hSRT) (3-5 treatments) regimens. It remains unclear which fractionation regimen provides superior outcomes.

Methods

Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Reviews were searched for studies either comparing hSRT with SRS or focusing on hSRT alone in treating VS. Primary endpoints included tumor control, serviceable hearing, tinnitus, and cranial nerve V and VII symptoms. A random-effects analysis was employed to compare pre- and post-treatment effects (hSRT alone) or SRS and hSRT outcomes (two-arm studies).

Results

This analysis included 21 studies focusing on hSRT alone and 13 studies comparing SRS and hSRT. Significant heterogeneity was observed. Overall, when hSRT was analyzed alone, crude tumor control was achieved in 94% (95% CI: 88%, 99%) of 1571 patients. There was no difference between pre- and post-treatment odds ratios (OR) of tinnitus, facial, or trigeminal impairment. Serviceable hearing was diminished following hSRT (OR = 0.60, 95% CI: 0.44, 0.83). Comparison with SRS showed no difference with respect to tumor control, serviceable hearing, trigeminal or facial nerve impairment.

Conclusions

hSRT achieved excellent tumor control and, with the exception of serviceable hearing, did not result in worse post-treatment cranial nerve symptomatology. Analysis of comparative studies between hSRT and SRS did not reveal any significant difference in either tumor control or treatment morbidities.
Prospective Cohort of Fluvoxamine for Early Treatment of Coronavirus Disease 19
Authors: Seftel David , Boulware David R
Published: February 2021

We report a real-world experience using fluvoxamine for coronavirus disease 19 (COVID-19) in a prospective cohort in the setting of a mass outbreak. Overall, 65 persons opted to receive fluvoxamine (50 mg twice daily) and 48 declined. Incidence of hospitalization was 0% (0 of 65) with fluvoxamine and 12.5% (6 of 48) with observation alone. At 14 days, residual symptoms persisted in 0% (0 of 65) with fluvoxamine and 60% (29 of 48) with observation.
How Do Pathogens Evolve Novel Virulence Activities?
Authors: Sacristán Soledad , Goss Erica M. , Eves-van den Akker Sebastian
Published: February 2021

This article is part of the Top 10 Unanswered Questions in MPMI invited review series.

We consider the state of knowledge on pathogen evolution of novel virulence activities, broadly defined as anything that increases pathogen fitness with the consequence of causing disease in either the qualitative or quantitative senses, including adaptation of pathogens to host immunity and physiology, host species, genotypes, or tissues, or the environment. The evolution of novel virulence activities as an adaptive trait is based on the selection exerted by hosts on variants that have been generated de novo or arrived from elsewhere. In addition, the biotic and abiotic environment a pathogen experiences beyond the host may influence pathogen virulence activities. We consider host-pathogen evolution, host range expansion, and external factors that can mediate pathogen evolution. We then discuss the mechanisms by which pathogens generate and recombine the genetic variation that leads to novel virulence activities, including DNA point mutation, transposable element activity, gene duplication and neofunctionalization, and genetic exchange. In summary, if there is an (epi)genetic mechanism that can create variation in the genome, it will be used by pathogens to evolve virulence factors. Our knowledge of virulence evolution has been biased by pathogen evolution in response to major gene resistance, leaving other virulence activities underexplored. Understanding the key driving forces that give rise to novel virulence activities and the integration of evolutionary concepts and methods with mechanistic research on plant-microbe interactions can help inform crop protection.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Hybrid Genome Assembly and Gene Repertoire of the Root Endophyte Clitopilus hobsonii QYL-10 (Entolomataceae, Agaricales, Basidiomycetes)
Authors: Peng Long , Shan Xiaoliang , Wang Yuchen , Martin Francis , Vilgalys Rytas , Yuan Zhilin
Published: February 2021

