bluuebunny/crossref_metadata_2025 huggingface dataset:
The Course of Physical Capacity in Wheelchair Users During Training for the HandbikeBattle and at 1-Yr Follow-up
Authors: Kouwijzer Ingrid , Valent Linda J.M. , Post Marcel W.M. , Wilders Lise M. , Grootoonk Anneke ,   HandbikeBattle Group, van der Woude Lucas H.V. , de Groot Sonja
Published: December 2020

Objective

The aims of this study were (1) to compare physical capacity at 1-yr follow-up with physical capacity before and after the training period for the HandbikeBattle event and (2) to identify determinants of the course of physical capacity during follow-up.

Design

This was a prospective observational study. Former rehabilitation patients (N = 33) with health conditions such as spinal cord injury or amputation were included. A handcycling/arm crank graded exercise test was performed before (January, T1) and after the training period (June, T2) and at 1-yr follow-up (June, T4). Outcomes were peak power output (W) and peak oxygen uptake (L/min). Determinants were sex (male/female); age (years); classification; physical capacity, musculoskeletal pain, exercise stage of change, and exercise self-efficacy at T1; and HandbikeBattle participation at T4.

Results

Multilevel regression analyses showed that peak power output and peak oxygen uptake increased during the training period and did not significantly change during follow-up (T1: 112 ± 37 W, 1.70 ± 0.48 L/min; T2: 130 ± 40 W, 2.07 ± 0.59 L/min; T4: 126 ± 42 W, 2.00 ± 0.57 L/min). Participants who competed again in the HandbikeBattle showed slight improvement in physical capacity during follow-up, whereas participants who did not compete again showed a decrease.

Conclusion

Physical capacity showed an increase during the training period and remained stable after 1-yr follow-up. Being (repeatedly) committed to a challenge might facilitate long-term exercise maintenance.
Implementation of the Stroke Action Plan for Europe 2018--2030 during coronavirus disease-2019
Authors: Christensen Hanne , Pezzella Francesca Romana
Published: December 2020

Purpose of review

To describe the background, principles and implementation of the Stroke Action Plan for Europe 2018--2030 (SAP-E) in the perspective of the current COVID-19 pandemic.

Recent findings

SAP-E sets targets for the implementation of evidence-based preventive actions and stroke services to 2030. A recent mapping of stroke care in Europe has documented massive inequalities and even in high-income European countries access to reperfusion therapy and mortality after ischaemic stroke varies significantly. Organized stroke care providing stroke unit care and access to reperfusion therapies reduces mortality and long-term disability. Stroke prevention and care are highly cost-effective. The COVID-19 pandemic has challenged organized care, diverged attention from stroke and necessitated a novel approach to the implementation program because of the continued need for social distancing and reduced travelling. Consequently, meetings, training and engagement will be handled by online resources.

Stroke can be prevented and treated but there remain massive inequalities in Europe. SAP-E has set targets for development of stroke care. COVID-19 pandemic has led to further challenges for stroke care and implementation of the Action Plan will rely on online meetings and resources as it is yet unforeseeable when things will return to normal.

Video abstract

http://links.lww.com/CONR/A53.
Optic neuropathy and diplopia from thyroid eye disease: update on pathophysiology and treatment
Authors: Johnson Brooke T. , Jameyfield Evan , Aakalu Vinay K.
Published: December 2020

Purpose of review

Thyroid eye disease (TED) is a disfiguring disease that can lead to neuro-ophthalmic manifestations including diplopia and optic neuropathy. The aim of this review is to shed light on the diagnosis of TED based on clinical examination findings and diagnostic imaging. We will also discuss gold standard as well as newly emerging therapies for TED.

Recent findings

We discussed diagnostic criteria for TED and differentiating TED from other causes of binocular diplopia. We also reviewed the pathophysiology and differential diagnoses for dysthyroid optic neuropathy as well as recent developments on controversial causes. New imaging techniques are available for evaluation and prognosis of TED comorbidities. Most of the recent developments in TED have been focused on new treatment modalities that have thus far had promising results. We reviewed recently approved and novel potential therapies that are helpful in treating both diplopia and dysthyroid optic neuropathy.

TED is a complicated disorder with many clinical manifestations as well as treatment modalities. Our aim of this review was to outline new developments in the diagnosis and management of TED.
Objective and graded calibration of recovery of consciousness in experimental models
Authors: Calderon Diany P. , Schiff Nicholas D.
Published: December 2020

Purpose of review

Experimental preclinical models of recovery of consciousness (ROC) and anesthesia emergence are crucial for understanding the neuronal circuits restoring arousal during coma emergence. Such models can also potentially help to better understand how events during coma emergence facilitate or hinder recovery from brain injury. Here we provide an overview of current methods used to assess ROC/level of arousal in animal models. This exposes the need for objective approaches to calibrate arousal levels. We outline how correlation of measured behaviors and their reestablishment at multiple stages with cellular, local and broader neuronal networks, gives a fuller understanding of ROC.

Recent findings

Animals emerging from diverse coma-like states share a dynamic process of cortical and behavioral recovery that reveals distinct states consistently sequenced from low-to-high arousal level and trackable in nonhuman primates and rodents. Neuronal activity modulation of layer V-pyramidal neurons and neuronal aggregates within the brainstem and thalamic nuclei play critical roles at specific stages to promote restoration of a conscious state.