Clitopilus hobsonii (Entolomataceae, Agaricales, Basidiomycetes) is a common soil saprotroph. There is also evidence that C. hobsonii can act as a root endophyte benefitting tree growth. Here, we report the genome assembly of C. hobsonii QYL-10, isolated from ectomycorrhizal root tips of Quercus lyrata. The genome size is 36.93 Mb, consisting of 13 contigs (N50 = 3.3 Mb) with 49.2% GC content. Of them, 10 contigs approached the length of intact chromosomes, and three had telomeres at one end only. BUSCO analysis reported a completeness score of 98.4%, using Basidiomycota_odb10 lineage data. Combining ab-initio, RNA-seq data, and homology-based predictions, we identified 12,710 protein-coding genes. Approximately, 1.43 Mb of transposable elements (3.88% of the assembly), 36 secondary metabolite biosynthetic gene clusters, and 361 genes encoding putative carbohydrate-active enzymes were identified. This genomic resource will allow functional studies aimed to characterize the symbiotic interactions between C. hobsonii and its host trees and will also provide a valuable foundation for further research on comparative genomics of the Entolomataceae.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Pristine microstructures in pseudotachylytes formed in dry lower crust, Lofoten, Norway
Authors: Dunkel Kristina G. , Morales Luiz F. G. , Jamtveit Bjørn
Published: February 2021

Feldspar-rich pseudotachylytes from the island of Moskenesøya, Lofoten, formed in dry granulites under lower crustal conditions during the Caledonian orogeny. The central parts of the pseudotachylytes, where the cooling rates were slowest, are characterized by microlites and spherulites of plagioclase and K-feldspar. K-feldspar surrounding plagioclase is consistent with crystallization from a melt during cooling instead of devitrification as the origin of the spherulites. Very thin (a few micrometres wide) injection veins, which experienced very rapid quenching, contain amorphous or cryptocrystalline material. The preservation of this material and of the fine-grained microstructures shows that, under fluid-absent conditions, recrystallization and reactions are slow and the original microstructures of the pseudotachylytes can be preserved.

This article is part of a discussion meeting issue ‘Understanding earthquakes using the geological record’.
What’s down there? The structures, materials and environment of deep-seated slow slip and tremor
Authors: Behr Whitney M. , Bürgmann Roland
Published: February 2021

Deep-seated slow slip and tremor (SST), including slow slip events, episodic tremor and slip, and low-frequency earthquakes, occur downdip of the seismogenic zone of numerous subduction megathrusts and plate boundary strike-slip faults. These events represent a fascinating and perplexing mode of fault failure that has greatly broadened our view of earthquake dynamics. In this contribution, we review constraints on SST deformation processes from both geophysical observations of active subduction zones and geological observations of exhumed field analogues. We first provide an overview of what has been learned about the environment, kinematics and dynamics of SST from geodetic and seismologic data. We then describe the materials, deformation mechanisms, and metamorphic and fluid pressure conditions that characterize exhumed rocks from SST source depths. Both the geophysical and geological records strongly suggest the importance of a fluid-rich and high fluid pressure habitat for the SST source region. Additionally, transient deformation features preserved in the rock record, involving combined frictional-viscous shear in regions of mixed lithology and near-lithostatic fluid pressures, may scale with the tremor component of SST. While several open questions remain, it is clear that improved constraints on the materials, environment, structure, and conditions of the plate interface from geophysical imaging and geologic observations will enhance model representations of the boundary conditions and geometry of the SST deformation process.

This article is part of a discussion meeting issue ‘Understanding earthquakes using the geological record’.
HTSlib - C library for reading/writing high-throughput sequencing data
Authors: Bonfield James K. , Marshall John , Danecek Petr , Li Heng , Ohan Valeriu , Whitwham Andrew , Keane Thomas , Davies Robert M.
Published: February 2021

Background

Since the original publication of the VCF and SAM formats, an explosion of software tools have been created to process these data files. To facilitate this a library was produced out of the original SAMtools implementation, with a focus on performance and robustness. The file formats themselves have become international standards under the jurisdiction of the Global Alliance for Genomics and Health.

Findings

We present a software library for providing programmatic access to sequencing alignment and variant formats. It was born out of the widely used SAMtools and BCFtools applications. Considerable improvements have been made to the original code plus many new features including newer access protocols, the addition of the CRAM file format, better indexing and iterators, and better use of threading.

Conclusion

Since the original Samtools release, performance has been considerably improved, with a BAM read-write loop running 5 times faster and BAM to SAM conversion 13 times faster (both using 16 threads, compared to Samtools 0.1.19).