A comprehensive, graded calibration of cortical, physiological, and behavioral changes in animal models is undoubtedly needed to establish an integrative framework. This approach reveals the contribution of local and systemic neuronal circuits to the underlying mechanisms for recovering consciousness.
Prenatal and perinatal metabolic risk factors for autism: a review and integration of findings from population-based studies
Authors: Katz Julia , Reichenberg Abraham , Kolevzon Alexander
Published: December 2020

Purpose of review

Given the ongoing rise in prevalence of autism spectrum disorder (ASD) and the challenges in developing and administering interventions to significantly alleviate ASD symptoms, there is an urgent need to identify modifiable risk factors for ASD. The goal of this review is to systematically evaluate the current evidence for an association between conditions related to maternal metabolic syndrome and risk for ASD in offspring focusing on methodically rigorous studies.

Recent findings

In recent years, multiple studies explored the association between various conditions related to maternal metabolic syndrome (obesity, hypertension, or diabetes prior to, or with onset during pregnancy) and ASD risk in the offspring.

Examining large, sufficiently powered, population-based epidemiological studies that explored the association between maternal metabolic syndrome and ASD, we found consistent evidence for an association between maternal preeclampsia and risk for ASD. Other conditions that are part of maternal metabolic syndrome, including maternal obesity, gestational weight gain, diabetes and gestational diabetes, should be studied further with careful attention paid to potential synergistic effects between different metabolic conditions. These findings highlight the need for rigorous, large, population-based epidemiological studies of potentially modifiable ASD risk factors that could inform public health interventions.
THE THERAPEUTIC POTENTIAL OF IVERMECTIN FOR COVID-19: A SYSTEMATIC REVIEW OF MECHANISMS AND EVIDENCE
Authors: Kalfas Stefanie , Visvanathan Kumar , Chan Kim , Drago John
Published: December 2020

Introduction

Ivermectin is a commonly used antihelminthic agent with over 35 years of established safety data in humans. Recent data demonstrates antiviral activity in vitro against SARS-CoV-2, in addition to a range of viruses. In vitro and animal models also provide evidence of immunomodulatory action. These additional modes of action are supported by in silico modelling, which propose a number of viral and host targets that would mediate these effects.

Objectives

The aim of this study is to systematically review the published and preprint clinical literature and study results that assessed the potential role of ivermectin as a COVID-19 therapeutic and prophylactic agent.

Methods

We conducted a comprehensive review of PubMed, medRxiv, ClinicalTrials.gov, Global Coronavirus COVID-19 Clinical Trial Tracker, World Health Organization International Clinical Trials Registry Platform, EU Clinical Trials Register, ANZ clinical trials registry, and references from relevant articles.

Results

Search keywords- “COVID-19 (and synonyms) AND ivermectin”- generated 86 articles on PubMed, 48 on medRvix and 37 on clinicaltrials.gov at the time of writing. Twelve of these were listed as completed clinical trials and of these, 8 were included as investigators had released results. Positive mortality benefit, reduced time to clinical recovery, reduced incidence of disease progression and decreased duration of hospital admission were reported in patients across all stages of clinical severity.

Limitations

Due to the time-critical nature of the COVID-19 pandemic our review included preprint data, which must be interpreted with caution while it awaits peer review.
Temporal Lobe Activation Predicts Episodic Memory Following Traumatic Brain Injury
Authors: Taing Abbie S. , Mundy Matthew E. , Ponsford Jennie L. , Spitz Gershon
Published: December 2020

The temporal lobes are critical for episodic memories and are preferentially affected following a traumatic brain injury (TBI). As such, episodic memory difficulties are common following TBI; however, the underlying neural changes that precipitate or maintain these difficulties in the early phase of recovery remains poorly understood. Here, we use functional magnetic resonance imaging (fMRI) to interrogate the relationship of temporal lobe activation in response to face, scene, and animal stimuli. Twenty-five patients with moderate to severe TBI were recruited an average of 2 months’ post-injury and compared with 21 demographically similar healthy controls. Findings indicate that memory for faces was preferentially impaired, compared to scene and animal stimuli. Decreased activity in temporal lobe structures was present for both face (right transverse temporal gyrus) and scene stimuli (right fusiform gyrus), but not for animals. Greater activation in these structures was associated with better long-term recognition. These findings provide evidence to suggest that TBI: a) preferentially affects memory for complex stimuli such as faces and scenes, and b) causes aberrant neuronal processes despite lack of evidence of significant impairment in behavioural performance. The mechanisms underpinning these findings are discussed in terms of differences in strategy use and reduced neural efficiency.
How to choose a time zero for patients in external control arms
Authors: Backenroth Daniel
Published: December 2020

When a sponsor carries out a single-arm trial of a novel oncology compound, it may wish to assess the efficacy of the compound via comparison of overall survival to an external control arm, constructed using patients included in some retrospective registry. If efficacy of the novel compound is compared to efficacy of physician’s choice of chemotherapy, patients in the retrospective registry might qualify for inclusion in the external control arm at multiple different points in time, when they receive different chemotherapy treatments. For example, a patient might qualify at the start of their second, third and fourth lines of therapy. From the start of which line of therapy should this patient’s survival be compared to survival of participants in the single-arm trial?