Widespread adoption has seen HTSlib downloaded over a million times from GitHub and conda. The C library has been used directly by an estimated 900 GitHub projects and has been incorporated into Perl, Python, Rust and R, significantly expanding the number of uses via other languages. HTSlib is open source and is freely available from htslib.org under MIT / BSD license.

Contact

samtools@sanger.ac.uk
Modeling the potential impact of indirect transmission on COVID-19 epidemic
Authors: David Jummy , Iyaniwura Sarafa A. , Yuan Pei , Tan Yi , Kong Jude , Zhu Huaiping
Published: February 2021

The spread of SARS-CoV-2 through direct transmission (person-to-person) has been the focus of most studies on the dynamics of COVID-19. The efficacy of social distancing and mask usage at reducing the risk of direct transmission of COVID-19 has been studied by many researchers. Little or no attention is given to indirect transmission of the virus through shared items, commonly touch surfaces and door handles. The impact of the persistence of SARS-CoV-2 on hard surfaces and in the environment, on the dynamics of COVID-19 remain largely unknown. Also, the current increase in the number of cases despite the strict non-pharmaceutical interventions suggests a need to study the indirect transmission of COVID-19 while incorporating testing of infected individuals as a preventive measure. Assessing the impact of indirect transmission of the virus may improve our understanding of the overall dynamics of COVID-19. We developed a novel deterministic susceptible-exposed-infected-removed-virus-death compartmental model to study the impact of indirect transmission pathway on the spread of COVID-19, the sources of infection, and prevention/control. We fitted the model to the cumulative number of confirmed cases at episode date in Toronto, Canada using a Markov Chain Monte Carlo optimization algorithm. We studied the effect of indirect transmission on the epidemic peak, peak time, epidemic final size and the effective reproduction number, based on different initial conditions and at different stages. Our findings revealed an increase in cases with indirect transmission. Our work highlights the importance of implementing additional preventive and control measures involving cleaning of surfaces, fumigation, and disinfection to lower the spread of COVID-19, especially in public areas like the grocery stores, malls and so on. We conclude that indirect transmission of SARS-CoV-2 has a significant effect on the dynamics of COVID-19, and there is need to consider this transmission route for effective mitigation, prevention and control of COVID-19 epidemic.
Surveillance-to-Diagnostic Testing Program for Asymptomatic SARS-CoV-2 Infections on a Large, Urban Campus - Georgia Institute of Technology, Fall 2020
Authors: Gibson Greg , Weitz Joshua S. , Shannon Michael P. , Holton Benjamin , Bryksin Anton , Liu Brian , Bramblett Sandra , Williamson JulieAnne , Farrell Michael , Ortiz Alexander , Abdallah Chaouki T. , García Andrés J.
Published: February 2021

A SARS-CoV-2 testing program combining pooled saliva sample surveillance leading to diagnosis and intervention surveyed over 112,000 samples from 18,029 students, staff and faculty, as part of integrative efforts to mitigate transmission at the Georgia Institute of Technology in Fall 2020. Cumulatively, 1,508 individuals were confirmed diagnostically. The surveillance strategy, including focused intensification of testing given case clusters, was effective in disrupting transmission following rapid case increases upon entry in August 2020, and again in November 2020. Owing to broad adoption by the campus community, the program protected higher risk staff while allowing some normalization of research activities.
Comparative performance of multiplex salivary and commercially available serologic assays to detect SARS-CoV-2 IgG and neutralization titers
Authors: Heaney Christopher D. , Pisanic Nora , Randad Pranay R. , Kruczynski Kate , Howard Tyrone , Zhu Xianming , Littlefield Kirsten , Patel Eshan U. , Shrestha Ruchee , Laeyendecker Oliver , Shoham Shmuel , Sullivan David , Gebo Kelly , Hanley Daniel , Redd Andrew D. , Quinn Thomas C. , Casadevall Arturo , Zenilman Jonathan M. , Pekosz Andrew , Bloch Evan M. , Tobian Aaron A. R.
Published: February 2021

Oral fluid (hereafter saliva) offers a non-invasive sampling method for the detection of SARS-CoV-2 antibodies. However, data comparing performance of salivary tests against commercially-available serologic and neutralizing antibody (nAb) assays are lacking. This study compared the performance of a multiplex salivary SARS-CoV-2 IgG assay targeting antibodies to nucleocapsid (N), receptor binding domain (RBD) and spike (S) antigens to three commercially-available SARS-CoV-2 serology enzyme immunoassays (EIAs) (Ortho Vitros, Euroimmun, and BioRad) and nAb. Paired saliva and plasma samples were collected from 101 eligible COVID-19 convalescent plasma (CCP) donors >14 days since PCR+ confirmed diagnosis. Concordance was evaluated using positive (PPA) and negative (NPA) percent agreement, overall percent agreement (PA), and Cohen’s kappa coefficient. The range between salivary and plasma EIAs for SARS-CoV-2-specific N was PPA: 54.4-92.1% and NPA: 69.2-91.7%, for RBD was PPA: 89.9-100% and NPA: 50.0-84.6%, and for S was PPA: 50.6-96.6% and NPA: 50.0-100%. Compared to a plasma nAb assay, the multiplex salivary assay PPA ranged from 62.3% (N) and 98.6% (RBD) and NPA ranged from 18.8% (RBD) to 96.9% (S). Combinations of N, RBD, and S and a summary algorithmic index of all three (N/RBD/S) in saliva produced ranges of PPA: 87.6-98.9% and NPA: 50-91.7% with the three EIAs and ranges of PPA: 88.4-98.6% and NPA: 21.9-34.4% with the nAb assay. A multiplex salivary SARS-CoV-2 IgG assay demonstrated comparable performance to three commercially-available plasma EIAs and a nAb assay, and may be a viable alternative to assist in screening CCP donors and monitoring population-based seroprevalence and vaccine antibody response.
Improving protein tertiary structure prediction by deep learning and distance prediction in CASP14
Authors: Liu Jian , Wu Tianqi , Guo Zhiye , Hou Jie , Cheng Jianlin
Published: February 2021

Substantial progresses in protein structure prediction have been made by utilizing deep-learning and residue-residue distance prediction since CASP13. Inspired by the advances, we improve our CASP14 MULTICOM protein structure prediction system in the three main aspects: (1) a new deep-learning based protein inter-residue distance predictor (DeepDist) to improve template-free (ab initio) tertiary structure prediction, (2) an enhanced template-based tertiary structure prediction method, and (3) distance-based model quality assessment methods empowered by deep learning. In the 2020 CASP14 experiment, MULTICOM predictor was ranked 7thout of 146 predictors in protein tertiary structure prediction and ranked 3rdout of 136 predictors in inter-domain structure prediction. The results of MULTICOM demonstrate that the template-free modeling based on deep learning and residue-residue distance prediction can predict the correct topology for almost all template-based modeling targets and a majority of hard targets (template-free targets or targets whose templates cannot be recognized), which is a significant improvement over the CASP13 MULTICOM predictor. The performance of template-free tertiary structure prediction largely depends on the accuracy of distance predictions that is closely related to the quality of multiple sequence alignments. The structural model quality assessment works reasonably well on targets for which a sufficient number of good models can be predicted, but may perform poorly when only a few good models are predicted for a hard target and the distribution of model quality scores is highly skewed.
12-lead Electrocardiogram in Hospitalized COVID 19 Patients
Authors: Shokr Mohamed , Chehab Omar , Ajam Mustafa , Singh Manmohan , Ashraf Said , Dawdy John , Pahuja Mohit , Reddy Vivek , Subahi Ahmed , Alraies M. Chadi , Afonso Luis , Lieberman Randy
Published: February 2021

COVID-19 pandemic resulted in considerable morbidity and mortality. We analyzed 345 Electrocardiograms of 100 COVID-19 patients admitted to our tertiary care center in Detroit, during the initial month of Covid-19. Findings were correlated with mortality, cardiac injury and inflammatory markers. Our cohort included 61% males and 77% African Americans. The median age and BMI were 66 years (57-74) and 31 kg/m2 (26.1-39), respectively. We observed atrial arrhythmias in 29% of the patients (17% new onset), First degree heart block in 12%, ST-T segment changes in 17%, S1Q3T3 pattern in 19%, premature ventricular complexes in 23%, premature atrial complexes in 13%, Q waves in 27%, T wave inversion in 42% of the cases. While presence of premature atrial complexes or left atrial abnormality correlated with mortality (P = 0.02 & 0.03, respectively), other findings did not show significant correlation in this small cohort of patients.
Vaccination strategies for minimizing loss of life in Covid-19 in a Europe lacking vaccines
Authors: Hunziker Patrick
Published: February 2021

Aim and Background

We aimed at identifying vaccination strategies that minimize loss of life in the Covid-19 pandemic in a Europe lacking vaccines. Covid-19 mainly kills the elderly, but the pandemic is driven by social contacts that are more frequent in the young. Vaccines elicit stronger immune responses in younger persons. As vaccine production is a bottleneck, many countries have adopted a strategy of first vaccinating the elderly and vulnerable, while postponing vaccination of the young.