Some sponsors have elected to include patients in the external control arm from the last available line of therapy in the retrospective database. Another possibility is to randomly select a line of therapy for each external control arm patient from among those available. In this paper, we show, via probabilistic arguments and also via simulation based on real data, that both of these methods give rise to a bias in favor of the single-arm trial. We further show that this bias can be avoided by instead including external control arm patients multiple times in the external control arm, once for each time they receive qualifying treatment.
Elucidating the phenotypic variability associated with the polyT tract and TG repeats in CFTR
Authors: Nykamp Keith , Truty Rebecca , Riethmaier Darlene , Wilkinson Julia , Bristow Sara L. , Aguilar Sienna , Neitzel Dana , Faulkner Nicole , Kahan Stephanie , Aradhya Swaroop
Published: December 2020

Purpose

To evaluate the risk and spectrum of phenotypes associated in individuals with one or two of the CFTR T5 haplotype variants (TG11T5, TG12T5 and TG13T5) in the absence of the R117H variant.

Methods

Individuals who received testing with CFTR NGS results between 2014 and 2019 through Invitae at ordering provider discretion were included. TG-T repeats were detected using a custom-developed haplotype caller. Frequencies of the TG-T5 variants (biallelic or in combination with another CF-causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider (via requisition form) or the individual (during genetic counseling appointments) was examined.

Results

Among 548,300 individuals, the minor allele frequency of the T5 allele was 4.2% (TG repeat distribution: TG11=68.1%, TG12=29.5%, TG13=2.4%). When present with a CFvar, each of the TG[11-13]T5 variants were significantly enriched in individuals with a “high suspicion” of CF/CFTR-RD (personal/family history of CF/CFTR-RD) compared to those with very “low suspicion” for CF or CFTR-RD (hereditary cancer testing, CFTR not requisitioned). Compared to CFvar/CFvar individuals, TG[11-13]T5/CFvar individuals generally had single organ involvement, milder symptoms, variable expressivity, and reduced penetrance.

Discussion

Data from this study provides a better understanding of disease risks associated with inheriting TG[11-13]T5 variants and has important implications for reproductive genetic counseling.
Vaccine acceptance among college students in South Carolina: Do information sources and trust in information make a difference?
Authors: Qiao Shan , Friedman Daniela B. , Tam Cheuk Chi , Zeng Chengbo , Li Xiaoming
Published: December 2020

Background

To control the COVID-19 pandemic, governments need to ensure a successful large-scale administration of COVID-19 vaccines when safe and efficacious vaccines become available. Vaccine acceptance could be a critical factor influencing vaccine uptake. Health information has been associated with vaccine acceptance. For college students who are embracing a digital era and being exposed to multimedia, the sources of COVID-19 vaccine information and their trust in these sources may play an important role in shaping their acceptance of vaccine uptake.

Methods

In September 2020, we conducted an online survey among 1062 college students in South Carolina to understand their perceptions and attitudes toward COVID-19 vaccination. Descriptive analysis and linear regression analysis were used to investigate vaccine information sources among college students and examine how COVID-19 vaccine acceptance was associated with information source and trust level in each source.

Results

The top three sources of COVID-19 vaccine information were health agencies (57.7%), mass media (49.5%), and personal social networks (40.5%). About 83.1% of the participants largely or always trusted scientists, 73.9% trusted healthcare providers, and 70.2% trusted health agencies. After controlling for key demographics, vaccine acceptance was positively associated with scientists as information sources but negatively associated with pharmaceutical companies as sources. Higher trust levels in mass media, health agencies, scientists, and pharmaceutical companies was significantly associated with higher COVID-19 vaccine acceptance. However, trust in social media was negatively associated with vaccine acceptance.

Discussion

College students use multiple sources to learn about upcoming COVID-19 vaccines including health agencies, personal networks, and social media. The level of trust in these information sources play a critical role in predicting vaccine acceptance. Trust in health authorities and scientists rather than social media is related to higher level vaccine acceptance. Our findings echo the call for restoring trust in government, healthcare system, scientists, and pharmaceutical industries in the COVID-19 era and highlight the urgency to dispel misinformation in social media. Effective strategies are needed to disseminate accurate information about COVID-19 vaccine from health authorities and scientific research to improve vaccine communication to the public and promote COVID-19 vaccine uptake.
Spatial risk factors for Pillar 1 COVID-19 case counts and mortality in rural eastern England, UK
Authors: Brainard Julii , Rushton Steve , Winters Tim , Hunter Paul R.
Published: December 2020