Methods

Based on published age-stratified immunogenicity data of the Moderna mRNA-1273 vaccine, we compared the established “one dose fits all” approach with tailored strategies by epidemic modeling: The known differential immunogenicity of vaccine doses in different age groups is exploited to vaccinate the elderly at full dose, while the young receive a reduced dose, increasing the number of individuals receiving the vaccine early. A modeling approach at European Union scale with population structure, Covid-19 case and death rates according to Europe in late January 2021 is used.

Results

When the elderly were vaccinated preferentially, the pandemic initially continued essentially unchecked, as it was dominantly driven by social contacts in other age groups. Tailored strategies, including regular dosing in the elderly but reduced dose vaccination in the young, multiplied early vaccination counts, and even with some loss in protection degree for the individual person, the protective effect towards stopping the pandemic and protecting lives was enhanced, even for the elderly. In the European Union, pandemic duration (threshold >100’000 cases/day) was shortened from 53 to 18-24 days; cumulative death count over 100 days was reduced by >30’000. Data suggest that the findings may be relevant to both, the Moderna and the Pfizer-BioNTech mRNA vaccines.

Conclusion

Protecting the vulnerable, minimizing overall deaths and stopping the pandemic in Europe is best achieved by an adaptive vaccination strategy using an age-tailored vaccine dose.
SFARI Genes and where to find them; classification modelling to identify genes associated with Autism Spectrum Disorder from RNA-seq data
Authors: Navarro Magdalena , Simpson T Ian
Published: February 2021

Motivation

Autism spectrum disorder (ASD) has a strong, yet heterogeneous, genetic component. Among the various methods that are being developed to help reveal the underlying molecular aetiology of the disease, one that is gaining popularity is the combination of gene expression and clinical genetic data. For ASD, the SFARI-gene database comprises lists of curated genes in which presumed causative mutations have been identified in patients. In order to predict novel candidate SFARI-genes we built classification models combining differential gene expression data for ASD patients and unaffected individuals with a gene’s status in the SFARI-gene list.

Results

SFARI-genes were not found to be significantly associated with differential gene expression patterns, nor were they enriched in gene co-expression network modules that had a strong correlation with ASD diagnosis. However, network analysis and machine learning models that incorporate information from the whole gene co-expression network were able to predict novel candidate genes that share features of existing SFARI genes and have support for roles in ASD in the literature. We found a statistically significant bias related to the absolute level of gene expression for existing SFARI genes and their scores. It is essential that this bias be taken into account when studies interpret ASD gene expression data at gene, module and whole-network levels.

Availability

Source code is available from GitHub (https://doi.org/10.5281/zenodo.4463693) and the accompanying data from The University of Edinburgh DataStore (https://doi.org/10.7488/ds/2980)

Contact

ian.simpson@ed.ac.uk
Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition
Authors: Bai Yuntao , Kim Ji Young , Jayne Laura A. , Gandhi Megha , Huang Kevin M. , Silvaroli Josie A. , Sander Veronika , Prosek Jason , Jhaveri Kenar D. , Baker Sharyn D. , Sparreboom Alex , Bajwa Amandeep , Pabla Navjot Singh
Published: February 2021

A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal dysfunction through on and off-target mechanisms. Interestingly, among the small-molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenib-associated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by off-target FECH inhibition.

Translational Statement

BRAF is the most frequently mutated protein kinase and a critical oncogenic driver in human cancers. In melanoma and other cancers with BRAF activating mutations, BRAF targeted small-molecule therapeutics such as vemurafenib, and dabrafenib have shown remarkable clinical benefits. However, recent clinical studies have shown that a significant number of patients that receive vemurafenib develop AKI through mechanisms that remain unknown. The present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.
How certain are we? Development of an ensemble based framework for assessing astronaut cancer risks from space radiation
Authors: Simonsen Lisa C. , Slaba Tony C.
Published: February 2021

I.