Understanding is still developing about risk factors for COVID-19 infection or mortality. This is especially true with respect to identifying spatial risk factors and therefore identifying which geographic areas have populations who are at greatest risk of acquiring severe disease. This is a secondary analysis of patient records in a confined area of eastern England, covering persons who tested positive for SARS-CoV-2 through end May 2020, including dates of death and residence area. For each residence area (local super output area), we obtained data on air quality, deprivation levels, care home bed capacity, age distribution, rurality, access to employment centres and population density. We considered these covariates as risk factors for excess cases and excess deaths in the 28 days after confirmation of positive covid status relative to the overall case load and death recorded for the study area as a whole. We used the conditional autoregressive Besag-York-Mollie model to investigate the spatial dependency of cases and deaths allowing for a Poisson error structure. Structural equation models were also applied to clarify relationships between predictors and outcomes. Excess case counts or excess deaths were both predicted by the percentage of population age 65 years, care home bed capacity and less rurality: older population and more urban areas saw excess cases. Greater deprivation did not correlate with excess case counts but was significantly linked to higher mortality rates after infection. Neither excess cases nor excess deaths were predicted by population density, travel time to local employment centres or air quality indicators. Only 66% of mortality could be explained by locally high case counts. The results show a clear link between greater deprivation and higher COVID-19 mortality that is separate from wider community prevalence and other spatial risk factors.
Detailed disease progression of 213 patients hospitalized with Covid-19 in the Czech Republic: An exploratory analysis
Authors: Modrák Martin , Bürkner Paul-Christian , Sieger Tomáš , Slisz Tomáš , Vašáková Martina , Mesežnikov Grigorij , Casas-Mendez Luis Fernando , Vajter Jaromír , Táborský Jan , Kubricht Viktor , Suk Daniel , Horejsek Jan , Jedlička Martin , Mifková Adriana , Jaroš Adam , Kubiska Miroslav , Váchalová Jana , Šín Robin , Veverková Markéta , Pospíšil Zbyšek , Vohryzková Julie , Pokrievková Rebeka , Hrušák Kristián , Christozova Kristína , Leos-Barajas Vianey , Fišer Karel , Hyánek Tomáš
Published: December 2020

We collected a multi-centric retrospective dataset of patients (N = 213) who were admitted to ten hospitals in Czech Republic and tested positive for SARS-CoV-2. The dataset contains baseline patient characteristics, breathing support required, pharmacological treatment received and multiple markers on daily resolution. Patients in the dataset were treated with hydroxychloroquine (N = 108), azithromycin (N = 72), favipiravir (N = 9), convalescent plasma (N = 7), dexamethasone (N = 4) and remdesivir (N = 3), often in combination. Most patients were admitted during the first wave of the epidemic. To explore association between treatments and patient outcomes we performed multiverse analysis, observing how the conclusions change between defensible choices of statistical model, predictors included in the model and other analytical degrees of freedom. Weak evidence to constrain the potential efficacy of azithromycin and favipiravir can be extracted from the data. Additionally, we performed external validation of several proposed prognostic models for Covid-19 severity showing that they mostly perform unsatisfactorily on our dataset.
Genome-wide analysis of 944,133 individuals provides insights into the etiology of hemorrhoidal disease
Authors: Zheng Tenghao , Ellinghaus David , Juzenas Simonas , Cossais François , Burmeister Greta , Mayr Gabriele , Jørgensen Isabella Friis , Teder-Laving Maris , Skogholt Anne Heidi , Banasik Karina , Becker Thomas , Bokelmann Frank , Brunak Søren , Buch Stephan , Clausnizer Hartmut , Datz Christian ,   DBDS Consortium, Degenhardt Frauke , Doniec Marek , Erikstrup Christian , Esko Tõnu , Forster Michael , Frey Norbert , Fritsche Lars G. , Gabrielsen Maiken Elvestad , Gräßle Tobias , Gsur Andrea , Gross Justus , Hampe Jochen , Hendricks Alexander , Hinz Sebastian , Hveem Kristian , Jongen Johannes , Junker Ralf , Karlsen Tom Hemming , Hemmrich-Stanisak Georg , Kruis Wolfgang , Kupcinskas Juozas , Laubert Tilman , Laudes Matthias , Leendertz Fabian H. , Lieb Wolfgang , Limperger Verena , Margetis Nikolaos , Mätz-Rensing Kerstin , Németh Christopher Georg , Ness-Jensen Eivind , Nowak-Göttl Ulrike , Pandit Anita , Pedersen Ole Birger , Günter Peleikis Hans , Peuker Kenneth , Rodríguez Cristina Leal , Rühlemann Malte , Schniewind Bodo , Schulzky Martin , Skieceviciene Jurgita , Tepel Jürgen , Thomas Laurent , Uellendahl-Werth Florian , Ullum Henrik , Vogel Ilka , Völzke Henry , Fersen Lorenzo von , Schoenfels Witigo von , Vanderwerff Brett , Wilking Julia , Wittig Michael , Zeissig Sebastian , Zobel Myrko , Zawistowski Matthew , Vacic Vladimir , Sazonova Olga , Noblin Elizabeth S. ,   The 23andMe Research Team, Wedel Thilo , Kahlke Volker , Schafmayer Clemens , D’Amato Mauro , Franke Andre
Published: December 2020

Hemorrhoidal disease (HEM) affects a large fraction of the population but its etiology including suspected genetic predisposition is poorly understood. We conducted a GWAS meta-analysis of 218,920 HEM patients and 725,213 controls of European ancestry, demonstrating modest heritability and genetic correlation with several other diseases from the gastrointestinal, neuroaffective and cardiovascular domains. HEM polygenic risk scores validated in 180,435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harboring genes whose expression is enriched in blood vessels and gastrointestinal tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses of affected tissue from HEM patients highlighted HEM gene co-expression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organization of the extracellular matrix. We conclude HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
Knowledge, attitude and willingness to accept the RTS,S malaria vaccine among mothers in Abuja Nigeria
Authors: Musa-Booth Tolulope O. , Enobun Blessing E. , Agbomola Adewumi J. , Shiff Clive J.
Published: December 2020

Objective

To assess mothers’ knowledge, attitude, and practices to malaria and its prevention as well as mothers’ willingness to accept the RTS,S/AS01 malaria vaccine.

Methods

A cross-sectional study design was used to administer questionnaires to 180 mothers within six public secondary health facilities in Abuja, Nigeria. Regression analyses were used to assess the effect of maternal demographics and exposure to malaria related messages on the outcome measures.

Results

Knowledge of malaria preventive measures was approximately 59% (124/180). Multivariate logistic regression analyses indicated ethnicity, education and number of messages or training on malaria were associated with mother’s knowledge of 3 or more preventive measures against malaria. About 30% (36/180) of respondents were aware of malaria vaccines but only four percent (7/180) had heard of RTS,S. Young maternal age (OR, 2.4; p = 0.03), self-employment (OR, 2.55; p = 0.04) and formal employment (OR, 3.74; p = 0.03) were associated with no prior knowledge of malaria vaccine. Ninety-one percent (163/180) had positive attitude to malaria vaccine and 98% (176/180) were willing to allow their child(ren) to be immunized with RTS,S despite the efficacy of the vaccine, route of administration and number of doses.

Conclusion

Knowledge of malaria preventive measures does not correlate with knowledge of RTS,S. Although willingness to accept RTS,S is high, consistent targeted messaging on RTS,S would be required to improve community knowledge and attitude prior to implementation to ensure maximum uptake.
Repeated measures ASCA+ for analysis of longitudinal intervention studies with multivariate outcome data
Authors: Madssen Torfinn S. , Giskeødegård Guro F. , Smilde Age K. , Westerhuis Johan A.
Published: December 2020

Longitudinal intervention studies with repeated measurements over time are an important type of experimental design in biomedical research. Due to the advent of “omics”-sciences (genomics, transcriptomics, proteomics, metabolomics), longitudinal studies generate increasingly multivariate outcome data. Analysis of such data must take both the longitudinal intervention structure and multivariate nature of the data into account. The ASCA+-framework combines general linear models with principal component analysis, and can be used to separate and visualize the multivariate effect of different experimental factors. However, this methodology has not yet been developed for the more complex designs often found in longitudinal intervention studies, which may be unbalanced, involve randomized interventions, and have substantial missing data. Here we describe a new methodology, repeated measures ASCA+ (RM-ASCA+), and show how it can be used to model metabolic changes over time, and compare metabolic changes between groups, in both randomized and non-randomized intervention studies. Tools for both visualization and model validation are discussed. This approach can facilitate easier interpretation of data from longitudinal clinical trials with multivariate outcomes.

Author summary

Clinical trials are increasingly generating large amounts of complex biological data. Examples can include measuring metabolism or gene expression in tissue or blood sampled repeatedly over the course of a treatment. In such cases, one might wish to compare changes in not one, but hundreds, or thousands of variables simultaneously. In order to effectively analyze such data, both the study design and the multivariate nature of the data should be considered during data analysis. ANOVA simultaneous component analysis+ (ASCA+) is a statistical method which combines general linear models with principal component analysis, and provides a way to separate and visualize the effects of different factors on complex biological data. In this work, we describe how repeated measures linear mixed models, a class of models commonly used when analyzing changes over time and treatment effects in longitudinal studies, can be used together with ASCA+ for analyzing clinical trials in a novel method called repeated measures-ASCA+ (RM-ASCA+).
A first-in-human evaluation of the safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein subunit vaccine for COVID-19 in healthy adults; a phase 1, randomised, double-blind, placebo-controlled trial
Authors: Richmond Peter , Hatchuel Lara , Dong Min , Ma Brenda , Hu Branda , Smolenov Igor , Li Ping , Liang Peng , Han Htay Htay , Liang Joshua , Clemens Ralf
Published: December 2020

Background

As part of the accelerated development of prophylactic vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) we report a first-in-human dose-finding and adjuvant justification study of SCB-2019, a novel protein subunit vaccine candidate composed of a stabilised trimeric form of the spike (S)-protein produced in CHO-cells, combined with two different adjuvants.

Methods

This phase 1 study was done in one centre in Western Australia in 151 healthy adult volunteers in two age groups (18–54 and 55–75 years), allocated to 15 groups (nine young and six older adults) to receive two doses, 21 days apart, of placebo, or 3 μg, 9 μg or 30 μg SCB-2019, alone or adjuvanted with AS03 or CpG/Alum. Reactogenicity was assessed for 7 days after each vaccination. Humoral responses were measured as SCB-2019 binding and ACE2-competitive binding IgG antibodies by ELISA, and as neutralising antibodies by wild-type SARS-CoV-2 microneutralisation assay; cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining.