A new approach to NASA space radiation risk modeling has successfully extended the current NASA probabilistic cancer risk model to an ensemble framework able to consider sub-model parameter uncertainty as well as model-form uncertainty associated with differing theoretical or empirical formalisms. Ensemble methodologies are already widely used in weather prediction, modeling of infectious disease outbreaks, and certain terrestrial radiation protection applications to better understand how uncertainty may influence risk decision-making. Applying ensemble methodologies to space radiation risk projections offers the potential to efficiently incorporate emerging research results, allow for the incorporation of future models, improve uncertainty quantification for underlying sub-models, and reduce the impact of subjective bias on risk projections. Moreover, risk forecasting across an ensemble of multiple predictive models can provide stakeholders additional information on risk acceptance if current health/medical standards cannot be met for future space exploration missions, such as human missions to Mars. In this work, ensemble risk projections implementing multiple sub-models of radiation quality, dose and dose-rate effectiveness factors, excess risk, and latency as ensemble members are presented. Initial consensus methods for ensemble model weights and correlations to account for individual model bias are discussed. In these analyses, the ensemble forecast compares well to results from NASA’s current operational cancer risk projection model used to assess permissible mission durations for astronauts. However, a large range of projected risk values are obtained at the upper 95thconfidence level where models must extrapolate beyond available biological data sets. Closer agreement is seen at the median + one sigma due to the inherent similarities in available models. Identification of potential new models, epidemiological data, and methods for statistical correlation between predictive ensemble members are discussed. Alternate ways of communicating risk and acceptable uncertainty with respect to NASA’s current permissible exposure limits are explored.
Robust, sensitive, and quantitative single-cell proteomics based on ion mobility filtering
Authors: Woo Jongmin , Clair Geremy C. , Williams Sarah M. , Feng Song , Tsai Chia-Feng , Moore Ronald J. , Chrisler William B. , Smith Richard D. , Kelly Ryan T. , Pasa-Tolic Ljiljana , Ansong Charles , Zhu Ying
Published: February 2021

Unbiased single-cell proteomics (scProteomics) promises to advance our understanding of cell functions within complex biological systems. However, a major challenge for current methods is their ability to identify and provide accurate quantitative information for low abundance proteins. Herein, we describe an ion mobility-enhanced mass spectrometry acquisition and peptide identification method, TIFF (Transferring Identification based on FAIMS Filtering), designed to improve the sensitivity and accuracy of label-free scProteomics. TIFF significantly extends the ion accumulation times for peptide ions by filtering out singly charged background ions. The peptide identities are then assigned by a 3-dimensional MS1 feature matching approach (retention time, accurate mass, and FAIMS compensation voltage). The TIFF method enabled unbiased proteome analysis to a depth of >1,700 proteins in single HeLa cells with >1,100 proteins consistently quantified. As a demonstration, we applied the TIFF method to obtain temporal proteome profiles of >150 single murine macrophage cells during a lipopolysaccharide stimulation experiment and identified time-dependent proteome profiles.
MYCcontrols metastatic heterogeneity in pancreatic cancer
Authors: Maddipati Ravikanth , Norgard Robert J. , Baslan Timour , Rathi Komal S. , Zhang Amy , Raman Pichai , Pitarresi Jason R. , Wengyn Maximilian D. , Yamazoe Taiji , Li Jinyang , Balli David , LaRiviere Michael J. , Folkert Ian W. , Millstein Ian D. , Bermeo Jonathan , Carpenter Erica L. , Lowe Scott , Iacobuzio-Donahue Christine , Notta Faiyaz , Stanger Ben Z.
Published: February 2021

The degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multi-fluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) – a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation ofMYCand its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC.
Performance of Heart Failure Clinical Prediction Models: A Systematic External Validation Study
Authors: Upshaw Jenica N. , Nelson Jason , Koethe Benjamin , Park Jinny G. , McGinnes Hannah , Wessler Benjamin S. , Konstam Marvin A. , Udelson James E. , Van Calster Ben , van Klaveren David , Steyerberg Ewout , Kent David M.
Published: February 2021

Background

Most heart failure (HF) clinical prediction models (CPMs) have not been externally validated.