Findings

We report on 148 participants with at least 4 weeks follow-up post dose 2. Three participants withdrew, two for personal reasons and one with an unrelated SAE (pituitary adenoma). Vaccination was well tolerated, with few Grade 3 solicited adverse events (AE). Most local AEs were mild injection site pain, which were more frequent with formulations containing AS03 than CpG/Alum or unadjuvanted SCB-2019. Systemic AEs, mostly transient headache, fatigue or myalgia, were more frequent in young adults than older adults after the first dose, but similar after second doses. Unadjuvanted SCB-2019 elicited minimal immune responses, but SCB-2019 with fixed doses of AS03 or CpG/Alum induced high titres and seroconversion rates of binding and neutralising antibodies in both young and older adults. Titres were higher than those observed in a panel of COVID-19 convalescent sera in all AS03 groups and high dose CpG/Alum groups. Both adjuvanted formulations elicited Th1-biased CD4+ T cell responses.

Interpretation

SCB-2019 trimeric protein formulated with AS03 or CpG/Alum adjuvants elicited robust humoral and cellular immune responses against SARS-CoV-2 with high viral neutralising activity. Both adjuvanted formulations were well tolerated and are suitable for further clinical development.

Clinical trial registration

ClinicalTrials.gov identifier NCT04405908.
Lots of movement, little progress: A review of reptile home range literature
Authors: Crane Matt , Silva Inês , Marshall Benjamin Michael , Strine Colin Thomas
Published: December 2020

Reptiles are the most species-rich vertebrate group with a broad diversity of life history traits. Biotelemetry is an essential methodology for reptiles as it compensates for several limitations when studying their natural history. We evaluated trends in reptile spatial ecology studies focusing upon quantifying home ranges for the past twenty years. We assessed 290 English-language reptile home range studies published from 2000-2019 via a structured literature review investigating publications’ study location, taxonomic group, methodology, reporting, and analytical techniques. Substantial biases remain in both location and taxonomic groups in the literature, with nearly half of all studies (45%) originating from the USA. Snakes were most often studied, and crocodiles were least often studied, while testudines tended to have the greatest within study sample sizes. More than half of all studies lacked critical methodological details, limiting the number of studies for inclusion in future meta-analyses (55% of studies lacked information on individual tracking durations, and 51% lacked sufficient information on the number of times researchers recorded positions). Studies continue to rely on outdated methods to quantify space-use (including Minimum Convex Polygons and Kernel Density Estimators), often failing to report subtleties on decisions that have substantial impact on home range area estimates. Moving forward researchers can select a suite of appropriate analytical techniques tailored to their research question (dynamic Brownian Bridge Movement Models for within sample interpolation, and autocorrelated Kernel Density Estimators for beyond sample extrapolation). Only 1.4% of all evaluated studies linked to available and usable telemetry data, further hindering scientific consensus. We ultimately implore herpetologists to adopt transparent reporting practices and make liberal use of open data platforms to maximize progress in the field of reptile spatial ecology.
Minimal information for Chemosensitivity assays (MICHA): A next-generation pipeline to enable the FAIRification of drug screening experiments
Authors: Tanoli Ziaurrehman , Aldahdooh Jehad , Alam Farhan , Wang Yinyin , Seemab Umair , Fratelli Maddalena , Pavlis Petr , Hajduch Marian , Bietrix Florence , Gribbon Philip , Zaliani Andrea , Hall Matthew D. , Shen Min , Brimacombe Kyle , Kulesskiy Evgeny , Saarela Jani , Wennerberg Krister , Vähä-Koskela Markus , Tang Jing
Published: December 2020

Chemosensitivity assays are commonly used for preclinical drug discovery and clinical trial optimization. However, data from independent assays are often discordant, largely attributed to uncharacterized variation in the experimental materials and protocols. We report here the launching of MICHA (Minimal Information for Chemosensitivity Assays), accessed viahttps://micha-protocol.org. Distinguished from existing efforts that are often lacking support from data integration tools, MICHA can automatically extract publicly available information to facilitate the assay annotation including: 1) compounds, 2) samples, 3) reagents, and 4) data processing methods. For example, MICHA provides an integrative web server and database to obtain compound annotation including chemical structures, targets, and disease indications. In addition, the annotation of cell line samples, assay protocols and literature references can be greatly eased by retrieving manually curated catalogues. Once the annotation is complete, MICHA can export a report that conforms to the FAIR principle (Findable, Accessible, Interoperable and Reusable) of drug screening studies. To consolidate the utility of MICHA, we provideFAIRifiedprotocols from five major cancer drug screening studies, as well as six recently conducted COVID-19 studies. With the MICHA webserver and database, we envisage a wider adoption of a community-driven effort to improve the open access of drug sensitivity assays.
Spatial distribution of local patch extinctions drives recovery dynamics in metacommunities
Authors: Saade Camille , Kéfi Sonia , Gougat-Barbera Claire , Rosenbaum Benjamin , Fronhofer Emanuel A.
Published: December 2020

Human activities lead more and more to the disturbance of plant and animal communities with local extinctions as a consequence. While these negative effects are clearly visible at a local scale, it is less clear how such local patch extinctions affect regional processes, such as metacommunity dynamics and the distribution of diversity in space. Since local extinctions may not be isolated events in space but rather cluster together, it is crucial to investigate their effects in a spatially explicit framework.

Here, we use experimental microcosms and numerical simulations to understand the relationship between local patch extinctions and metacommunity dynamics. More specifically, we investigate the effects of the amount and spatial autocorrelation of extinctions in a full factorial design. Experimentally, we found that local patch extinctions increased inter-patch (β-) diversity by creating differences between perturbed and unperturbed patches and at the same time increased local (α-) diversity by delaying the competitive exclusion of inferior competitors. Most importantly, recolonization dynamics depended more strongly on the spatial distribution of patch extinctions than on the amount of extinctions per se. Clustered local patch extinctions reduced mixing between perturbed and unperturbed patches which led to slower recovery, lowerα-diversity in unperturbed patches and higherβ-diversity. Results from a metacommunity model matched the experimental observations qualitatively when the model included ranked competitive interactions, giving a hint at the underlying mechanisms.

Our results highlight that local patch extinctions can increase the diversity within and between communities, that the strength of these effects depends on the spatial distribution of extinctions and that the effects of local patch extinctions can spread regionally, throughout a landscape. These findings are highly relevant for conservation and management of spatially structured communities under global change.
Roles of hostplant availability and quality for the distribution and climate change response of a dietary specialist herbivore
Authors: Carvajal Acosta A. Nalleli , Mooney Kailen
Published: December 2020

Species distributions are recognized to be driven by abiotic factors, but the importance of biotic interactions that provide critical resources is less well understood, especially with respect to variation in critical resource quality. Disentangling the relative importance of these factors – abiotic environment, presence of critical resources and their quality-may be critical to predicting species response to climate change. We used species distribution models (SDMs) to address these questions for the western monarch butterfly (Danaus plexippus), a species that obligately feeds upon plants in the genusAsclepias, and for which hostplant quality in this region varies among species by an order of magnitude. We modeled the distribution of 24Asclepiasspecies to develop and compare three monarch distribution models with increasing levels of ecological complexity: (i) a null model using only environmental factors (a climate envelope model), (ii) a model using environmental factors andAsclepiasspp. distribution, (iii) and a model using environmental factors andAsclepiasspp. distribution weighted by hostplant quality assessed through a greenhouse bioassays of larval performance.Asclepiasmodels predicted that half of theAsclepiasspp. will both expand their ranges and shift their distribution towards higher latitudes while half will contract within the study region. Our performance analysis of monarch models revealed that the climate envelope model was the poorest performing. Adding hostplant distribution produced the best performing model, while accounting for hostplant quality did not improved model performance. The climate envelope model estimated more restrictive contemporary and future monarch ranges compared to both hostplants models. Although all three models predicted future monarch range expansions, the projected future distributions varied among models. The climate envelope model predicted range expansions along the Pacific coast and contractions inland while hostplants models predicted range expansions in both of these regions and, as a result, estimated 14 and19% increases in distribution relative to the climate envelope model, respectively. These results suggest that information on biotic interactions that provide critical resources is needed to predict future species distributions, but that variation in the quality of those critical resources may be of secondary importance.
Manifold learning analysis suggests novel strategies for aligning single-cell multi-modalities and revealing functional genomics for neuronal electrophysiology
Authors: Huang Jiawei , Sheng Jie , Wang Daifeng
Published: December 2020

Recent single-cell multi-modal data reveal multi-scale characteristics of single cells, such as transcriptomics, morphology, and electrophysiology. However, our understanding of functional genomics and gene regulation leading to various cellular characteristics remains elusive. To address this, we applied multiple machine learning methods to align gene expression and electrophysiological data of single neuronal cells in the mouse brain. We found that nonlinear manifold learning outperforms other methods. After manifold alignment, the cell clusters highly correspond to transcriptomic and morphological cell-types, suggesting a strong nonlinear relationship between gene expression and electrophysiology at the cell-type level. The aligned cells form developmental trajectories and show continuous changes of electrophysiological features, implying the underlying developmental process. We also found that the manifold-aligned cell clusters’ differentially expressed genes can predict many electrophysiological features. Functional enrichment and gene regulatory network analyses for those cell clusters revealed potential genome functions and molecular mechanisms from gene expression to neuronal electrophysiology.
Zika Virus Infection Prevents Host mRNA Nuclear Export by Disrupting UPF1 Function
Authors: Leon Kristoffer , Flynn Ryan , Khalid Mir M. , Fontaine Krystal A. , Nguyen Tom , Kumar G. Renuka , Simoneau Camille R , Tomar Sakshi , Jimenez-Morales David , Dunlap Mariah , Kaye Julia , Shah Priya S , Finkbeiner Steven , Krogan Nevan J , Bertozzi Carolyn , Carette Jan E. , Ott Melanie
Published: December 2020