Methods

We performed a systematic review to identify CPMs predicting outcomes in HF, stratified by acute and chronic HF CPMs. External validations were performed using individual patient data from 8 large HF trials (1 acute, 7 chronic). CPM discrimination (c-statistic, % relative change in c-statistic), calibration (calibration slope, Harrell’s E, E90), and net benefit were evaluated for each CPM with and without recalibration.

Results

Of 135 HF CPMs screened, 24 (18%) were compatible with the population, predictors and outcomes to the trials and 42 external validations were performed (14 acute HF, 28 chronic HF). The median derivation c-statistic of acute HF CPMs was 0.76 (IQR, 0.75, 0.8), validation c-statistic was 0.67 (0.65, 0.68) and model-based c-statistic was 0.68 (0.66, 0.76), Hence, most of the apparent decrement in model performance was due to narrower case-mix in the validation cohort compared with the development cohort. The median derivation c-statistic for chronic HF CPMs was 0.76 (0.74, 0.8), validation c-statistic 0.61 (0.6, 0.63) and model-based c-statistic 0.68 (0.62, 0.71), suggesting that the decrement in model performance was only partially due to case-mix heterogeneity. Calibration was generally poor - median E (standardized by outcome rate) was 0.5 (0.4, 2.2) for acute HF CPMs and 0.5 (0.3, 0.7) for chronic HF CPMs. Updating the intercept alone led to a significant improvement in calibration in acute HF CPMs, but not in chronic HF CPMs. Net benefit analysis showed potential for harm in using CPMs when the decision threshold was not near the overall outcome rate but this improved with model recalibration.

Conclusions

Only a small minority of published CPMs contained variables and outcomes that were compatible with the clinical trial datasets. For acute HF CPMs, discrimination is largely preserved after adjusting for case-mix; however, the risk of net harm is substantial without model recalibration for both acute and chronic HF CPMs.
Subcellular Localization of Signal Peptide Fusion Proteins Expressed in E. coli
Authors: Kielkopf Clara L. , Bauer William , Urbatsch Ina L.
Published: February 2021

For expression of some proteins in Escherichia coli, export to the periplasmic space is preferred over conventional expression in the cytosol. Export can be accomplished by fusing the coding sequence to DNA encoding a signal peptide (e.g., using pET-22b), which is cleaved by the bacterial signal peptidase as the protein is exported into the space between the inner and outer membranes of E. coli. This protocol uses osmotic shock to release polypeptides from the periplasm. Although not quantitative, it should provide preliminary information on the cellular location of signal peptide fusion proteins.
Solubilization of Expressed Proteins from Inclusion Bodies
Authors: Kielkopf Clara L. , Bauer William , Urbatsch Ina L.
Published: February 2021

The expression of foreign proteins at high levels in Escherichia coli often results in the formation of cytoplasmic granules or inclusion bodies composed of insoluble aggregates of the expressed protein. These inclusion bodies can be seen with a phase-contrast microscope and are readily separated from most soluble and membrane-bound bacterial proteins, as described in this protocol.
Expressing Cloned Genes for Protein Production, Purification, and Analysis
Authors: Kielkopf Clara L. , Bauer William , Urbatsch Ina L.
Published: February 2021

Obtaining high quantities of a specific protein directly from native sources is often challenging, particularly when dealing with human proteins. To overcome this obstacle, many researchers take advantage of heterologous expression systems by cloning genes into artificial vectors designed to operate within easily cultured cells, such asEscherichia coli,Pichia pastoris(yeast), and several varieties of insect and mammalian cells. Heterologous expression systems also allow for easy modification of the protein to optimize expression, mutational analysis of specific sites within the protein and facilitate their purification with engineered affinity tags. Some degree of purification of the target protein is usually required for functional analysis. Purification to near homogeneity is essential for characterization of protein structure by X-ray crystallography or nuclear magnetic resonance (NMR) and characterization of the biochemical and biophysical properties of a protein, because contaminating proteins almost always adversely affect the results. Methods for producing and purifying proteins in several different expression platforms and using a variety of vectors are introduced here.