Zika virus (ZIKV) is a mosquito-borne RNA virus that can infect fetusesin uterocausing characteristic neurodevelopmental disorders including microcephaly. We previously showed that ZIKV infection downregulates expression of up-frameshift protein 1 (UPF1), a helicase/ATPase and central regulator of the nonsense-mediated mRNA decay pathway. Here, we identify a novel function of nuclear UPF1 in mRNA export. Using crosslinking immunoprecipitation of UPF1 followed by sequencing of associated transcripts as well as fluorescence in situ hybridization experiments, we find widespread mRNA accumulation in the nucleus of human neural progenitor cells (NPCs) upon ZIKV infection or UPF1 knockdown. Knockdown ofFREM2, a top UPF1 target transcript encoding an extra-cellular matrix protein critical in fetal development, decreased expression of pluripotency markers and increased expressed neuronal differentiation in NPCs, consistent with the model that trappingFREM2mRNA in the nucleus perturbs proper NPC function. Collectively, our data uncover a new posttranscriptional mechanism by which ZIKV “shuts off” host mRNA export via UPF1. As we find UPF1 linked to many neurodevelopment pathways, we propose that the lack of host mRNA export contributes to the neurodevelopmental defects associated with ZIKV infection.
The Impact of Digital Histopathology Batch Effect on Deep Learning Model Accuracy and Bias
Authors: Howard Frederick M. , Dolezal James , Kochanny Sara , Schulte Jefree , Chen Heather , Heij Lara , Huo Dezheng , Nanda Rita , Olopade Olufunmilayo I. , Kather Jakob N. , Cipriani Nicole , Grossman Robert , Pearson Alexander T.
Published: December 2020

The Cancer Genome Atlas (TCGA) is one of the largest biorepositories of digital histology. Deep learning (DL) models have been trained on TCGA to predict numerous features directly from histology, including survival, gene expression patterns, and driver mutations. However, we demonstrate that these features vary substantially across tissue submitting sites in TCGA for over 3,000 patients with six cancer subtypes. Additionally, we show that histologic image differences between submitting sites can easily be identified with DL. This site detection remains possible despite commonly used color normalization and augmentation methods, and we quantify the digital image characteristics constituting this histologic batch effect. As an example, we show that patient ethnicity within the TCGA breast cancer cohort can be inferred from histology due to site-level batch effect, which must be accounted for to ensure equitable application of DL. Batch effect also leads to overoptimistic estimates of model performance, and we propose a quadratic programming method to guide validation that abrogates this bias.
Unscrambling cancer genomes via integrated analysis of structural variation and copy number
Authors: Shale Charles , Baber Jonathan , Cameron Daniel L. , Wong Marie , Cowley Mark J. , Papenfuss Anthony T. , Cuppen Edwin , Priestley Peter
Published: December 2020

Complex somatic genomic rearrangement and copy number alterations (CNA) are hallmarks of nearly all cancers. Whilst whole genome sequencing (WGS) in principle allows comprehensive profiling of these events, biological and clinical interpretation remains challenging. We have developed LINX, a novel algorithm which allows interpretation of short-read paired-end WGS derived structural variant and CNA data by clustering raw structural variant calls into distinct events, predicting their impact on the local structure of the derivative chromosome, and annotating their functional impact on affected genes. Novel visualisations facilitate further investigation of complex genomic rearrangements. We show that LINX provides insights into a diverse range of structural variation events including single and double break-junction events, mobile element insertions, complex shattering and high amplification events. We demonstrate that LINX can reliably detect a wide range of pathogenic rearrangements including gene fusions, immunoglobulin enhancer rearrangements, intragenic deletions and duplications. Uniquely, LINX also predicts chained fusions which we demonstrate account for 13% of clinically relevant oncogenic fusions. LINX also reports a class of inactivation events we term homozygous disruptions which may be a driver mutation in up to 8.8% of tumors including frequently affectingPTEN,TP53andRB1, and are likely missed by many standard WGS analysis pipelines.
NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma
Authors: Hu Shikai , Molina Laura , Tao Junyan , Liu Silvia , Hassan Mohammed , Singh Sucha , Poddar Minakshi , Bell Aaron , Sia Daniela , Oertel Michael , Raeman Reben , Nejak-Bowen Kari , Singhi Aatur , Luo Jianhua , Monga Satdarshan P. , Ko Sungjin
Published: December 2020

Intrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD regulated SOX9 and YAP1 during ICC development.Yap1deletionor TEADinhibition impaired HC-to-biliary epithelial cell (BEC) reprogramming and ICC proliferation;Sox9loss repressed tumor growth; andYap1-Sox9combined loss abolished ICC development in AKT-NICD model. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directed HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch-dependent HC-to-ICC development, and DNMT1 re-expression restored ICC development following TEAD repression. Coexpression of DNMT1 with AKT was sufficient to induce hepatic tumor development including ICC. Thus, we have identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-driven ICC development.

SIGNIFICANCE

We evaluated the clinical relevance of hepatocyte-driven ICC model and revealed critical but distinct roles of YAP1 and SOX9 in AKT-NICD-driven hepatocyte-derived ICC. We also identified NOTCH-YAP1/TEAD-DNMT1 axis as a critical driver for hepatocyte-to-ICC reprogramming, which might have biological and therapeutic implications in ICC subsets.